nm0260: can i just say a few words [0.7] before i actually formally start 
lecturing [0.4] er [0.2] i want to explain just a little bit [0.3] about what 
we're trying to do [0.3] er in these half-dozen or so lectures [0.5] er [0.7] 
my [1.5] aim in a way with these lectures has been to try [0.3] and illustrate 
a s-, [0.2] er a chunk of medical practice [0.4] er today now [0.3] er rather 
than [0.3] have sort of all a lot of theoretical stuff about the epidemiology 
of disease [0.3] and genetics of disease and so on [0.2] just trying to show 
you how actually [0.3] er clinicians cope with disease [0.3] and try and relate 
that to the science to the biology underlying the pathology of the disease [0.
3] and the nature of the treatments they're using [0.6] so sometimes people 
find this these few lectures a little bit [0.2] bitty [0.3] which i'm afraid 
they are [0.4] er now you had Dr namex [0.5] er was it this morning [0.3] er 
talking to you about the physiology of kidney [0.4] er kidneys [0.4] er and of 
kidney disease the way kidney diseases develop [0.6] and talking you to you i 
think in general terms about the nature of treatment of kidney 
disease [0.3] now Dr namex is not er the usual lecturer i have to say that the 
usual lecturer that gives those lectures is Dr er Dr namex [0.3] whom i know 
very well and i don't know Dr namex [0.4] and i i'm er [0.2] told that he did a 
good job and i sincerely hope he did [0.4] er but the point about that [0.3] is 
to give you background in-, into the understanding of renal disease [0.5] now 
[1.4] my colleague [0.2] Dr [0.3] er [0.5] golly my colleague Dr his name drops 
out of my mi-, namex [0.3] er on Thursday will be talking to you about [0.2] 
care and maintenance [0.2] looking after of [0.4] er patients who've been 
transplanted for kidney disease [0.3] and he'll be talking to you a little bit 
about the ethics of transplantation [0.3] and inevitably he will go over some 
of the ground [0.3] that i'm going to present now [0.3] what i want to talk 
about as you can see [0.5] is the science of transplantation in other words i'm 
going to present to you the biology [0.4] underlying [0.3] transplantation of 
organs and of bone marrow [0.4] er and how [0.4] the 
physicians [0.4] er can cope with that and make it work [0.3] okay [0.7] so i'm 
providing the scientific backup [0.3] er as it were [0.4] to the clinical side 
[0.4] and a and as i say the aim is overall to get you some give you some feel 
[0.4] for how modern clinical medicine works [0.3] in a rather [0.3] highly 
technical biological area [0.4] now we can't hope to cover the whole of 
medicine so we've honed in homed in i'm sorry [0.3] on this little area [0.3] 
of [0.2] renal disease [0.3] and renal transplantation [0.6] okay [0.4] now [0.
7] those of you and i know some of you have already looked at the web [0.3] may 
have looked at my lecture notes er and i'm sorry [0.4] i but i've actually 
revised the lectures and what i'm presenting this afternoon [0.5] is related to 
what's on the web already [0.3] but is in fact [0.2] presented in quite a 
different way [0.3] what i've deliberately done is actually cut down on the 
detail and try i'm trying to bring out [0.3] a bit more clearly the principles 
[0.4] because in my experience if i try and teach too 
much [0.3] about histocompatibility [0.3] and about how [0.4] er T-cells 
respond [0.3] to histocompatibility antigens in detail [0.3] er er people don't 
really cope with that [0.4] er in the short period that i have to present it [0.
3] so i'm giving it to you in rather more general terms today [0.5] er and i 
know some people may not like that some people i know [0.3] prefer to have much 
more detail well you can find detail in your textbooks i always say [1.3] these 
[0.4] lecture notes will go up onto the web [0.2] er within the very next few 
days [0.3] what i haven't done yet either [0.3] is revised er the reading [0.4] 
that i have on the web [0.3] site [0.2] i will do that before the end of term 
which i'm very much aware is Friday [0.7] okay [0.3] so i hope by Friday i 
won't absolutely guarantee but i hope by Friday to have [0.3] some reading some 
more up to date reading [0.2] some of the reading material as i say is still 
perfectly valid [0.5] so it will remain there [0.3] but i will try to put some 
new stuff on as well [0.6] okay 
nm0260: we've got a 
two hour slot [0.5] now the material i'm going to present i suspect will take 
more than an hour but i'm hoping [0.2] very much that it won't take two hours 
but in the past i've tried to present it in one hour [0.3] and i've had to rush 
it so i've extended it to two hours but i don't think i need two hours [1.5] 
right so let's actually get on with things [0.3] the title [0.2] of these 
lectures is The Science of Transplantation [0.3] and that's very much what i'm 
going to be talking about er rather than the medical clinical aspect of 
transplantation which as i've said [0.4] i'm leaving to namex er namex [0.9] so 
[0.8] the first point the first thing i want to do is just show you the aims a 
little bit about the aims of these lectures [0.4] what i want to cover [0.4] er 
is the range of transplant medicine the sorts of areas where transplantation is 
done and why it's done [0.7] okay [0.7] secondly [0.4] i want to give you [0.4] 
er an understanding [0.2] of the immunological basis of graft rejection [0.5] 
i'll define these terms presently [0.4] er then i shall go on 
to talk to you about immunosuppressive therapy and how that works to present 
prevent [0.2] grant rejection [0.5] and finally a few words on what might be 
the future [0.5] er the way forward for transplantation science [0.4] and its 
application to medicine [1.7] so i shall start off [0.4] with a few [0.2] 
simple definitions [0.5] er [1.0] couple of them are pretty obvious [0.8] we 
talk about the host [0.9] that is the person who receives the transplantation 
whatever it is [0.4] although in fact more commonly the term we use is 
recipient somebody who receives [0.3] the graft [0.7] and then secondly [0.4] 
the partner in this business of course [0.3] is the donor [0.6] and that is the 
one who provides the graft [0.5] now donors [0.5] are going to fall into two 
main categories those that are alive [0.6] and those that are dead [0.3] now 
living donors [0.3] er would may be either unrelated to the recipient [0.3] or 
related a sibling or or parent or whatever [1.5] obviously living donors can 
donate things like blood [0.4] bone marrow [0.4] and one of your two kidneys 
but they're going to 
be hard-pressed [0.3] indeed [0.2] to donate [0.3] lungs or something like that 
[0.4] so [0.9] more often in fact much more often [0.4] er in transplantation 
medicine [0.5] the s-, donor [0.3] is dead [0.4] and is a cadaver [0.4] 
cadaveric donor [0.3] and obviously under those circumstances [0.3] the whole 
range of organs potentially is available for transplantation [0.4] now just [0.
3] in passing [0.3] when i say d-, dead cadaveric [0.3] er r-, rather 
ghoulishly w-, er it ha-, the the the the person has to be [0.3] somewhat 
freshly dead because of course [0.4] er very shortly after death [0.5] the 
tissues and the organs [0.3] of the cadaver start to decay [0.3] and and 
disintegrate [0.3] and so [0.3] if somebody dies in a traffic accident [0.3] or 
is in the intensive therapy unit or something like that and is on a heart lung 
machine which they're about to turn off [1.2] okay [0.3] then the surgeons come 
in [0.5] and whip out [0.4] the bits the kidney the liver the lungs and so on 
[0.3] now i'm not going to go into the ethical aspects of that [0.3] but 
obviously there's a lot of ethics [0.4] er which well namex will deal with 
tomorrow [0.3] 
Thursday rather [0.3] a lot of ethical issues are around about organ donation 
[0.5] in both living [0.5] and [0.3] cadaveric donors [0.9] okay [2.9] more 
simple definitions [0.3] the word transplant is er synonymous we use th-, them 
synonymously [0.3] use it synonymously with graft [0.4] the transplanted graft 
may be actually [0.2] tissue of some sort such as blood or marrow or indeed 
skin [0.9] or may be er an intact whole organ such as kidney [0.6] all right [0.
7] now there are three other [0.7] simple terms that i need to define [0.3] one 
is autograft [0.5] that means that you're grafting from one part of the body [0.
3] to another part of the body [0.3] and that's very commonly done for skin in 
the case of burns [0.4] obviously autografting we er the [0.4] equivalent term 
is autologous graft [0.3] autografting [0.3] presents [0.2] no immunological 
differences because you're just moving a bit of tissue [0.4] from one part of 
the body to another part of a body [1.3] autografting is actually very 
important and i was talking to a surgical friend of mine 
and she was describing to me the sort of facial reconstructions that happen in 
severe burn patients [0.4] er [0.4] i-, or severe or in situations where 
there's been a severe d-, dec-, severe accident and there's been extensive 
damage say to the face [0.4] they transplant bits of bone [0.3] er from the 
femur or a humerus or something like that to reconstruct the bone [0.4] and 
muscle they get from somewhere else and skin from somewhere else and they 
reconstruct [0.5] er the person's face [0.3] and that is of course [0.2] 
autografting [1.4] [1.6] in the case [1.5] of things like kidneys [0.4] what's 
much more often [0.3] done is an allograft now people [0.4] you will recollect 
the use of the world word allele [0.3] which means different [0.2] an allograft 
comes from a different individual of the same species [0.7] okay [0.8] er 
allogeneic graft is a term which is often used simultaneously s-, synonymously 
i'm sorry [0.8] and finally [0.7] in this sort of er hierarchy of grafting [0.
3] we 
have a xenograft now xeno [0.2] means foreign [0.6] and xenografts come from [0.
4] or or xenogeneic graft [0.3] comes from a member of a different species [0.
5] for example pig to man [0.6] yeah [4.5] so let's [0.2] [0.2] briefly look at 
the range of transplant medicine what is done and why [1.0] [4.6] i'm going to 
talk [0.2] briefly about currently successful grafts that is grafting 
transplanting which [0.2] in which is [0.2] w-, which is in use in medical 
practice today [0.3] right at the end i shall refer to perhaps [0.2] some 
possible future types of graft [0.5] now blood transfusion [0.3] is obviously a 
kind of graft which has been in use for a very long time [0.8] er [0.3] bone 
marrow [0.5] or stem cell transplantation [0.4] is much more recently used [0.
4] er and i'll describe that in a moment [0.4] and then finally [0.4] er we 
have solid organ transplantation things like kidneys and livers [0.3] so there 
are these three [0.3] broad areas of transplantation bone [0.2] sorry [0.2] 
blood [0.3] 
bone marrow [0.3] and solid organs [0.3] and they are actually [0.3] all of 
them really [0.3] somewhat different in their characteristics [5.0] now blood 
transfusions [0.6] er [0.4] have been attempted [0.3] were attempted in th-, in 
in the nineteenth century [3.4] and th-, there were a number of problems 
immediately discovered the major problem [0.5] comes from the A-B-O blood group 
system [0.4] er which i guess many of you will be familiar with [0.3] there are 
on the surface [0.2] there is on the surface of [0.3] red cells [0.2] an 
antigen [0.3] which occurs in three er [0.2] allelic forms there's the A form 
[0.3] the B form [0.3] and the null or zero form [0.4] okay [0.6] er obviously 
you can get heterozygotes so you get A-A A-B B-B [0.3] A-BO and B-O and 
whatever [0.5] now obviously if you transfuse blood [0.3] of one [0.5] er blood 
group type [0.2] into an individual of another blood group type [0.6] the 
immune system of the recipient will recognize the blood as foreign [0.4] 
and you will get [0.3] an immune response typically [0.4] you will get an 
antibody response to the [0.3] A-B-O antigen [0.3] and that will lyse the red 
cells with the aid of complement [0.3] and do all sorts of serious damage to 
the individual [0.4] er the consequence [0.3] o-, of the damage that's done is 
often very severe illness [0.4] er indeed death in some cases if you transfuse 
the wrong blood [1.1] once the A-B-O group [0.5] system [0.5] blood system is 
properly was properly worked out [0.4] m-, early in the last century [0.5] er 
[0.4] er s-, b-, blood transfusion is obviously a simple straightforward and 
life saving [0.2] treatment [0.4] okay [0.3] so having overcome the A-B-O 
problem [0.3] that's fine [0.3] but [0.3] still [0.3] you will [0.2] recollect 
you will understand [0.4] er that there are residual problems [0.3] in blood 
transfusion [0.4] particularly [0.2] this issue of the transmission of blood 
borne pathogens [0.5] er and virologists will recognize [0.3] all those 
acronyms [0.3] H-I-V [0.3] er er human immunodeficiency virus and H-B-V and H-C-
V too [0.3] hepatitis viruses [0.3] and of course C-J-D [0.3] now these are 
blood borne [0.3] pathogens [0.2] which of course if you transfuse blood 
contaminated with those pathogens [0.3] you pass [0.2] the er transmit [0.3] er 
the disease [1.2] obviously [0.3] er the viral problems can be resolved by 
screening you check [0.4] the blood for the presence of the er viruses either 
antigenically by serotype [0.5] se-, serological assays [0.3] or by some sort 
of molecular assay [0.3] and if the blood is clear [0.3] then you're happy to 
use it [0.5] C-J-D [0.6] Creutzfeldt-Jakob Disease is much more problematic [0.
4] er because there's no simple test to detect C-J-D so you can't screen [2.0] 
this [0.2] er problem if it is a problem [0.4] er has been solved [0.3] largely 
by separating the leukocytes from the red blood cells [0.4] when you're doing a 
regular blood transfusion what's needed is not the leukocytes but of course the 
red cells for carrying oxygen around the body [0.9] you can eliminate the 
leukocytes fairly straightforwardly by a a kind of er gradient [0.5] 
centrifugation [0.5] so that 
you can prepare blood which is essentially completely free of leukocytes now 
prions [0.4] which are the C-J-D organism [0.5] er are in leukocytes if they're 
in blood at all [0.4] not in the red cells so if you get rid of the leukocytes 
then you can transfuse the blood [0.3] safely [0.7] okay [0.2] so blood 
transfusion is a form of transplantation which is very [0.3] straightforward [0.
5] er and sorted out [2.0] go on to bone marrow transplantation now everybody 
is familiar with what bone marrow is bone marrow [0.4] is the [0.4] er or is 
the tissue which generates all the haema-, haematopoietic tissues the blood and 
the white blood cells [0.4] er and o-, other parts of the haematopoietic system 
[0.7] er individuals [0.3] who have failed bone marrow [0.6] er are going to be 
very sick [0.7] er and a life saving treatment is [0.3] the trans [0.2] 
plantation of bone marrow into those individuals [0.3] now when i say [0.4] 
bone marrow transplantation [0.5] actually i mean it [0.2] in a slightly wider 
sense [0.3] it can be the actual bone marrow which is taken from 
the donor's [0.3] bone [0.6] and i have had it [0.2] i have done it and i tell 
you it is very painful [0.4] don't recommend it except for very close friends 
[0.5] er [0.2] so you can take the actual bone marrow [0.5] or you can take [0.
6] what are called C-D-thirty-four cells now [1.2] those of you who are 
familiar with immunology will recollect [0.4] that [0.2] C-D-thirty-four [0.4] 
is the antigen [0.2] which [0.2] defines [0.3] the [0.4] er pluripotent stem 
cell which generates all cells [0.3] of the haematopoietic ser-, system [0.4] 
now the C-D-thirty-four cells are normally within the bone marrow that's why 
you go for the bone marrow [0.5] but you can get C-D-thirty-four cells [0.2] 
out of the bone marrow [0.6] into the peripheral circulation [0.3] by treating 
people with certain cytokines [0.3] which cause the C-D-thoity-fo thirty-four 
cell [0.3] to proliferate [0.3] and move [0.2] from the bone marrow into the 
periphery [0.2] into the circulation [0.4] so that's why we speak about [0.4] 
mobilization [0.6] of C-D-thirty-four cells into the periphery [0.5] and then 
of course you can get these cells by simply taking blood [0.7] and 
that's much less painful than bone marrow donation [0.9] okay [0.3] so you can 
get [0.3] the stem cells [0.2] of the haematopoietic system either from the 
bone marrow [0.4] or [0.3] from the blood if you treated patients people [0.3] 
with a cert-, with the cytokines [1.8] now bone marrow transplantation [0.5] is 
used broadly in these two situations [1.0] [1.0] the one [0.8] major condition 
[0.3] er where [0.2] the bone marrow [0.3] completely is non-functional is a 
condition called SCID severe combined [0.6] immunodeficiency [0.4] okay [0.9] 
and the other situation [0.4] er [0.4] where bone marrow fails completely [0.4] 
is in certain therapeutic [0.9] manoeuvres carried out in the treatment of some 
cancers and i'll talk about both these in a moment [0.9] so let's [0.2] go on 
briefly and talk about SCID just for a moment [0.8] some of you writing the 
essay on on gene therapy will have heard about [0.4] SCID in the context of [0.
3] gene therapy [0.5] so you will recollect that SCID is an inherited failure 
[0.3] of the ontogeny of T-cells individuals who've inherited this condition [0.
3] 
fail [0.2] to produce functional T-cells [0.7] what that means [0.3] is not 
having T-cells is that essentially you have no immune responsiveness at all you 
have [0.3] you have the non-adaptive immune system things like natural killer 
cells [0.5] but your T-cell system has failed [0.2] and so the adaptive immune 
system is essentially absent [0.3] you can neither generate [0.3] cell-mediated 
immunity [0.3] nor can you make antibodies so you are [0.2] very sick extremely 
susceptible [0.4] to infection [0.8] okay [1.4] quite simply in this situation 
[0.4] bone marrow transplantation provides the patient with normal T-cells [0.
3] which are of course derived from the donor [0.9] okay [0.3] so the 
transplanted r-, the r-, r-, recipient's T-cells [0.4] after the transplant are 
of course [0.3] of donor origin not his own [0.2] that goes without [0.4] 
saying [4.7] now in certain cancers er [1.0] [1.7] the therapy of cancer [0.5] 
often depends on the use of so-called cytotoxic drugs now these cytotoxic drugs 
[0.4] are 
designed [0.3] to kill the cancer cells [0.6] but they are never completely 
specific well rarely are they even slightly sic-, specific in fact [0.4] er to 
the cancer cells [0.3] and so if you treat patients with cancer [0.3] with 
these drugs a consequence is damage [0.4] to all those organs and tissues which 
are rapidly proliferating [1.0] all right [0.6] so if you give a large dose of 
this sort of therapy [0.5] you will damage [0.4] er the bone marrow [0.3] of 
the patient [0.3] to such an extent that the bone marrow [0.3] will no longer 
function is no longer able to produce [0.3] haematopoietic cells [0.4] under 
those circumstances the patient [0.3] will die [0.9] okay [0.4] so what we do 
what is done rather [0.5] is that [0.4] the patients who are treated with very 
large doses of therapy to destroy the cancer [0.7] are what [0.2] what is 
called [0.2] rescued [0.5] by bone marrow transplantation now what that simply 
obviously means [0.3] is that the bone the patient [0.3] is [0.2] in a se-, es-,
essentially brought back to life by the transplantation of bone marrow [1.7] 
now equally [1.4] transplanted marrow [0.5] in this 
in some situations [0.3] also seems to have an anti-cancer effect which is a by-
product a bonus if you like [0.4] in other words [0.2] the transplanted marrow 
[0.3] seems to develop [0.6] some sort of immune response to the cancer and 
that actually helps survival in some circumstances but i'm not going to talk 
about that in detail [2.2] now [0.9] [1.4] talking about SCID [2.0] the graft 
[0.3] obviously [0.2] has to be an allograft [0.7] because the patient has no 
bone marrow of his own no no no [0.2] adequate bone marrow at least so the [0.
3] situation there it has to be an allograft [0.6] in the case of the cancer 
therapy [0.4] you can actually autograft in other words you can take the 
patient's own bone marrow [1.0] treat the guy with cytotoxic therapy [0.3] and 
then replace his own bone marrow [2.0] okay [1.0] [1.2] you can also do an 
allograft in that situation [0.4] and both [0.2] these techniques have their ad-
, [0.2] advantages and disadvantages [0.6] the advantage of the autograft is 
you have er you no 
immunological problems again [0.7] the disadvantage of the autograft [0.5] is 
that potentially [0.7] the engrafted marrow carries with it cancer cells [0.9] 
okay [0.6] which [0.2] of course is self-defeating [0.3] because the cancer 
cells will then start growing again 'cause they haven't been subjected to the 
therapy [0.6] so the autograft has the disadvantage that in fact you may be 
grafting cancer cells at the same time [0.4] as you're grafting back [0.2] the 
patient's marrow [2.3] in the case of the allograft you have immunological 
problems which i'll describe presently [1.3] but the allograft seems [0.2] 
surprisingly [0.3] to have a better [0.5] er anti-cancer effect [1.3] than the 
autograft [0.3] so there are advantages both ways [1.4] from a clinical point 
of view [0.2] er i think [0.8] the autograft generally is preferred because 
it's easier to manage because the immunological consequences of the allograft 
can be very severe which we'll get on to in a moment [1.7] okay [3.1] pause a 
moment to let you catch up [5.3] so this [0.7] 
is showing it [0.2] diagrammatically this is the sick patient [0.4] who has a 
cancer say originating in the stomach [0.5] which has spread about the body now 
this patient is going to die unless you can treat the cancer that's spread 
about the body [0.5] so you give him very large dose of anti-cancer drugs [1.0] 
sufficient to kill all the cancer cells but at the cost of destroying the bone 
marrow [0.2] so that's what that bomb is [0.5] so this guy is flat out [1.0] 
and you put back in stem cells by stem cells i mean either bone marrow [0.3] or 
the C-D-thirty-four [0.2] cells [0.6] er and who from either i autograft or 
allograft [0.4] to replace the haematopoietic system [0.4] and then [0.4] with 
luck [0.3] the patient's cured and there is actually good evidence that cures 
do occur under these circumstances [0.8] so this is a sort of therapy [0.9] 
important therapy [3.2] so let's go on to solid organ grafts [1.6] and the idea 
here is very straightforward and simple [0.6] er if an 
organ fails [0.3] replace it [1.0] all right [1.3] straightforward [0.7] but we 
do there are a number of problems as you imagine [0.3] the first [1.1] problem 
er er and this was [0.2] and continues to be a very serious problem [0.4] is 
that the success of the graft [0.4] depends on the feasibility of the surgery 
[0.4] required to transfer [0.3] the solid organ from the donor to the 
recipient [0.5] now in the case of things like kidney and liver [0.3] er to [0.
2] a large extent lung and heart [0.5] the plumbing if you like the blood 
vessels and the various [0.3] er er nervous connections [0.3] are relatively 
straightforward [0.5] and so the surgeon can transfer an organ from one 
individual to another [0.3] without too much difficulty [0.9] with other organs 
and the arch-example is the pancreas it would be marvellous to transplant the 
pancreas to treat diabetes remember [0.8] the pancreas [0.3] the plumbing [0.4] 
is so complex [0.3] that [0.4] surgically [0.2] it's not feasible it's simply 
too complex [0.3] for the surgeon [0.3] to be able successfully to transfer the 
organ [0.3] it's just not possible [0.2] take too long [0.3] 
too detailed too many tubes too many [0.3] arteries too many veins too many [0.
4] this and that and the other [0.4] so it's not practical to transplant things 
like pancreas [0.4] so this is the first consideration [0.3] is the surgery 
practical [3.9] so [0.7] assuming [0.3] that we have got through to the 
situation where we have [0.4] er [0.9] practical surgery [0.4] for the 
transplantation of a tissue [2.4] [0.4] now i want to move along to [0.2] 
talking about the immunological basis of graft rejection [0.6] now obviously 
this is the scientific aspect [0.3] that i really need to [0.5] talk about to 
dwell on [0.4] in some detail [1.6] right [0.7] do recommend [0.5] er that you 
review your second year immunology notes and think about [0.5] er immunology [0.
3] i should have should have said at the beginning [0.3] that some of the 
material that i'm presenting now obviously is related [0.3] to what [0.4] i 
presented to you in the second year so some of it will be familiar i hope it'll 
be familiar [0.4] and you should also look 
at your second year notes [5.3] so what's the problem [1.5] manifestly the 
problem is graft rejection [1.4] graft rejection [0.4] is the [0.3] er 
phenomenon [0.2] in which the transplanted organ [0.4] er is damaged [0.5] 
fails through large-scale inflammation [0.4] er and then literally starts to 
fall apart under immunological attack [0.9] okay [0.6] now the reason for this 
is that [0.3] in an allograft not an autograft i should have included with 
autografts [0.5] grafting from identical twins of course that's equivalent to 
an autograft [1.0] but in the case of allografts [1.4] the immune system of the 
recipient [0.8] sees the graft [0.6] as non-self [0.8] somebody else manifestly 
[0.9] and this is because there are alloantigens on the in the and on [0.2] the 
graft [0.3] which are different from the self-antigens [2.0] these alloantigens 
[0.2] you see the word allo it's related to allele again [0.4] different 
alleles of the same gene [0.5] okay related to allogeneic and allograft [0.3] 
the alloantigens [0.8] are recognized by the host immune system [1.4] and 
adaptive 
immune [0.2] mechanisms [0.4] develop in the host [0.3] which will eliminate 
the transplanted the non-self organ [0.3] non-self tissue [3.2] now [0.3] [1.2] 
what we have to [0.4] recognize what you have to understand [0.4] is that the 
situations with bone marrow transplantation [0.9] and solid organ [0.3] 
transplantation [2.1] is that in the bone marrow transplantation [0.3] the 
recipient [0.3] the host [0.3] doesn't have an immune system [0.9] so obviously 
[0.3] the host is not going to recognize the engrafted marrow [0.4] as foreign 
[0.3] got no ho-, go-, the host has got no immune system [0.4] but of course [0.
4] the engrafted [0.3] marrow [0.3] is a source of immune cells [0.8] and those 
immune cells [0.4] as they encounter the host's tissues [0.3] will recognize 
the host [0.3] the recipient as foreign [1.2] so in bone marrow transplantation 
and this is what makes [0.4] this such a hazardous situation [0.8] er [0.8] the 
the bone marrow transplant [0.4] actually [0.5] rejects the host [1.4] a rather 
unpleasant [1.0] thought [2.7] obviously in the situation of the solid organ 
allograft [0.3] or indeed xenograft [0.5] er [0.5] the 
host [0.7] er which has an intact immune system is rejecting [0.2] the graft [1.
4] okay so we have these two different situations [0.4] in the bone marrow [0.
4] and the solid [0.7] organ gr-, er graft [1.8] [1.8] so [0.9] in sort of [0.
4] clinical terms [0.9] what's happening in graft rejection [1.4] basically 
you're getting an immune response to the host tissue in G-V-H-D i should have 
defined graft versus host disease is abbreviated as G-V-H [0.7] or G-V-D or G-V-
H-D [0.4] okay [0.4] in this situation you get [0.3] severe damage to the host 
epithelial [0.5] er tissues [0.5] the skin [0.5] er and the lining of the gut 
[2.3] but perhaps more seriously you get [0.4] damage to the endothelium now 
you remember [0.6] that the endothelium [0.4] er is the lining of blood vessels 
and in the case of capillaries [0.7] the very fine blood vessels [0.3] the 
endothelial cells [0.3] are the entire wall of the blood vessel [0.7] so if 
you're getting an immunological reaction [0.6] er [0.3] to [0.7] the 
endothelium [0.3] you're going to get extensive bleeding into the tissues [0.3] 
and remember 
that particularly in the kidney say [0.3] the endothelium provides a very has a 
very important [0.4] functional role 'cause this the endothelium which performs 
[0.3] the filtration [0.6] in the glomerulus [0.5] and the various other bits 
and pieces of the kidney [0.7] so if you're damaging the glomerulus with immune 
response [0.3] then the kidney function's going to fail [0.4] so in the case of 
graft versus host disease the patient [0.5] has severe [0.2] er generalized 
organ failure [0.8] and if it's not treated that will inevitably result er in 
death of the patient [1.1] now in the case of solid organ rejection [0.6] of 
course essentially the same thing is happening [0.4] and you're getting damage 
[0.4] again particularly to the endothelium but also again [0.4] to the actual 
cells within the organ [0.8] okay leading to failure of the organ [0.6] so that 
[0.4] simply is the nature of rejection it's the destruction [0.4] of the cells 
of the organ [6.3] right [0.3] now [0.2] 
i'm going to [0.4] specialize now and talk particularly about kidney 
transplantation because that's the subject of these lectures [0.4] and it 
happens to be what i know about most [0.7] [1.4] so [0.2] we'll get on now and 
talk specifically about kidneys [0.7] now [0.2] as you will have heard from Dr 
namex [0.4] er earlier [0.5] er [0.4] kidney transplantation without any 
question [0.7] is the best [0.5] er treatment for what is called end-stage 
renal failure [0.6] end-stage renal failure is when you have irrespo-, 
irreversible [0.3] and total failure of the kidney [0.9] okay [1.2] er [1.7] 
because [0.5] transplantation allows the patient [0.3] to have essentially [0.
2] normal function [0.2] normal functioning [0.4] they can walk around as usual 
go swimming doesn't have to have the dialysis bag [0.5] er doesn't have to 
worry about things like [0.3] haematopoietin injections [0.3] his diet can be 
fairly free [0.4] he can drink reasonably [0.3] modest amounts of alcohol and 
so on [0.3] so a kidney transplant patient [0.3] really has a [0.2] more or 
less normal function [0.3] 
whereas somebody on dialysis is severely limited [0.3] in lifestyle [0.3] and 
in health [0.8] and i think the point has been made quite clearly [0.6] that 
transplantation despite the initial costs of the actual operation [0.4] is in 
the longer run [0.4] much cheaper [0.2] than dialysis dialysis i forget what it 
costs [0.4] five-thousand a year something like that [0.3] whereas [0.2] once 
you've done the transplant which maybe costs ten-thousand the cost of 
maintaining the patient [0.4] is much less so over a period of ten years [0.4] 
the transplant is teacher [0.3] and in our modern new up to date N-H-S it cost 
that matters [0.3] very much indeed [1.9] the main limitation [0.3] as i 
suspect [0.2] you are all familiar [0.6] is er the availability of donors [0.3] 
now [0.3] again namex will talk about this more tomorrow [0.3] so i won't go 
into that in detail [0.4] but the lack [0.4] of donors the [0.2] few number of 
small number of donors means that there are [0.4] serious scientific 
consideration [0.4] to other [0.3] ways and means [0.3] of 
restoring organ function replacing organ function i should say [2.7] so [0.4] 
[1.0] as i was saying just now [0.9] kidney transplantation is [0.9] surgically 
straightforward surgically quite feasible [0.4] there's the ureter to reconnect 
[0.3] there's a couple of arteries a couple of veins to reconnect [0.3] but 
basically surgeons find this fairly straightfoward [0.6] er [2.1] so the main 
problem [0.3] is as i've been saying [0.3] rejection of the graft [0.2] and 
you've got to control that rejection [0.8] now [1.4] experience with [0.2] 
patients who've been transplanted implies has told us taught us that there are 
actually three [0.6] forms [0.6] of [0.2] rejection [1.0] three different kinds 
of rejection [0.5] er which are described as hyperacute [0.6] and acute [0.5] 
and chronic [2.7] [0.7] now the hyperacute rejection [0.4] happens more or less 
immediately as soon as the kidney [0.4] is [0.2] plumbed into the recipient [0.
3] and the veins and arteries are reconnected [0.3] and blood [0.4] starts to 
flow 
through the kidney the host's blood starts [0.3] the flow through the kidney [0.
4] what happens is that if there is hyperacute rejection going on [0.3] 
immediately or very very quickly before the [0.3] cessation of the operation [0.
4] er it will be seen that the kidney starts to swell [0.2] become oedematous 
[0.6] okay starts to swell [0.5] and [0.4] goes much darker in colour [0.7] er 
and the consequence [0.4] of the rejection is that the organ very quickly will 
fail [0.4] and immediately has to be replaced [0.3] and they have to rejoin the 
various bits and pieces [0.3] close up the patient [0.3] and put him back onto 
dialysis until a more suitable kidney comes along [2.3] okay [0.2] so that 
happens immediately during the operation we'll talk about the causes in a 
moment [0.9] acute [0.3] rejection [0.3] despite the term acute meaning again 
more or less immediate acute rejection [0.4] tends to occur [0.3] some weeks 
after the actual transplantation six to twelve weeks typically [1.2] what 
happens in this situation of course you can't see [0.2] what's 
happening [0.5] er [laugh] [0.7] obviously [0.3] er but [0.6] clinically what's 
happening is that kidney function starts rapidly to decline [0.4] so it's all 
the symptoms of end-stage renal failure that you will have heard from Dr namex 
this morning [0.4] er where [0.3] you start to get [0.3] protein in the urea [0.
3] er urine [0.4] er and you start to get [0.6] large amounts of creatinine [0.
4] in the circulation because of damage to tissues and things like that [0.7] 
okay [0.4] now [1.0] i should have said that hyperacute [0.3] rejection is 
actually irreversible once it's set in there's nothing can be done [0.5] okay 
and that's why you have to remove it and start again [1.4] in the case of acute 
[0.2] rejection [0.6] usually [0.4] er it can be reversed we'll go on to why 
and how if there's time presently [1.1] okay [0.9] 
sf0261: does that if the [0.2] if the hyperacute one [0.4] does that kill the 
kidney [0.2] 
nm0260: yes 
sf0261: so you can't use it 
nm0260: can't use it it's dead finished [0.3] and i'll tell you why in a moment 
[0.8] okay [1.6] now the acute rejection as 
i say usually can be reversed by w-, adjusting the therapy that's being carried 
out [1.1] [0.3] chronic rejection [1.0] happens years [0.2] after the 
transplantation five years ten years [0.2] longer [1.8] what it is it's a 
gradual slow [0.4] but [0.2] sadly irreversible decline in kidney function over 
a period of years [0.3] and u-, ultimately the kidney fails completely [0.4] 
and the patient is back [0.6] er in square one [0.8] okay [0.5] so let's go on 
[0.5] er and actually talk about [0.4] the causes [0.3] the immunological [0.4] 
causes [0.3] of these different kinds of [0.4] rejection [0.5] now [0.3] 
hyperacute rejection is actually pretty straightforward [2.4] it's due to the 
presence in the patient [0.3] of antibodies [0.4] circulating antibodies [0.2] 
which are specific for the transplanted tissue which recognize antigens [0.3] 
on a transplanted tissue [0.3] especially [0.4] by recognizing alloantigens [0.
3] on the endothelium [1.1] of the transplanted tissue [1.0] okay [0.5] having 
recognized antigens on the endothelium [0.5] er you remember complement [0.4] 
okay [0.3] and how antigen-antibody 
complexes [0.4] activate complement [0.5] and the co-, activated complement 
destroys [0.3] cell membranes locally [0.9] so you've got [0.2] a complement-
mediated [1.0] lysis [0.4] of the endothelium [0.4] of the organ [0.5] now i've 
mentioned endothelium as a target for attack [0.4] er in rejection phenomena [0.
3] the result is [0.4] loss massive loss [0.4] of fluid into the organ [0.3] 
and that causes the swelling [0.3] okay the organ becomes oedematous [0.4] and 
of course the damage to the glomerulus in this situaton completely [0.4] er 
destroys the function of the kidney [0.3] so that kidney [0.4] is dead [0.7] 
now [0.2] you might ask where did these antibodies arise [0.4] how do they 
arise rather [0.6] er and the answer is [0.2] er [0.9] often through pregnancy 
[0.9] the fetus [0.8] is in effect in effect an allograft [0.4] because 
immunologically the fetus [0.3] is a hybrid between the father and the mother 
[1.0] so the mother [0.3] will potentially become sensitized [0.4] to the 
paternal antigens of the fetus now there is [0.3] a little bit of exchange [0.
3] of [0.2] blood [0.3] across the placenta [0.3] there's no qu-, it it's quite 
clear 
that there will be fetal cells in the maternal circulation [0.4] so [0.2] the 
mother will develop antibodies to the fetus [0.4] okay [0.3] now suppose [0.9] 
that the transplant [0.5] for whatever reason maybe it comes from the husband 
or father perhaps i should say partner [0.5] maybe that transplant comes from 
the husband you wouldn't do this in fact for these reasons [0.5] er but 
obviously er under those circumstances the transplant will share [0.7] antigens 
with the fetus [0.3] and the mother's [0.3] antibodies will destroy it [0.9] er 
the other situation where [0.2] you are likely to get these [0.2] antigens 
antibodies sorry arising [0.3] is where there's been blood tranfusions now if 
you've had blood transfusion [0.5] in the past that meant [0.3] you will have 
had the leukocytes as well from the donor [0.8] er [0.9] and you obviously you 
had the blood the red blood cells but the leukocytes will bear [0.4] antigens 
that are shared by the endothelium [0.9] okay [0.3] so if by chance you've been 
transplanted with blood [0.3] that shares antigens [0.3] with [0.3] your tran-, 
sorry [0.3] so if by 
chance you've been transfused [0.3] with blood that shares [0.3] antigens with 
[0.4] the donor [0.6] tissue [0.2] then you will have antibodies to it [0.3] 
okay [6.0] so how to avoid [0.2] hyperacute [0.5] [0.3] rejection [0.3] it is 
actually very straightforward as i've said [0.3] there's obviously no point [0.
5] in transplanting an organ if it's going to be immediately rejected [0.3] so 
[0.3] quite simply you check in advance that the recipient does not have any 
anti-donor antibodies [0.6] and that's actually very simply done by the so-
called crossmatch test [0.9] [1.0] so you take donor leukocytes [0.7] all right 
[0.8] and you incubate those leukocytes with serum [0.2] from the recipient [1.
0] if the ser-, s-, recipient [0.8] a-, a-, a-, and sorry and a source of 
complement [0.7] so if the donor cells lyse under those circumstances you know 
[0.3] there are antibodies [0.3] in the recipient serum [0.5] which with 
complement will lyse the target leukocytes [0.6] okay [0.2] so under those 
circumstances if the crossmatch test fails [0.3] you would not transplant that 
particular [0.3] organ into that particular recipient [0.5] okay [0.4] you may 
ask where the leukocytes come from to do this test [0.4] in the case of a live 
related live donor [0.3] it's [0.3] perfectly obvious you take a little bit of 
blood [0.7] in the case of the cadaveric donor you use usually the spleen [0.4] 
as a sort of l-, source of leukocytes for this test [0.5] okay [0.3] very 
straightforward simple test [0.3] and if a-, and if if it if you fail then you 
don't do the transplant [2.4] but [0.3] acute rejection [0.5] is a very 
different situation [0.8] er and this is due to the development over a period 
of weeks [1.1] cell-mediated responses to donor alloantigens [0.4] okay [0.4] 
er [0.2] these [0.3] responses [0.3] particularly [0.4] are C-D-eight-positive 
cytotoxic T-cells now you've all [0.4] come across [0.3] cytotoxic cells in 
immunology before now [0.5] er [0.2] if you generate anti- [0.7] donor [0.6] C-
D-eight cells [0.3] those will [0.8] obviously damage 
the donor tissues [0.4] and in particular again [0.3] it's the endothelium 
which is damaged [0.7] and a little bit of techno-, technical terminology here 
if the endothelium is being damaged [0.6] this is r-, [0.2] er described as 
vascular rejection for obvious reasons 'cause the endothelium is the 
vasculature [1.9] and [0.3] may also [1.3] as well [0.4] or alternatively [0.3] 
er damage the actual cells of the organ and that is described as cellular 
rejection [0.6] after infiltrating into the organ [1.7] now i make this 
distinction [0.3] er because [0.4] vascular rejection [0.4] is much more severe 
[0.3] than straightforward cellular rejection [0.3] er celluclar rejection is 
much more easily coped with [0.3] than is vascular rejection for the obvious 
reason [0.3] that if you're getting vascular damage damage to the endothelium 
[0.3] that is going to do much more severe damage to the organ [0.3] than a l-, 
than damage to the er parenchymal cells of the organ [5.2] okay [0.5] few more 
words about [0.3] the acute rejection [3.8] as a part of the diagnostic process 
for 
acute rejection [0.5] er perhaps i should say if a if a patient is [0.7] er 
well i've already said that you get [0.4] er [0.3] protein in the urea and you 
get an increase of creatinine [0.2] during acute rejection [0.3] but the 
patient also becomes feverish [0.3] now you remember fever is a symptom [0.3] 
of immunological activations and the patient is feverish has these other 
problems [0.4] er now there are various reasons [0.3] why the patient may 
become feverish and have these sorts of problems [0.3] not all of them are rec-,
are rejection [0.4] so as a part of the diagnosis [0.3] of rejection [0.5] 
what is done is that a biopsy is taken to do that [0.3] er the physician 
inserts [0.4] a needle [0.5] er into the kidney under ultrasonic [0.3] er 
direction [0.3] and takes [0.3] in the needle hollow needle obviously a 
hypodermic needle [0.3] takes [0.3] a piece of core [0.4] a core of tissue [0.
4] and removes that [0.5] and you can stain this and examine it histologically 
[1.1] and if you do that [0.2] and there's rejection occurring [0.3] then you 
see all the classical hallmarks of inflammation [0.8] which i hope you 
recollect [0.3] are 
things like leukocytic infiltration [0.5] into the organ [0.4] things like 
activation of adhesion molecules remember [0.8] release of cytokines remember 
[0.6] and chemokines [0.3] so if the biopsy [0.4] the histological [0.2] 
appearance of the biopsy is that [0.3] then you've got a clear [0.4] er [0.6] 
diagnosis [0.5] of rejection [0.3] and if it's vascular involvement it's 
vascular rejection if it's just cellular involvement it's cellular rejection [0.
4] i've already said about damage to the endothelium [0.5] that will lead to 
kidney failure [3.2] so [1.7] the question that arises is how to avoid [0.5] 
graft loss due to acute rejection [2.3] now since the point that i have been 
making [0.6] is that [0.5] the immunological [0.8] response is due to allo-, 
alloantigenic differences between the donor [0.4] and the recipient [1.2] 
manifestly one of the things that is going to be done is to try and minimize [0.
3] the differences the antigenic differences [0.4] between the donor [0.3] and 
the host [0.7] okay [1.3] and this [0.7] you may understand is called tissue 
type matching [0.9] tissue typing 
for short [1.3] so you match as closely as possible [0.4] the antigenic 
properties [0.3] of the donor tissue [0.4] to the antigenic properties of the 
[0.6] recipient i'll go into this in more detail presently [2.2] and quite 
obviously the other thing [0.5] that's done [1.8] is that in the case of these 
patients [0.3] the immune response [0.3] will be suppressed [0.6] by drug 
treatment [0.7] okay so you do have two [0.6] er two [0.2] strategies one is [0.
2] reduce the antigenic differences by tissue typing [0.9] tissue matching [1.
2] and suppress [0.3] the immune response so that the immune response when it 
occurs and it will occur [0.7] er is minimized [0.8] doesn't do too much damage 
[0.2] is the hope [1.9] so we go on to chronic rejection [0.7] now this [0.8] 
is actually a somewhat different situation [1.2] er [0.8] histologically [0.5] 
er that is microscopically [0.4] er the a-, [0.2] appearance of the tissue 
undergoing chronic rejection [0.4] is quite different from the [0.2] t-, 
appearance of tissue undergoing acute rejection [0.4] there is no clear-cut 
evidence of inflammatory responses [0.3] there may be some 
evidence of minor inflammation but not much [1.0] okay [0.4] so it's not really 
[0.5] an immunologically-mediated rejection [1.0] but what is found is that in 
these situations [1.5] that you get deposition [0.2] of [0.5] quantities of 
fibrous scar tissue er collagen and [0.5] and fibres er fibroblastic [0.3] 
cells in large numbers [0.4] and suchlike [1.8] obviously [0.4] if you have a 
lot of fibrous scar tissue deposited in in in the organ er in the kidney [0.4] 
whose [0.6] function is crucially dependent on the delicate structure of the 
glomerulus [0.6] and the other bits and pieces [0.6] then [0.3] er you'll get 
[0.3] literally quite literally clogging up of these parts of the organ [0.4] 
and gradual [0.5] loss of function [1.0] okay [0.8] as i've already said [0.3] 
this [0.3] is irreversible cannot be reversed [0.3] and once the organ has 
failed it [0.2] has to be removed and you start again [1.0] [1.0] though i've 
said [0.4] that it is probably not an immunological response immunological [0.
2] er effect [0.3] because you see no real signs of inflammation [0.4] and 
inflammation is 
the hallmark [0.4] of an immune response [1.8] almost certainly this chronic 
rejection is due to [0.2] a long period of chronic but low-level inflammation 
there are there is a little bit of inflammation going on [0.4] so there is 
continuous [0.3] minor damage to the tissues [0.3] okay [1.4] in order to 
repair this minor damage [0.3] you have [0.3] what amounts to wound healing 
responses occurring now wound healing [0.4] is a very interesting biological 
phenomenon [0.3] you've all of you experienced wound healing [0.3] you cut 
yourself [0.3] and a scar [0.3] develops [0.5] to [0.2] close up the tissue [0.
4] the scar [0.3] is the deposition of fibrous tissue particularly collagen 
collagen fibrals [0.6] and obviously [0.4] that happens in the kidney [0.2] or 
the liver of whatever [0.3] you have the consequence of the failure of the 
organ [0.6] so almost certainly [0.5] er [0.2] we've got [0.2] a wound healing 
response generating [0.6] fibrous tissue in response [0.3] in as a consequence 
of the chronic inflammation [1.3] so what can we do [0.8] about that [0.4] now 
as i've said [0.4] there is [0.3] no 
effective therapy [1.1] and [0.9] it is supposed that in fact [0.4] probably 
all grafts eventually [0.5] are lost [0.2] through chronic rejection [0.3] but 
[0.3] er it might be such a slow process that the patient [0.4] may actually in 
fact outlive the graft and there is quite [0.3] good evidence that this does 
happen people die from other causes [0.3] before [0.5] the organ fails [0.8] 
now [2.0] if as i say the chronic rejection is due to [0.2] chronic [0.3] 
inflammation [0.4] or is due to the inflammation which was generated perhaps in 
the acute rejection [1.2] then [0.2] one supposes that chronic rejection is 
less likely to develop if you can minimize [0.6] the acute rejection in other 
words if you manage the patient carefully [0.3] so that the acute response [0.
3] to the tissues [0.4] is minimized [0.3] so if you want to reduce [0.6] 
chronic infection and this very much appears to be the situation [0.4] the way 
to do that [0.4] is to [0.3] reduce the probability [0.3] of [0.3] acute infec-,
acute rejection [0.3] at the early stage [0.5] of the transplantation [0.7] 
okay [5.9] i will have a break 
in a few minutes because Natalie has to change her [0.3] er tape in any case [0.
9] so i'll stop in a few minutes and we'll have a short break [0.7] but i want 
to talk first before i stop [0.4] a little bit about this issue of tissue 
matching [1.7] and this is [0.3] where we [0.4] could [0.4] get into some 
pretty heavy immunology i'm not going to [3.9] animal in animal models when you 
graft from one mouse to another [0.7] it's long been established [0.3] that 
there are two [2.3] antigenic differences which matter [0.6] and we talk about 
major histocompatibility antigens [0.2] okay major histocompatibility [0.4] 
alloantigens strictly speaking [0.8] you've heard of these [0.8] they are H-L-A 
in the human [0.3] and H-two in the mouse [1.0] if [0.4] two individuals differ 
in their H-L-A in their major histocompatibility antigens [0.7] what happens is 
severe [0.3] and rapid rejection occurs that's why these things are called 
major histocompatibility antigens [2.9] but they aren't the only 
histocompatibility antigens they aren't the 
only alloantigens which mediate [0.4] er tissue rejection [0.4] and there's 
actually a whole bundle [1.4] of minor histocompatibility antigens [0.9] two 
examples in the human are H-Y [0.3] and H-A-one [0.6] and in the mouse [0.3] 
it's everything that's not H-two H-one H-three H-four H-five and so on [0.7] 
okay if anybody had ever wondered [0.3] why the M-H-C of the mouse was H-two [0.
5] it's because there are multiple loci controlling tissue rejection [0.3] 
which were numbered one to N [0.4] and two happened to be the major [0.9] 
complex [0.4] okay [0.5] now if you have [0.3] if you have [0.4] identity [0.2] 
for the major histocompatibility antigens [0.4] for differences [0.3] in the 
minor histocompatibility antigens [0.3] you still get rejection it still occurs 
[0.5] but [0.2] as [0.8] the minor implies [0.6] er the rejection is less 
severe [0.7] and rather slower [0.2] but [0.3] nonetheless quite short [5.5] 
now [0.8] just very briefly [0.8] when we take [0.2] two individuals from a 
population if we ask the question can we match [0.5] 
absolutely [0.5] er tissues from those two individuals taken at random they're 
not [0.4] twins [0.4] two individuals taken at random [0.4] and the answer is 
that total matching of tissues [0.4] is in fact completely impossible [1.8] for 
two reasons one is [0.2] i hope you recollect that the H-L-A system is 
extremely polymorphic [0.4] what that means [0.3] is that there are many 
alleles dozens of alleles [0.3] at any one locus and they are [0.5] not 
randomly distributed amongst the population [0.4] but m-, [0.2] er [0.2] fairly 
randomly distributed amongst the population [0.6] okay [0.6] and there are [0.
2] six ma-, six major loci [0.3] on each chromosome [0.9] and there are two [0.
3] chromosomes [0.3] so an in any in any individual [0.4] there's going to be 
twelve loci [0.3] with dozens of alleles at each loc-, locus [0.3] so you can 
quickly imagine [0.3] that the probability of finding 
two identical individuals is going to be very small indeed [1.2] er i won't [0.
4] well i will remind you class one and class two A B C D-R D-P D-Q [1.8] all 
right [0.3] now even supposing by chance you're lucky enough to match all the 
majors [0.5] the probability of matching all the minors [1.1] is nil [0.4] 
because a minor antigen essentially [0.6] is [0.3] the product [0.3] of any 
gene [0.5] for which you have [0.6] different alleles [0.4] okay now when you 
think about the n-, [0.3] the way [0.3] genetics works [0.3] it's going to be 
impossible to find two individuals that have no allelic differences at all [0.
2] except twins [0.9] okay [0.2] so total matching is impossible [1.0] so that 
is why in transplantation [0.5] you have to have [0.5] immunosuppression [0.8] 
okay [0.4] we'll make a short break there er if you want to nip out and get a 
cup of coffee [0.4] i will restart in ten minutes [1.2] okay 
nm0260: 
can we settle down [7.6] as i was saying at the end of the [0.5] previous [0.4] 
hour [0.4] tissue matching total tissue matching is obviously impossible [0.6] 
er for the reasons i've given you [1.5] that doesn't mean to say that [0.5] 
partial matching is not impo-, not [0.3] is not possible [0.4] er [0.2] there's 
a couple of phenomena [0.3] which make partial matching [0.2] quite possible [0.
5] one is the the phenomenon of linkage disequilibrium [0.5] what that means is 
that s-, er within a population [0.3] some sets of alleles tend to stick 
together [0.4] okay [0.3] and occur [0.2] at a higher frequency than others [0.
4] what i mean by the term of haplotype i think you'll probably [0.5] 
intuitively understand [0.3] is you have a series of loci [0.4] along a 
chromosome [0.4] linked along a chromosome [0.3] then a haplotype [0.6] is a 
set of alleles [0.5] on along those particular [0.5] along that [0.3] along 
those p-, of those particular loci and we'll talk about haplotypes [0.3] er 
with namex next t-, on on Thursday [1.8] so [0.2] linkage diseq-, equilibrium 
ensures that some [0.6] haplotypes are more common than others [0.7] okay so 
the chance of getting a set [0.9] of [0.3] histocompatibility antigens together 
in two individuals is rather better [0.3] than y-, than you'd expect if there 
really was [0.3] random segregation now you remember that Mendel said that 
traits [0.3] are randomly segregated that's not true as you know they are 
linked [0.4] and so what we're talking about is linkage keeping together [0.3] 
a chunk of the chromosome [0.3] so that the chances of having a set of [0.6] 
alleles together is [0.3] actually much higher than you'd expect by chance [3.
5] the second point that matters [0.2] that's important is although i said 
there are six loci [0.4] er [0.5] some H-L-A antigens [0.3] i'm talking 
exclusively about humans of course that's why i use the terminology H-L-A and 
not M-H-C [0.8] okay [0.2] some H-L-A antigens seem to matter much more [0.4] 
in transplantation [0.3] in particular it seems that the D-R [0.4] of class two 
is very important [0.6] and A and B of 
class one [0.3] is also very important [0.3] implying that D-P and D-Q [0.4] 
and C don't matter so much which it seems to be the case [2.2] now another 
point [0.5] er which [0.2] course you'll immediately understand [0.4] is that 
if you're working with live related donors [0.6] er [1.2] those individuals 
will have at least one haplotype in common [1.9] er er er perhaps i should be a 
little bit careful what i say here but there's been one or two unfortunate [0.
2] situations [0.5] where fathers and children are found not to be related [0.
3] and that's always very embarrassing [0.4] for the transplant physician to 
explain [3.1] the important [0.3] essential thing is that [0.5] if we can 
partially match [1.5] and that does actually improve graft survival [0.2] again 
namex will talk about this on Thursday [1.0] many other factors matter [0.4] a-,
as well [0.4] m-, some factors perhaps matter more [0.5] er than matching but 
matching is not unimportant so that [0.3] is [0.3] an end an aim [1.0] now how 
is it done [1.2] how do you tissue match [0.4] the old-fashioned way [0.3] is 
to use 
antibodies specific for particular [0.3] H-L-A types [0.7] in much the same 
sort of way as in the crossmatch test [0.4] if you have an antibody say to [0.
5] H-L-A [0.3] B-twenty-seven [0.8] and that will lyse the target cells from 
the donor [0.3] then those target cells must be H-L-A B-twenty-seven [0.6] so 
there's a simple [0.6] serological test [0.3] the disadvantage of serological 
tests [0.4] comes from the very polymorphism [0.3] that they use to detect [0.
3] there are so many [0.4] different possible t-, antigenic types [0.3] that 
you have to have very large batteries [0.5] of [0.4] er [0.4] antibodies [1.2] 
and a worse problem [0.4] is that antibodies [0.4] do not cannot distinguish 
between some closely related [0.4] allelic types [0.2] okay [0.3] so you have 
an antibody that says two types are the same [0.3] whereas in fact they're 
different [1.0] w-, don't want to go into that in any detail but [0.5] because 
[0.3] er [1.6] what happens what happens now [0.4] is that P-C-R techniques are 
used for typing [1.2] er [0.3] using allele specific primers okay [0.3] so that 
primer [0.3] will only prime that particular allele [0.5] so you can only 
detect that 
particular a-, allele [0.5] and you set up the reactions [0.4] in a multiplex 
fashion [0.3] so you can use use multiple primers in the same reaction [0.4] 
and run just one track [0.2] on a gel and you see [0.3] various bands depending 
on which one [0.4] is is there which [0.4] haplotype which which antigenic type 
is there [0.6] and of course if you run multiplex reactions [0.3] er and 
multiple gel tracks [0.4] you can very easily and quickly [0.3] analyse dozens 
[0.4] of different H-L-A types [0.2] in the same [0.6] in in the same er [0.2] 
test [0.8] so it's done by multiplex [0.3] P-C-R [0.3] which with [0.2] which 
now makes [0.4] er antibody typing [0.2] quite obsolete [2.1] okay [0.8] so 
there we are [0.3] we match as closely as possible [3.0] er but we can never 
completely match so let's go on now and talk about how the immune system 
actually does recognize the foreign tissue [0.7] er this is where we perhaps 
get into slightly heavy immunology [2.7] i hope that you recogni-, r-, remember 
recollect the classical paradigm of T-cell recognition of antigen [0.6] okay [0.
4] cast 
your mind back to the second year immunology lectures [0.4] where you were 
taught [0.3] that the T-cell receptor for antigen [1.2] recognizes on the 
surface of the target cell [0.3] or the antigen presenting cell call it what 
you will [0.6] not [0.2] the antigen [0.5] not the foreign antigen i should say 
[0.4] but a fragment [0.4] of the pep-, of the foreign antigen a peptide 
fragment of the foreign antigen [0.4] in association with [0.2] the H-L-A 
antigen [1.1] and the essential point with that [0.4] is that the T-cell will 
only recognize [0.5] the foreign peptide in association [0.3] with self [0.2] H-
L-A [0.5] this is the phenomenon [0.3] of H-L-A restriction [0.4] that the T-
cell will only recognize [0.2] foreign antigenic peptides [0.4] in the context 
of its own [0.4] H-L-A [0.8] own H-L-A [2.0] self H-L-A [2.1] that's what 
happens for example in virus infections [0.8] now [0.7] in transplantation [2.
1] there's a rather different situation [0.3] and on the face of it [0.3] it [0.
2] contradicts this paradigm [0.5] because what is being recognized and this is 
very well established [0.5] is not [0.3] self [0.5] plus [0.3] foreign peptide 
but instead [0.4] is [0.5] the 
foreign [0.8] M-H-C antigen itself the foreign H-L-A itself which is recognized 
by the T-cell [1.4] so this is different from the classical paradigm of [0.2] 
antigenic recognition by T-cells [2.1] okay [0.8] now [0.7] i know i talked 
about this a little bit [2.2] in the second year [2.8] we distinguished [0.4] t-
, actually [0.2] two forms [0.5] of [0.2] antigenic recognition and 
transplantation [0.3] one is so-called [0.2] direct recognition [1.3] where 
what is happening is what i've just said [0.5] is if the host and the donor 
differ in H-L-A [0.5] and that the T-C-R [0.3] of the T-cell T-cell receptor 
recollect [0.4] of the T-cell [0.4] is binding to the foreign H-L-A [0.3] now i 
showed you this diagram and i probably didn't explain it very well [2.3] but 
this is the classical situation [1.3] with viral antigens [0.4] this is the T-
cell receptor of the T-cell [0.7] this [0.6] is the [0.2] is the self [0.7] H-L-
A antigen [0.3] with which is associated [0.2] a peptide a foreign peptide [0.
4] and these [0.4] double [0.3] lines [0.4] are supposed to imply [0.6] 
recognition [0.8] by the T-cell receptor [0.2] of [0.3] 
this target structure [0.6] okay [0.3] so that's what normally happens that's 
what the T-cell receptor's for [0.8] now what we are saying [1.1] is [0.2] 
where we have [0.5] er [0.2] foreign H-L-A being recognized [0.9] essentially 
this same T-cell receptor [1.1] is cross-reacting [1.1] remember [0.4] 
antigenic cross-reaction [0.6] this is an equivalent situation [0.5] it's cross-
reacting [0.5] with the foreign H-L-A which as you can see has a different 
shape [0.5] from the safe s-, self H-L-A [1.2] in conjunction with [0.2] a 
different peptide [0.6] but the point is by chance [0.5] these two structures 
are similar [0.5] by chance [0.3] so that the same T-cell receptor recognizes 
both [2.9] and that is the basis [0.4] of so-called [0.4] allorecognition [0.4] 
of foreign H-L-A [2.2] so that's direct recognition direct [0.4] because it's 
the H-L-A [0.8] which is being recognized [3.0] should say in passing [0.3] 
that H-L-A antigens [0.4] on the cell surface are never empty [0.5] they always 
have a peptide associated with them [0.8] okay [0.2] so again the structure is 
[0.2] always peptide plus [0.3] H-L-A [0.7] 'cause you never get empty H-L-A on 
cell surface [0.5] so it's a 
rather complicated situation [0.3] but there is good experimental evidence 
plenty of good experimental evidence [0.4] that this actually is what's going 
on and i don't want to go into the experimental evidence because it really is 
too complicated [0.9] don't have time [3.2] now [2.2] having said that there's 
direct recognition [1.7] that implies also that there is indirect recognition 
[1.7] now this indirect recognition [0.4] is much more like [0.3] the classical 
paradigm [0.3] of self H-L-A plus foreign peptide [0.8] 'cause the situation 
here [0.6] is where the host [0.3] and the donor [0.5] have at least one 
matched H-L-A antigen [0.7] okay now i've been saying [0.3] that you make an 
effort to match H-L-A antigens for a transplant [0.6] so normally [0.5] you 
transplant there will be matched [0.4] H-L-A antigens between donor [0.5] and 
recipient [0.6] now the matched H-L-A antigen [0.9] will be seen as self [1.0] 
by the host T-cell receptors [0.9] okay [1.7] and [0.4] if [0.4] you have [0.4] 
shall we say a foreign peptide [0.9] in 
the H-L-A groove in the peptide groove [0.3] that complex [0.2] of foreign 
peptide [0.5] plus matched H-L-A [0.5] in effect [0.7] is equivalent to a say a 
virus peptide [0.3] and self H-L-A [0.3] and potentially will activate the T-
cell [0.7] now this [0.3] is exactly the same situation as with virus 
recognition [0.2] exactly the same [2.0] the question that arises [0.3] is [0.
2] where then does the foreign [0.2] peptide come from [1.5] okay [1.7] to sit 
in the peptide groove [0.3] of the matched H-L-A [1.0] where does that foreign 
peptide come from [2.0] and the answer is [0.3] that it is [0.5] potentially 
derived from any [0.6] alloantigen [1.4] in the donor cell [1.2] now i've 
talked about minor antigens remember [1.5] so if the minor antigen [0.3] 
provides a peptide which can associate [0.3] with the matched H-L-A [0.4] that 
[0.3] can drive the T-cell response in exactly the same way [0.3] as a viral 
antigen will there's no difference [0.6] so the indirect recognition pathway [0.
3] is actually equivalent [0.3] to the classical [0.8] virus [0.2] peptide [0.
4] activation pathway [0.3] so it's [0.3] that's the simple one [0.4] the 
complex one is the direct because you 
have to think about [0.4] er cross-reaction [0.8] okay so i say the foreign 
peptide can be derived from any alloantigen [0.3] i've said minor [0.2] 
antigens or i'll [0.2] mention a a minor antigen in a moment [0.8] but 
obviously [0.9] peptides derive from mismatched [0.6] H-L-A antigens in the 
donor tissue [0.3] could also provide [0.6] er peptides [0.4] which would 
function in this way [0.9] okay [1.0] so we have direct recognition [0.3] and 
indirect recognition two different pathways [0.4] of T-cell activation [0.3] 
which [0.5] essentially amount to the same end result which is activation of 
the T-cell and damage to the tissues [1.9] i won't show you that again [2.2] 
but i will give you an example of a minor antigen [0.7] now [1.5] again [0.4] 
from your genetics you know that a major genetic difference between males and 
females [0.4] is that males in addition to the X chromosome possess a Y 
chromosome [0.6] now Y chro-, chromosomes don't [0.7] don't encode very much [0.
5] they encode maleness [0.7] they do encode [0.4] what's called the male 
specific antigen [0.9] 
okay which is not surprising isn't it [0.3] the H-, the Y chromosome is going 
to have [0.5] pro-, [0.2] going to encode proteins [0.2] which are not present 
in the female [0.4] so you've got w-, male specific antigen which [0.4] er is 
called the H- [0.2] Y [0.3] antigen [0.4] H for histocompatibility [0.3] Y for 
the Y chromosome [0.5] encoded by the Y chromosome [0.4] it's expressed in all 
male tissues [1.7] so you your kidney your liver [0.2] or my kidney my liver [0.
3] er bear Y [0.7] antigen [1.9] and fragments [0.2] of that Y antigen [0.4] 
can be presented by H-L-A A-one [0.5] or B-seven [0.4] or B-eight [1.3] what 
does that point-two mean i can't remember [0.9] what i mean by that is 
obviously different er [0.2] one fragment is presented by H-L-A A-one [0.3] 
which is a particular [0.3] H-L-A A type [0.4] another fragment of the H-Y 
antigen [0.3] is presented by B-seven [0.3] another fractio-, fragment of the Y 
antigen is presented by B-eight [0.9] so [0.7] what happens [0.3] when you 
transplant male tissues into a female [0.7] these H-Y antigens [0.3] will 
activate [0.4] T-cell responses in the female [2.2] okay [1.3] and you can 
demonstrate these T-cell responses [3.3] get a 
C-D-eight T-cell responses to the female [0.7] to the male tissue [0.2] to the 
male tissue [0.4] in the female [2.3] again for reasons that i'm not going to 
go into at the present but b-, that namex will go into [0.4] er that actually 
doesn't matter terribly much [0.4] so when you have the choice of a if you're a 
a woman [0.3] and you have the choice of a male [0.3] or a female kidney it 
actually doesn't matter [1.1] but in bone marrow transplantation it does [0.6] 
'cause bone marrow transplantation [0.4] the matching actually is much more 
critical [0.7] and it is clear [0.4] that if you have [0.3] Y or other minor 
antigen mismatches [0.4] in bone marrow transplantations [0.3] that can cause 
[0.2] distinct problems immunological problems [0.3] but in solid organ 
transplantation it doesn't really matter [2.3] as things are clinically i 
should say [1.5] but the point that i want to make there [1.2] that i'm leading 
up to [0.6] is that you have a [0.5] in tran-, tissue matching [0.3] there is 
[0.3] not not so much [0.3] a double whammy as the catch-twenty-two situation 
[0.6] if you match [0.4] 
H-L-A [0.8] completely which is not impossible but unlikely [0.7] er there'll 
be no direct recognition [1.0] 'cause the H-L-As are all the same [1.8] but 
there will still be indirect recognition [0.6] of minor antigens [2.5] on the 
other hand [0.5] if you [0.3] completely mismatch so there are no shared H-L-A 
antigens [0.6] there'll be no indirecognition because there'll be no [0.4] 
inverted commas self H-L-A to present [0.3] the peptides [0.3] but there will 
be massive direct rejec-, er recognition [0.9] okay [0.3] so [0.2] this just is 
to reinforce give you a bit of background [0.3] to the science of immunology of 
transplantation [0.4] a bit of background to why [0.4] how it [0.3] what are 
the causes for rejection [0.6] and lead me [0.3] to this point [0.6] that under 
any circumstances [0.4] immunosuppression [0.5] is going to be always necessary 
to suppress [0.5] the immune responses [0.3] which are inevitably going to 
arise to the transplanted tissue [3.9] so that logically brings me on to the 
next section [0.3] which is [0.7] how does 
immunosuppressive therapy work [3.0] quite simply immunosuppression is the use 
of drugs [0.5] to prevent the development of the immune response [0.4] 
obviously these drugs [0.4] had to be chosen so that they're not too toxic so 
they don't damage the individual too much which they do they have side effects 
[0.4] but they suppress immune responses [0.3] so that you do not [0.2] reject 
the tissue [0.7] okay [3.2] there's actually lots and lots and lots of 
immunosuppressive drugs available now many many many [0.2] er dozens [0.4] some 
are fantastically expensive [0.5] er [0.5] none is completely effective [1.9] 
all have more or less severe side effects some less severe some very [1.3] some 
essentially trivial some really unpleasant [0.9] and [1.5] the worst thing 
about them [1.0] is that all of them are non-specific by non-specific i mean 
they suppress all immune responses [0.3] not just the immune response of the 
grafted tissue which is what you want [0.4] you don't want to suppress immune 
response to other things [0.4] obviously [0.6] so none of 
these drugs is ideal [1.9] and just very quickly [0.4] er we talk about first 
line drugs now first line drugs [0.4] are those that are [0.3] the first choice 
of drugs in clinical treatment [0.6] and there are three types of drugs which 
are in in [0.2] common use [0.7] er you'll get a bit more fr-, about this from 
namex and there's plenty to read about about these drugs [0.4] there are the so-
called calcineurin inhibitors [0.4] what these do is intervere [0.3] interfere 
[0.5] with the activation of the I-L-two gene [0.6] okay [0.4] so I-L-two gene 
I-L-two production [0.4] is blocked [1.3] okay [0.8] remember I-L-two [0.3] is 
an essential T-cell [0.4] factor T-cell growth factor [0.3] so in the absence 
of I-L-two T-cells will not proliferate [0.3] so that's why the calcineurin 
inhibitors [0.4] are good [0.2] immunosuppressive drugs they prevent T-cell 
proliferation [1.1] the second class [1.4] are the steroids things like 
prednisolone [0.4] er which [0.9] fairly broadly suppress production of a range 
of cytokines now you remember the importance of cytokines in immune responses 
[0.6] so if you've suppressed cytokine production 
you're going to generally [0.4] depress [0.3] er inflammatory responses across 
the board immune responses across the board [0.4] so steroids are often used or 
are used they're a front line drug [0.4] first line drug [0.9] and then the 
third class [0.4] are inhibitors of D-N-A synthesis [0.4] which [0.6] block 
cell proliferation in a non-specific way [0.5] now remember [0.3] in an immune 
response [0.3] a major part of the immune response the development of the 
immune response is clonal [0.5] proliferation [0.3] clonal expansion [0.3] so 
if you have drugs which prevent cell proliferation you'll block clonal [0.5] 
expansion [0.5] so [0.3] these three classes of drugs [1.1] ah [0.4] other 
drugs [1.1] that are also used [0.5] tend to be [0.8] the expensive drugs which 
are good drugs very effective drugs [0.3] but they're so expensive [0.5] er 
that they're only used [0.2] if the other drugs aren't working [0.8] okay [0.3] 
and they tend to be used transiently [0.4] examples of those are antibodies to 
T-cells [0.4] you imagine perfectly well [0.3] if you treat an individual with 
antibody to C-D-three antigen [0.4] that will lyse with complement [0.2] all 
the T-cells [0.5] 
so this [0.2] anti-C-D-three [0.3] or for that matter I-L-two-R [0.6] is going 
to be a very potent immunosuppressive drug [0.5] but it's so expensive [0.6] er 
monoclonal antibodies [0.6] er cost [0.2] if we have to use them in gram 
quantities and in gram quantities they are very expensive [0.6] and there's 
more drugs [0.4] which are coming into clinical practice now [0.4] rapamycin 
looks like a favourite [0.6] which seems to be another inhibitor of self-
proliferation [0.4] and this one works by blocking growth factor [0.5] er 
signalling within the cell [0.8] okay [0.3] so these are second line drugs [2.
4] how are they used [1.0] now the general principi for many kinds of 
chemotherapy for all sorts of disease now [0.4] is to use combinations of drugs 
not one drug alone [0.4] but two or three or four or five drugs together [1.3] 
it's found that these tend to be more effective the combinations are more 
effective than single drugs [0.2] now let's for example suppose that drug A [0.
4] inhibits ninety per cent of the immune response drug B 
ditto drug C ditto [0.6] supposing that these three drugs work in different 
ways [0.4] you might expect that the combination [0.3] will inhibit ninety-nine-
point-nine per cent of the immune reponse [0.5] okay [0.5] which is much better 
[0.4] so they're used in combination [0.7] and it's also found [0.4] er that 
using them in combination [0.3] you can actually [0.3] reduce the doses that 
are used [0.4] and that reduces the s-, undesirable side effects of the drugs 
which i'll come on to [0.5] so actually [0.3] this a-, [0.2] tells us er [1.5] 
some important things about drug therapy generally in medicine [0.3] and i can 
mention drug therapy for cancer for example [0.4] drug therapy for H-I-V 
infections [0.6] the tendency is to use multiple drugs because in combination 
[0.3] they're more effective than the single drugs alone [0.4] perhaps it's not 
so surprising [1.9] now initially [0.7] the drugs are used in high 
concentrations high doses [0.5] er er er and this is because [0.3] when the 
patient has just been transplanted [0.4] obviously that's a situation [0.3] 
where the immune system of the patient [0.3] is getting 
this tremendous jolt half a kilo or so [0.3] of foreign tissue being put in [0.
5] and so you get tremendous activation potentially [0.5] of the immune 
response so that's the point [0.4] where you the s-, physicians come in with 
very large amounts of these drugs [0.3] in order to suppress [0.5] the very 
strong immune response [0.5] which will occur [0.6] initially [1.5] the happy 
thing is that in fact [0.5] the drug doses can be tapered down and this tells 
us actually something quite important [0.6] you can reduce over a period of 
months the amount of drugs that are used [0.5] and this is telling us that in 
fact [0.4] that the patient is becoming acclimatized if you like become adapted 
to the graft [1.2] okay getting used to the graft immunologically speaking 
that's an important observation [2.1] it's never reduce to zero because 
generally if the drugs are abandoned then the tissue the the organ is rejected 
so you er is what it means is that [0.5] the patients who have transplants [1.
5] are going to be treated by im-, with 
immunosuppression forever [0.8] or well the [0.2] continue the rest the rest of 
the their life or at least the rest of the [0.7] graft's life [3.7] now i've 
mentioned [0.9] this issue of acute rejection one wants to minimize acute 
rejection [0.4] so as soon as patients start to show symptoms of acute 
rejection [0.4] the dosage [0.5] of the drugs is increased [0.6] and if that 
doesn't work to prevent the rejection [0.3] then the second line drugs like 
anti-C-D-three [0.3] are used as well [1.0] so the acute rejection is a sort of 
emergency situation [0.6] where the drug dosages are put up [0.6] in an attempt 
to prevent rejection [2.1] and the fact is that the physicians have got so used 
to using these drugs and so accustomed to their patients [0.5] that in fact [0.
2] er [0.6] acute rejection is now quite rare er i can't remember the figures 
but [0.3] the actual so-called episodes [0.3] where acute rejection occurs [0.
3] when i say acute rejection i don't mean that the tissue is lost i mean that 
symptoms of r-, rejection [0.2] develop [0.4] which have to be treated [0.3] 
successful treatment of course prevents 
the acute rejection so you don't lose the tissue [0.6] must make that clear [1.
1] er and the physicians [0.4] have got this so well under control that graft 
loss [0.5] to acute rejection almost never happens now it's very rare [0.5] 
well not very rare but it's it's rare [6.3] okay [0.4] so that summarizes these 
points really [1.7] in the absence of immunosuppression grafts are [0.3] 
inevitably rejected [1.3] acute rejection occurs [0.9] after a delay i suppose 
because in the presence of immunosuppression it takes a long time [0.4] for the 
immune responses to develop [0.4] something that w-, should normally take a few 
days [0.3] takes a few weeks because you're reducing the proliferation of the 
cells [2.7] and that's what i'm saying in this last point that anti-graft T-
cells grow more slowly under immuno-, immunosuppression [3.8] now [0.7] this 
brings us to another point i mentioned [0.3] that there looks as if there's 
some sort of adaptive phenomenon [0.4] which occurs [0.2] in the patient 
because you can taper off the drug dosage without losing [0.4] the graft [2.2] 
studies [0.2] 
with mice and other rodents [0.2] have shown have suggested [0.4] that if you 
graft foreign tissues into the animal [0.3] whilst that animal is strongly 
immunosuppressed [0.7] okay [0.4] you indru-, induce [0.5] a condition called 
tolerance which [0.5] i hope you're familiar with [0.4] in which [0.4] you do 
not get an immune response with the foreign [0.3] antigen [3.1] in that 
situation [0.3] you can stop all [0.2] the immune suppression and the graft 
does not reject it because the animal is tolerant [1.6] okay and this has been 
demonstrated repeatedly in mice [1.9] i will say [0.3] that mouse mice are 
really very different from humans [0.3] and you cannot transfer [0.5] er 
experimental data from murine models [0.3] directly to human [0.4] so it is not 
the case [0.4] er that [0.3] tolerance [0.2] is sure to arise [0.4] and there 
are many differences again i'm not got time to go into the differences between 
the mouse models and the human situation but the differences [0.4] are 
significant enough [0.4] to persuade one that the two situations are not the 
same [0.9] but still the question 
arises [0.4] does some sort of [0.5] tolerance phenomenon [0.3] arise in humans 
[1.8] now i'm going to [0.5] dip into [1.2] a little bit of [0.9] my own 
research [2.5] [0.4] er which we've done [0.3] here er in collaboration with 
the local hospitals the local transplant unit [1.0] er [1.4] in principle [0.4] 
you can [0.2] d-, [0.2] detect [0.3] the development of tolerance in [0.2] 
transplanted humans [0.5] because what you can do [0.5] is measure [0.4] the 
numbers of T-cells in the recipient [0.6] who are able which are able [0.4] to 
respond [0.2] to the donor's antigens [0.6] okay [0.3] so if you can count the 
numbers of [0.4] er T-cells that respond to the patient to to the donor [0.4] 
tissues [0.5] enumerate them [0.4] er then [0.3] if you can show [0.4] that 
these numbers are declining with time [0.9] okay [0.3] you can then argue that 
tolerance is developing [0.9] but unfortunately in experimental terms this is 
not an easy thing to do [0.6] and i just want to give you a little bit of the 
technology [0.5] er c-, we are talking about science after all [0.8] okay [1.2] 
the way this [0.4] has 
been done is by the so-called lymphocyte dilution [0.2] assay [0.7] lymphocyte 
dilution i've forgotten to write that down oh there it is lymphocyte dilution 
assay i'm sorry [1.7] what we do here those of you that have done [1.0] some 
tissue culture may be [0.3] familiar with ninety-six well plates you will have 
done [0.4] those that are done by others you will have used them for the [0.3] 
for the er [0.8] what's that red blood cell assay i've forgotten 
haemagglutination assay [0.6] er so you can you take these ninety-six well 
plates [0.7] er and you put [0.4] in each well [0.6] a fixed number of [0.3] 
the cell of cells from the donor these we call the stimulator cells fixed 
numbers same across the plate every well gets the same number [0.9] okay [1.7] 
what you do then [0.2] is titrate [0.2] across the plate [0.5] er successively 
reducing numbers [1.1] of the recipient cells which we describe as the 
responder [0.7] cells okay 'cause they're going to respond to the antigens on 
the donor cell [0.5] and you will have noticed i've made a [0.4] bog-up here of 
these numbers [0.8] but what i'm trying to 
show is [0.2] doubling dilutions as you go across the plate [1.2] okay [0.6] 
now [0.6] if you score [0.4] some [0.3] measure [0.3] of T-cell activation [0.
6] in these wells [0.3] and i should say [0.2] all this particular column has 
got the same number of responder cells [0.4] all this column have got the same 
number so you've got [0.2] twelve sorry eight [0.4] replicates [0.8] for each 
column [0.4] okay so you do this [0.4] in eight replicates across the plate [1.
2] if [0.5] the responder T-cell [0.3] does in fact respond if there is a 
responder T-cell and it does respond [0.4] then if you have some sort of 
readout for the response you can score [0.4] the well as positive [1.2] or 
negative [0.7] okay [0.6] so if you go across the plate [0.4] at this very high 
number of responder cells [0.5] all the wells [0.2] show response [0.5] the 
next [0.2] all the wells show response again [0.2] the next [0.4] all the wells 
show response [0.4] then [0.5] you find [0.5] a column on your plate [0.3] 
where not all the wells show response okay so X is response [0.2] blank is no 
response [0.8] so along here you've got one two three four five six out of 
eight [1.0] has my arithmetic 
gone wrong again [0.7] however many [2.8] a number [0.4] of responding wells [0.
3] and in this column [0.3] you've got a smaller number of responding wells and 
in this column you've got no responding wells [0.3] now what you can argue [0.
5] is where there's a response there's at least one [0.8] responding T-cell at 
least one [0.6] okay [1.4] so [0.4] by the application of simple statistical 
methods [0.3] you can then calculate back [1.1] what is the proportion [0.3] of 
responding T-cells [0.4] in the original starting population [0.4] now this [0.
4] is [0.5] a classical dilution analysis assay [0.3] now you've done dilution 
analysis [0.3] you did dilution analysis or the virologists did anyway [0.6] er 
in your haemagglutination titrations [0.3] which is exactly the same principle 
you dilute [0.6] across a plate [0.3] an indicator [0.4] and you score positive 
or negative [0.4] and then you [0.9] have an end point [0.5] it's exactly what 
we're doing here [0.3] but what we're doing in essence is counting [0.3] the 
number of responding T-cells in the patient [0.5] okay [0.6] and i'll show you 
[0.3] some 
typical er [0.3] data slightly difficult [0.3] data to understand [2.0] the c-, 
the rows [0.9] indicate [0.8] individual patients patients one to five for 
ethical reasons i can't tell you who they were [2.5] this is the response [0.3] 
to the donor [0.5] cells as i've just described [0.4] and as a control [1.0] we 
have what we call the anti-third party response let's not worry too much about 
that [0.9] er let's in fact leave the third party response out [0.4] because 
what i want to concentrate on [0.4] is the anti-donor response [0.4] prior to 
transplantation [0.3] and sometime post-transplantation [0.6] in some patients 
you find that the number [0.3] of responding cells [0.4] declines these are 
cells per million [0.4] C-D-three cells [0.4] going down roughly tenfold there 
[0.3] and roughly tenfold there [1.0] in these other individuals they've stayed 
pretty much the same [0.5] or gone down a little bit [0.6] okay [0.3] so there 
clearly are differences between the individual patients [0.3] and in some 
patients the numbers of responding cells [0.4] go down quite 
dramatically [0.3] implying some sort of tolerance [0.5] and if we [0.4] put 
together [0.3] the data [0.5] generally [0.4] er [1.1] again i don't want er 
haven't got the time to go into detail here [0.4] but these [0.3] are the 
responses that i've just been describing [1.2] in terms of [0.3] cells per 
million [0.7] prior to the transplantation [0.6] and in the same patients 
that's why they're joined up [1.3] okay [1.0] sometime after the 
transplantation [0.3] now in these patients the numbers clearly have gone down 
[0.3] in these patients they've stayed static or clearly gone up [0.9] now 
again i'm not going to go into the clinical details of this [0.4] but [0.4] 
these patients actually [0.5] are doing less well [0.4] than those patients [0.
9] okay [1.1] so in experimental terms [0.3] one can demonstrate [0.3] that 
some sort of tolerance does indeed develop [0.4] in some patients who have 
transplanted [0.4] so in theory [0.5] these guys [1.9] do not need [0.4] full 
[0.4] immune respon-, er er immune suppression [0.6] and indeed these patients 
[0.5] er [1.1] there 
were [0.4] steroids [0.4] were no longer used in their treatment [0.5] and they 
got no worse so they were able to do without steroids so y-, they only needed 
[0.3] two [0.3] of the three [0.2] drugs that are normally used [0.4] so these 
patients who [0.2] appear tolerant [0.4] clearly are better [0.4] than those 
patients that [0.2] that don't [0.4] okay [0.3] so you can do it [0.4] you can 
demonstrate tolerance [4.2] so the implications of the development of tolerance 
[0.2] in in patients then [0.6] er is that [0.5] at least in principle [0.4] 
you can discontinue [0.6] the drug use [0.7] or perhaps [0.2] drastically 
reduce the drug use you want to perhaps have a little bit of immunosuppression 
but very much less than you would [1.1] normally [0.6] er [0.5] and in fact [0.
4] very occasionally patients have abandoned the use of their drugs they get 
fed up taking all these drugs all their life and say bugger it i'm not going to 
take them any more [0.7] usually what happens then is that the graft is 
rejected but in a few [0.6] lucky people [0.4] er the [0.4] graft is not 
rejected and they are genuinely 
obviously tolerant [0.5] okay [0.5] but [0.2] er if you talk to namex on 
Thursday he will say this will be a very brave physician [0.4] that will say 
okay we've got laboratory information that tells us the patients are tolerant 
[0.2] therefore we shall stop the drugs [1.9] so there are ethical issues here 
again [1.4] all right so that's a little bit of er [0.5] a sideway [2.3] 
sideline [2.5] why would we want to discontinue drugs [0.6] it's because of the 
side effects of drugs you don't want to use these nasty things you can avoid th-
, avoid it [0.7] side effects [1.5] in increasing severity in fact are 
hairiness [0.4] er [0.6] it wouldn't bother me so much but i daresay there are 
some ladies that would [0.2] object to growing beards well they do don't they 
[0.6] er [0.3] also [0.3] some of the drugs [0.2] are actually toxic [0.2] to 
the kidney they damage the kidney that's not an ideal situation no [0.8] 
there's even some argument that the development of chronic rejection is due to 
the nephrotoxicity of the drugs that are used to prevent rejection [0.4] 
i think that's not the case [1.1] obviously [0.6] a considerable [0.2] problem 
is infection [1.3] okay [0.5] er patients on immunosuppression [0.4] by 
definition [0.5] are susceptible to infection [0.3] in fact that's not too bad 
[0.3] because by [0.2] and large [0.3] er the guys who are transplanted [1.5] 
people that are transplanted are a little bit older [0.2] in their fifties 
sixties usually [1.3] these guys have experienced most common infections [0.3] 
and so they have lots of antibodies circulating [0.3] so they are essentially 
[0.3] immune [0.3] to common infections like common colds or perhaps more 
severe things like streptococcus sore throats and so on [0.7] one of the few 
compensations for growing old [0.3] is that you tend not to get colds because 
you're immune to all the cold viruses that circulate [0.5] so by and large 
infection normally is not too much of a problem [1.1] but what is a very severe 
problem is cancer [0.4] er and it turns out that in in [0.4] transplanted [0.2] 
immunosuppressed individuals [0.4] can't forget can't remember the exact 
numbers [0.4] the exact risk of 
cancer but it's a significantly elevated risk [0.4] of cancer in patients who 
are immunosuppressed [1.2] okay [0.4] er and the cancers that arise the most 
common ones are skin cancers [0.7] those don't matter too much [0.6] because 
they're [0.6] easily visible i'm not talking about melanoma if anybody has 
heard of melanoma there are other skin cancers i'm talking about non-melanoma 
skin cancers [1.5] these [0.7] are alarming [0.2] but not dangerous because 
they're quite well treated and obviously they're easily recognized quickly and 
easiy recognized [0.4] so skin cancers are not too much of a problem [1.6] but 
what is a problem are B-cell lymphomas [0.5] er [0.4] and now those of you that 
are virologists will recollect Epstein-Barr virus [0.7] and that this can 
transform B-cells and make them into malignant cells [0.5] normally [0.3] the 
immune system prevents [0.3] the transform the Epstein-Barr virus transform 
cells from [0.6] cour-, [0.2] developing into a cancer [0.3] but if you 
immunosuppress [0.6] then there is probability [0.7] er that the transformed 
B-cells will develop into a lymphoma and that is a very serious situation [0.5] 
very serious indeed for all sorts of reasons [0.4] so [0.4] these [0.3] side 
effects [0.5] are all very undesirable so that is why [0.4] drug treatment is 
tapered off [1.3] luckily that can be done [0.4] and ideally drug treatment 
would be reduced to nothing [1.5] okay [0.4] so i'm close to winding up now we 
will l-, [0.2] end a little before five o'clock [0.9] what may be the future [1.
8] better drugs [0.3] okay [0.2] more effective [0.5] less toxic [0.3] ideally 
graft specific [0.3] that's the ideal [3.6] there are [0.2] problems in the 
development of new drugs and again from a pharmaceutical those of you who are 
interested in the pharmaceutical industry this strikes me [0.5] as actually [0.
3] really quite a problem for the pharmaceutical industry [1.0] present [0.6] 
immunosuppressive regimes are very good they work very well as i've said you 
almost never lose [0.2] transplants through acute rejection [3.9] so [1.2] to 
demonstrate better drugs is going to take [0.2] years of 
clinical study years v-, very long clinical trials [0.4] because i forget what 
is the average survival of a graft nowadays but it's many years several years 
five eight years something like that [0.4] so if you set up [0.4] a clinical 
trial to compare two different [0.5] er drug regimes immunosuppressive regimes 
[0.3] it's going to be years [0.4] before you're going to get a result and drug 
companies are not happy with that [2.6] and the second thing [0.3] which 
actually [0.6] in some ways [0.7] is more difficult [2.2] is that testing new 
drugs [0.2] may well be unethical [0.4] now you will not have been exposed to 
much ethics [0.4] sadly i think you ought to be [0.5] but the point is [0.3] 
that if you have [0.4] a drug [0.5] regime [0.3] which is an effective therapy 
[0.8] there is no way [0.3] that you can [0.2] say to a patient [0.3] we are 
not going to treat you because we want to [0.2] test a new drug [0.9] so 
inevitably [0.4] in [0.5] immunotherapy and other kinds o-, [0.2] sorry 
immunosuppression [0.3] and in other kinds of therapy [0.4] if you want to test 
a new drug that is usually 
going to be [0.4] by adding it in [0.6] to the previous set of drugs [0.5] or 
at best exchanging it [0.3] for one of the currently used drugs [1.0] for 
ethical reasons [0.6] now [0.2] unless the new drug is significantly better [0.
3] clearly better than the old drug [0.9] and remember the old drugs are very 
good [0.5] then it's going to be extremely difficult [0.5] to demonstrate a 
real difference because you can't leave the patient untreated except for your 
new drug [0.7] in other words you can't and you cannot possibly [0.4] do 
placebo trials people will have h-, have [0.4] heard of what a place-, or heard 
of the term placebo [0.3] that's when you use a dummy drug [0.7] when you want 
to test a new drug you couldn't possibly use dummy drugs in this situation [0.
7] so there are ethical problems in testing new drugs [0.8] as well as [0.5] 
straightforward practical problems [1.7] now [0.8] another severe problem which 
i pointed out right at the beginning [0.4] is that actually transplantation [0.
6] er is presently limited [0.4] not by the clinical [0.3] 
skills [1.2] but by the numbers of donors i forget [0.2] what the numbers of [0.
4] people on the waiting lists are locally it's large numbers [0.4] and after 
the Alder Hey [0.4] thing that you [0.2] may have heard of [0.3] er numbers of 
donors declined dramatically [0.2] in this country people decided they weren't 
going to give up their [0.2] or-, organs even after death [1.3] and [laugh] [0.
2] another [0.2] er significant thing is that with the reduction [0.3] of the 
violence [0.2] in Northern Ireland which is an excellent thing [0.4] there are 
fewer [0.2] freshly dead cadavers to provide [0.4] transplants so the numbers 
of [0.4] organs from Northern Ireland has dried up [0.4] in fact i think namex 
will be telling you [0.2] on Thursday [0.3] that one of the main sources of 
organs is actually Spain [0.5] er where they drive so badly [0.5] that there 
are [0.5] large numbers of traffic accidents which are a source of [0.9] 
transplant tissues [0.5] okay [0.3] so there are things like that [0.2] anyway 
[1.3] w-, we talk about xenografting [0.2] to overcome shortage of donors [0.2] 
pig [1.1] kidneys [0.7] primates [0.6] are obviously [0.3] a potential source 
of grafts because they're so closely related to us but they're ruled out for 
all sorts of reasons [1.3] pig kidneys are about the same size as ours and 
their biochemistry is similar [0.3] but [0.4] there is [0.2] a severe problem 
of hyperacute [0.2] er rejection [0.5] for reasons which aren't very clear to 
er to me [0.6] all of us or very nearly all of us have [0.2] large amounts of 
circulating antibodies [0.3] which will react with pig tissues [0.3] and cause 
hyperacute rejection [0.5] so this problem actually as you know has been solved 
and i don't know if i [0.7] showed you this by humanizing kidneys [1.1] 
basically what is done is that the kidney tissues are [0.3] genet-, kidney the 
sorry the pig [0.5] is genetically engineered [0.3] so that the [0.2] the 
tissues are not susceptible to complement lysis [0.5] and again the details 
don't matter [0.3] but the t-, [0.2] tissues are not lysed by complement [0.5] 
so humanization [0.3] of pigs [0.3] prevents [0.3] hyperacute rejection [0.4] 
now [0.4] this has never been tested [0.6] in human [0.6] er [0.4] 
transplantation [0.3] it has been tested in primate transplantation so you take 
[0.3] humanized [0.6] pig kidney [0.3] and transplant it into a chimpanzee this 
has been done on a smaller scale [0.3] half a dozen or so chimpanzees or 
whatever [1.7] and you find that the hyperacute rejection problem is overcome 
[0.4] but [0.3] er [0.6] the [0.4] the acute rejection which occurs [0.3] is 
violent and cannot be controlled [0.4] with the immunosuppressive drugs [0.8] 
so [0.2] any human trial [0.5] of xenografting [0.4] irrespective of any other 
problems ethical or otherwise [0.4] any sort of xenograft trial in humans is a 
long way off if ever [3.9] we have talked about therapeutic stem cell cloning 
and i for one [0.4] have got [0.7] serious ethical reservations about stem cell 
cloning [0.8] er sorry embryonic stem cells it depends how you go about it 
perhaps but i have reservations [1.7] give it a little bit of thought [0.4] [1.
8] you might be able to generate 
stem cells we could regenerate say T-cells [0.5] which [0.3] as you appreciate 
[0.3] will function in suspension you do not need to have an organized tissue 
[0.5] for stem cells T-cells to work [0.4] well that's not quite true because 
you know [0.4] know i i hope [0.4] that the main immunological interactions [0.
3] occur in lymphoid tissues [0.8] so the T-cells do function [0.5] in an 
organized tissue environment [0.4] but [0.2] T-cells are as you know able to 
circulate [0.4] and put themselves into the tissues where they want to be [0.4] 
so [0.2] you can well imagine [0.5] er that [0.5] T-cells which function in 
this way [0.4] could be used [0.4] could be derived from embryonic stem cells 
and effectively used [0.5] but i for one [0.3] i cannot see that you would be 
able to generate in vitro [0.7] notice in vitro [0.4] an organ such as a kidney 
which is a complex assembly of many different cell types [0.3] put together in 
a very elaborate manner [0.9] okay [0.6] so i do not see that an organ can be 
made in vitro even if [0.5] er we could genuinely m-, generate [0.4] stem cells 
which could potentially [0.5] generate a kidney it's 
just too complicated [0.8] so if you want a kidney that means you and you want 
it by embryonic technology [0.4] that means you've got to grow the fetus [0.7] 
to a point at which it has intact kidneys and that is to my mind [0.3] 
ethically [0.3] obviously [0.2] completely [0.4] impossible [1.6] so [0.3] 
therapeutic stem cell cloning there's a big question mark over that except in 
perhaps in simple situations [4.2] now [0.2] if you think [0.3] i've talked 
about [0.3] basically bone marrow blood bone marrow kidneys liver [0.6] er [0.
4] heart and lung [2.9] and i've said that some kinds of [0.6] transplants are 
impractical because the surgery is just too difficult [1.1] now [0.2] people 
have talked about limb transplantation and and rather horrifying [0.2] to me [0.
4] thought is face [0.2] transplantation has been talked about [1.2] the 
surgeons say that this is technically possible and indeed a hand has been 
transplanted [0.7] but i don't know if anybody recollects the patient got very 
unhappy [0.5] and had it amputated [0.8] he was very unhappy with having 
somebody else's hand [0.3] could see it all 
the time [0.4] 'cause a kidney [0.3] okay [0.4] you can forget about it but not 
a hand [1.1] so the guy had the hand [0.4] amputated [2.1] face transplants [0.
5] it has been said they are technically possible the technology the surgical 
technology there is very complicated because your face [0.4] has lots of 
different muscles which work in a very complex way so we are [0.3] have very 
expressive faces er most other animals [0.3] do not have expressive faces we do 
[0.4] and that's because of the complicated nervous [0.5] er er er and and 
vasculature [0.6] n-, nerves and vasculature in the face [0.4] okay [1.5] but 
the surgeons say that it's technically possible [0.4] but again there's a 
massive ethical problem here which doesn't seem to have been recognized [0.5] 
is that what if [0.5] subsequently that patient [0.5] er [0.5] acute rejection 
or chronic rejection occurred [0.5] and the face [0.2] [0.6] was rejected what 
do you do you nip out and find another corpse [1.2] or what [1.0] so for 
ethical reason although it's been discussed in the press [1.0] in the media a 
face transplant is [0.2] not really on [1.3] pancreas [0.2] 
that was the example that i used at the beginning o-, of something which is 
surgically impractical [0.2] but highly desirable because of diabetes [0.7] if 
you could transplant the pancreas into a into a diabetic [0.7] perhaps that 
might er give you [0.4] er a cure for diabetes remember [0.3] diabetes is 
treatable [0.3] by insulin but is not curable but if you can transplant a 
pancreas [0.3] that would cure it [0.5] now what is being attempted [1.8] is to 
[0.5] generate beta cells the islet cells which make insulin remember from the 
pancreas [0.8] prepare those in vitro from a pancreas [0.3] and invue infuse 
them [0.3] through the portal vein which takes them into the [0.2] liver [0.5] 
er and with luck [0.5] the beta cells will [0.3] lodge in the liver tissue and 
there be functional [0.9] er and secrete insulin [0.7] perhaps [0.3] in 
brackets [0.3] this is [0.4] this sort of technology is just coming into 
clinical testing [0.8] so that's a possibility [1.8] but [0.2] to bring my [0.
3] me to the s-, final conclusion [0.8] er [2.4] plainly [0.3] spare part 
surgery [0.3] and bone 
marrow transplantation and things like that [0.3] does work [0.2] whereas [0.6] 
technically a-, [0.2] and ethically possible it does work [1.1] er and it works 
so well that in fact in many cases the graft as it were outlives the patient 
patient dies from other some other cause [0.6] er and the kidney liver whatever 
[0.3] is still functioning at the time of death [0.4] the other cause may be [0.
4] due to the underlying disease perhaps [0.6] give you an example er d-, [0.5] 
diabete-, diabetics sadly [0.4] er often have [0.7] kidney failure [0.6] er and 
they can be treated obviously with kidney transplantation [0.5] but sadly they 
tend to die [0.5] er from other complications of diabetes such as heart disease 
[0.5] and if they die of heart disease their kidney may be still perfectly all 
right [0.4] so spare part surgery [0.4] as we have it now is actually pretty 
good [2.1] but [0.5] you might 
might think me that i'm a [0.2] think of me as a bit of a sceptic er er er [0.
2] and perhaps i am [0.4] but in fact [0.2] for [0.7] very good reasons [0.3] i 
don't myself see any radical improvements likely in the near future [0.3] and i 
think pretty well all [0.3] the clinicians i talk to and indeed the scientists 
the rational scientists [0.4] that i talk to about this [0.3] tend to agree 
that in in in in in [0.2] transplantation [0.3] and indeed in a number of areas 
of modern medicine [0.4] we have reached [0.4] some sort of [0.4] er [1.0] 
limit [0.5] which we seem [0.3] to be unable to get across all the simple sort 
of problems have been solved [0.5] the hard problems [0.3] are too hard [1.4] 
okay well i'll leave it there [0.4] er and as i say namex will be talking to 
you about [0.4] more clinical aspects of how to care for transplant patients on 
Thursday