Immunological compatibility should be the prime factor in allocating organs

Frans Claas, Leiden, The Netherlands

Chairs:Jacques Bernheim, Kfar Saba, Israel

Jaap Homan van der Heide, Amsterdam, The Netherlands

Prof. Frans Claas

Department of Immunohematology and Blood Transfusion

Leiden University Medical Center

Leiden , Netherlands

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Thank you very much for your kind introduction and the possibility to discuss important

parameters for the allocation of organs. I was asked to come up with some arguments saying that

immunological compatibility is useful and should be a prime factor in allocating organs.

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Being a transplant immunologist that’s no problem at all to have sufficient arguments for that

statement because if you put a foreign organ in a patient, then the immune system of the patient

immediately looks at the foreign HLA molecules and says ‘OK these are not mine, I have to kill

this organ’. That is really the reason why we see so often graft rejection. So, the HLA molecules

being the target of this rejection then of course, if you match for HLA, you would expect less

figures and immune responses and better survival. But there are more arguments to say that we

should keep compatibility as the prime factor for allocation.

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So these arguments can be graft-related. If you want to use a graft in an optimal way, the best

survival is found with an HLA matched graft. So you have an optimal use of the --- donor organs

but also many arguments can be found which are patient-related. Also the patient is happier if the

graft stays longer in situ, the patient has less clinical complications, the patient has a lower chance

to form antibodies and if something is going wrong with the graft and risks rejection, the patient

has a higher chance to get a re-transplantation. I would like to give you in short a few examples

of these arguments.

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So, in the old days we were all convinced, everybody said HLA is very important and we have to

do HLA matching. Eurotransplant was the prime factor for allocation for a long period of time. This

is a historical slide where you see that there is a clear effect of HLA matching in transplantation.

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That was very nice for the patient who got a matched graft but this was not a very fair system

because patients with common HLA phenotypes were transplanted in a very easy way, whereas

patients with rare HLA phenotype remained on the waiting list and could not be transplanted.

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So that is the reason why Eurotransplant changed the allocation system in 1996 and still HLA

matching is one of the important factors but also the chance that the patient gets an organ is one

of the arguments, the waiting times, the cold ischemia is taken into consideration. So for all these

parameters, patients get points now and in this way the kidneys are allocated. So, HLA is still

very important but all other factors are taken into consideration as well.

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Then you wonder is HLA matching still important? Because what we see if you see the results of

the transplants performed in your transplant, then you see a gradual increase in graft survival in

time and here starting with the new allocation system in 1996, you see that the graft survival is

very, very good, excellent. So, this is an argument for many people, stop with HLA, it’s working

very nicely irrespective of HLA but that’s not really the case.

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If you look at the graft survival of the patients transplanted in the early period of this new

allocation system, you still see that the well-matched do far better than the poorly matched.

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An even more recent study by Gerhard Opelz shows that patients who were transplanted between

2005 and 2011, they also see here really a clear effect of HLA matching. So HLA matching is still

associated with a better graft survival. So that is one argument say to continue with looking for a

compatible donor.

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The second argument is that you not only have say a better graft survival but you also will have

less clinical complications when you take HLA into consideration.

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So this is a summary of a recent study of Gerhard Opelz who showed several parameters, which

are really beneficial if you take HLA matching into account. So if you have poor HLA matching,

you have a higher incidence of post-transplant non-Hodgkin’s lymphomas, you have a higher

incidence of viral and bacterial infections, you have a higher incidence of hip fractures and you

have a higher incidence of death with a functional graft due to infection or cardiovascular disease.

This is all probably related to the higher dose of immunosuppression you need when you

transplant fully HLA mismatched grafts.

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So that’s the second argument. Let’s go for another argument and that is a very popular

argument at the moment, everybody in the world is now looking for DSAs because these are

really the bad guys after transplantation, donor specific antibodies formed after transplantation.

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If you look here, this is the study form the group in Berlin, if you look at antibody formation after

transplantation, then some patients do not form antibodies and their graft survival is very good.

Some patients make antibodies but not directed against the donor, they already do a bit poorer

but the ones who make antibodies against some specific donor they have a very poor graft

survival. So, antibody formation after transplantation is bad.

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What is the main reason that you form these antibodies? That is the number of HLA mismatches.

So this is a study from the United States, where you see the more HLA class 1 mismatches, here

we have HLA-A and here the HLA-B mismatches. The more mismatches, the higher chance that

your patient makes antibodies after transplantation.

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So this is not an argument, let’s go in this direction, so let’s match in order to prevent this

antibody formation because related to the antibody formation after transplantation and when

things are going wrong, then patients need a re-transplant and if you are highly immunised, it’s

very difficult to get a re-transplantation. Also here, HLA matching plays a crucial role.

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Here I show you the results of the study from the group in Cambridge who looked at what the

results were of patients who have been transplanted with different degrees of HLA matches and

the chance that such a patient becomes highly sensitised so makes antibodies against a lot of HLA

antigens. Here they took a calculated panel reactive activity of 85%, which means that the

patients have antibodies against 85% of potential donors. The chance is increasing with the

number of HLA mismatches. So that holds true for HLA-A, B and C. You see from 15% to 50% and

also for HLA-DR and DQ it increases from 6% and 63%. So here also HLA matching really is

important because then you will get less highly sensitised patients.

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Of course, in a highly sensitised patient, there’s a problem because we all know when a patient

needs re-transplantation and the patient has donor specific antibodies, then you should not

perform the transplantation because it will lead to hyper acute rejection.

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That’s the reason why we and all laboratories perform crossmatches, especially the CDC

crossmatch is here very relevant. If the patient doesn’t have antibodies against the donor, we say

ok transplantation, ok. If the patient has antibodies to the donor, we don’t do the transplant. The

problem is a highly sensitised patient and every time you say ‘no it’s not ok’ and the patient

remains on the waiting list. Here, that’s really a point, the waiting time for a patient because in

the past the highly sensitised patient had to wait for 10-15 years and didn’t get any organ.

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So that’s the reason why in Eurotransplant we decided to find something to help these highly

sensitised patients for patients who are at very low risk to be transplanted. Now two approaches

to help these patients. This is an approach where we say I don’t care about compatibility. The

patient has antibodies to the donor but I just remove the donor, the antibodies and then I can use

this donor for transplantation. Desensitisation is very popular, especially in the United States. So,

they use plasmapheresis, IV Ig, anti-CD20, Bortezomib and then finally transplant the patient with

a donor to what the patient already has antibodies. This works in a number of patients but it is

associated with more complications because you give more immunosuppressive drugs. Still the

incidence of antibody-mediated rejection is very high. So, we are still very old fashioned and we

say ok we need a compatible donor, we want to look for a crossmatch negative donor. So, in

Eurotransplant we have developed the so-called acceptable mismatch program for this purpose.

So this is a program to enhance transplantation of highly sensitised patients but also you can do

the same with a living donor population by a paired donor exchange program. But let’s discuss

very shortly this acceptable mismatch program. So you have now patients who are supposed to

wait for a very long period of time and you don’t want your patients to wait very long and Uwe

will agree with this. So that’s the reason why we said if we can find a patient who is supposed to

wait for a very long period of time, we have to find a trick to have this patient transplanted

earlier.

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That’s what we do in the acceptable mismatch program. So, what we do with these highly

sensitised patients is we define those HLA agents towards which the patient never formed

antibodies so we are sure that against this mismatch the patients will not have antibodies so the

crossmatch will be negative. That is what we want to do, we want to predict a negative

crossmatch and what we do now in Eurotransplant with these patients, these highly sensitised

patients, is once a donor becomes available with an HLA type which is compatible with the

combination of the patient’s own HLA and these acceptable mismatches. So with a predictable

negative crossmatch then the kidney must be shipped immediately to the recipient. So this is

really an advantage for the patients who are otherwise supposed to wait for a very long period of

time.

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Really, what you see in this patient group is this is the chance that the patient will be transplanted

if we do nothing then less than 20% of the patients will be transplanted after 2 years when you

define the acceptable mismatches, you will see that 60% of these difficult patients are

transplanted within two years’ time. So really, this has an impact on the waiting time for these

patients.

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Of course, patients are transplanted in a fast way but also the results of this program are

excellent, so the survival of these highly sensitised patients is the same as the survival of the

non-sensitised patients within Eurotransplant. So this is really an argument for a different way of

looking at compatible donors.

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So I hope that I have convinced you so far that compatibility has many advantages but of course,

the argument is yes, ok but then you have to do those complicated HLA typing and it takes time

and you have a very long cold ischemia time.

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But if you look into the literature, then if you can do all these tricks within 18 hours and we are

certainly able to do so, then you see that that does not impact on graft survival very much. Only if

your cold ischemia time gets longer than 18 hours, then it really has an impact on the function of

the graft. So, HLA matching is important I hope that I have convinced you of that but I think we

have to change our way of HLA matching because we make HLA very complicated. At the

moment, we have more than 10.000 different HLA antigens, so it’s fiercely impossible to find an

HLA matched donor for every patient.

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So we want to go now to alternative matching strategies within Eurotransplant and we have too

many HLA antigens to say ok, let’s have donor and recipient with the same antigen. What we

would like to have is develop an alternative matching algorithm, which is based on the relevant

epitopes on the HLA molecules because what we know at the moment is that there are for

instance, five thousand different HLA class 1 alleles but you can define these on the basis of only

180 epitopes and that will make HLA matching even easier than it is at the moment.

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So I want to show you what I mean with this. So, if you look now at the different HLA molecules

here, then in yellow are all amino acids, which are different between the different HLA molecules

and you can make antibodies against all these variations. So at a first glance you say OK you

make the system even more complicated. In the past, we said HLA-A2 and 68 is only a different

antigen but now I’m saying there are many different epitopes, which may be targeted for

antibodies. But the nice thing with HLA is HLA molecules are like patchwork molecules.

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So here you see a lot of structures of HLA molecules and the colour indicates the kind of strange

amino acid, which is present. What we show here is say that some variations are shared between

HLA molecules so an HLA molecule does not have exclusive epitopes; they are shared between

different HLA molecules.

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So if you know this and you take this into consideration, you really can predict the

immunogenicity of an HLA mismatch. So if we see here this HLA molecule, it has many strange

polymorphic amino acids almost top side and on the side chain. But what we know is that some of

these are shared with other HLA molecules and a patient will not make antibodies against cell

structures. So, you should always look at these polymorphic sites in the context of the HLA type of

the patient.

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That is the principle of a computer algorithm we are already using in our laboratory and if you

look in this way at HLA mismatches, so we have here several patients that will be transplanted

with the same HLA mismatch, HLA-B51, then for patient A you see there are many strange

epitopes present, so this patient will make a lot of antibodies. For patient B and C and D there are

less because the other ones are present on the patient’s own HLA. There are even patients who

don’t have this HLA antigen but they do not see any strange things on the foreign HLA molecules.

So it’s an alternative way of HLA matching.

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That really works because if you look at patients who have rejected previous kidney grafts or HLA

mismatches and there were no strange epitopes present on this HLA molecule, then none of these

patients will make antibodies. The more of these epitopes mismatches, the higher the chance that

it may start to make antibodies. But if you are now looking for alternative matching strategies,

you should not say ok I take every HLA mismatch as the same, you should find HLA mismatches

like here because then you have a lower chance of making antibodies and a lower chance of the

patients getting problems. Finally, you can also use this as a matching algorithm.

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By accident within Eurotransplant, we have transplanted about 100 patients, which had an HLA

mismatch, but no epitope mismatches and the graft survival of this patient group is the same as

the zero mismatch situation.

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So if I can conclude my talk, I think the beneficial effects of HLA compatible transplant must be

taken into consideration when you allocate organs. Now, our view on compatibility is changing, so

future algorithms should be based on epitope matching rather than antigen matching and I’m sure

that we can reuse compatibility as a prime factor without overruling the beneficial effect of

matching with cold ischemia time because we can do everything within 18 hours and waiting time

as in waiting time for patients for which you predict they will have a long waiting time, you can

make a special program like the acceptable mismatch program. Thank you.

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