The pas de deux of immune tolerance

Characterisation of HLA cells by immunoblot. Colouring of the ‘electrophoretic’ strips using monoclonal antibodies marked with peroxidase. © INSERM/Michel Depardieu
Characterisation of HLA cells by immunoblot. Colouring of the ‘electrophoretic’ strips using monoclonal antibodies marked with peroxidase.
© INSERM/Michel Depardieu
Modelling of human HLA class 1 cells. The HLA B57 cells are represented as well as certain anchoring regions that permit the association with the antigenic peptide. © INSERM/U44S
Modelling of human HLA class 1 cells. The HLA B57 cells are represented as well as certain anchoring regions that permit the association with the antigenic peptide.

Too many transplants fail because the transplanted organ is rejected by the recipient’s immune system. We are beginning to define with considerable precision the underlying molecular mechanisms that cause this. The challenge now is to change these mechanisms to induce a tolerance that will make it possible to dispense with heavy immunosuppressor treatment.

There are around 250 000 people living in Europe today with a transplanted kidney, liver, lung or heart. To avoid their immune system rejecting the organ, which it recognises as a foreign body, they have to follow a permanent and heavy course of immunosuppressor treatment that is not only expensive (EUR 15 000 a year) but also likely to produce many side effects, including renal toxicity, increased susceptibility to infection and increased risk of cancer. Controlling this immune rejection response is therefore crucial for improving transplant effectiveness.

The rapid increase in organ transplants from the 1960s was only possible thanks to the discovery of the HLA (Human Leukocyte Antigen) system. This group of proteins present on our cell surfaces enables lymphocytes (a kind of white corpuscle) to distinguish between what ‘belongs’ and ‘does not belong’ to the body and constitute, in a sense, our biochemical ID. It was the identification, in man, of six major HLA families that permitted the first organ transplants between unrelated individuals, just as, in the 1920s, the description of blood groups had opened the door to blood transfusions.

But progressively, as transplants became widespread, it became clear that HLA matching was a necessary but insufficient condition for the transplantation to be successful in the long term. The acute rejection of the transplant during the days or weeks following the operation is today controlled effectively by medicines, while chronic rejection, which appears after a number of years, remains a problem. After 15 years, half of all kidney transplants are no longer functional. The only solution then is to envisage a second transplant, with all the inherent risks.

The memory of lymphocytes

‘We are at present unable to predict whether or not a patient’s immune system will tolerate the transplant, or will develop a hypersensitivity response leading to chronic rejection. We also do not know whether or not a transplant patient can be allowed to cease his immunosuppressor treatment,’ explains Michel Goldman of the Institute of Medical Immunology in Charleroi (BE). One of the reasons for this difficulty is that our immune system has a prodigious memory. Any foreign substance or body (bacteria, virus, parasite) with which it has at any time been in contact is susceptible to leave a trace that takes the form of antibodies or T lymphocytes (so named because they are produced in the thymus) that are able to recognise the foreign cell and break it down. These defence responses to what ‘does not belong’ are in principle very specific… but not totally. All it takes is for a molecular motif on the transplanted tissue surface to bear a certain resemblance to a foreign body that the immune system learned to recognise in the past for a so-called heterologous response to be produced. The T lymphocytes then attack the transplanted organ or tissue that degenerates as fibrosis sets in and progressively loses its biological function.

This heterologous response is particularly difficult to study as animal models are unable to mimic it totally. In mice we can administer various chemical treatments to induce a very strong, although never total, tolerance of the immune system to foreign organs or tissue. But when applied to man the same treatment proves much less effective. ‘The environment in which we are living is much less regulated than that of laboratory animals,’ explains Hans-Dieter Volk of the Institute of Medical Immunology at Berlin’s Charity University Hospital. ‘This means we have many more memory T lymphocytes and therefore a much greater risk of a heterologous immune response in the event of a transplant.’

An education in tolerance

The studies on mice nevertheless served to shed light on two ways forward, which the Reprogramming the Immune System for the Establishment of Tolerance (RISET) programme has started to explore by carrying out pilot tests on man. The aim is to develop selective immunosuppressor treatment that neutralises the T lymphocytes responsible for the transplant rejection only and not the entire immune system, as present medicines do. Progress in biotechnologies has made it possible to produce molecules that intervene in the activation of T lymphocytes and transform them into regulating cells that inhibit responses that are pernicious for the transplanted organ.

Another way forward is to accompany the transplant with an infusion of donor cells that can then educate the recipient’s immune system to recognise the transplant as ‘belonging’ to the body. Although results on animals have been encouraging, such cell treatment approaches remain heavy solutions that can only be administered at a limited number of high-tech centres. There is also the problem of the absence of standardised industrial production of these precious medicinal cells.

Emergency markers

While waiting for these innovative therapies to be perfected, the most urgent task is to define biomarkers able to predict rejection. Under the Sixth Framework Programme, the RISET and AlloStem projects served to define around 10 of these markers. Some, such as the presence of anti-HLA antibodies or cytokine dosage (molecules that permit communication between the cells of an immune system) are pre-transplantation markers. Their presence in the recipient indicates a major rejection risk. Others, such as certain ARN messengers characteristic of T lymphocyte activation, are posttransplantation markers. They indicate that a rejection response is starting up or, on the contrary, that the recipient has developed a hyper-responsiveness to the donor’s antigens. At present these can be measured in the recipient’s biological fluids and, in the future, possibly by molecular imaging of the transplant. At some point, monitoring these levels could guide the immunosuppressor treatment administered by the medical team.

However, each transplantation centre has developed its own biomarkers and its own tests, making it very difficult to compare results and sometimes even to reproduce them. ‘No biomarker of rejection or of the risk of rejection today has a consensus,’ observes Michel Goldman. ‘We must take inspiration from what has been done in cancer research to arrive at a standardisation of detection tests.’ The Transplant Research Integration in Europe (TRIE) project that he coordinates has thus set itself the goal to define the best rejection biomarkers by working closely together with the industry and regulating authorities. The rewards would be a reduction in immunosuppressor treatment and an improvement in the long-term success rate of transplants, for the great benefit of the many transplant patients living in Europe and for the tens of thousands of persons awaiting a transplant.

Mikhaïl Stein


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Leukaemia and bone marrow transplants

The treatment of certain types of leukaemia and cancer involves the transplanting of hematopoietic stem cells, the cells that form the different categories of blood cells. The stem cells are taken from a donor’s bone marrow or a bank of umbilical cord cells.

The therapeutic effect is due to the fact that the T lymphocytes in the transplanted material attack and destroy the cancer cells. But in certain cases this reaction runs out of control and the transplanted cells also attack the mucosa of the recipient’s cells, the latter being unable to put up any defence due to the immunosuppressor treatment required by the transplant. This is what is known as graft versus host disease. It is thus a response that is symmetrical to that which leads to the rejection of a transplanted liver or kidney: it is no longer the host’s immune system but the immune system of the transplant that is activated. That said, the biochemical mechanisms involved in these two phenomena are largely identical.