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Indices
of Tolerance
Demonstrating the applicability of novel indices of immunological
tolerance to clinical practice using immunosuppression-free transplant
recipients.
This website is here to inform the public and professionals of this ongoing kidney transplantation project which is taking place in various clinical centres throughout Europe and coordinated by King's College London.
Basically, We are trying to identify renal transplant patients who have stopped their immunosuppressive regimens, without then going on to reject their Kidneys. Once we have identified these patients we will try to indentify those biolgical factors that lead to transplant tolerance and apply this knowledge to future renal recipeints, in the hope that we can reduce or even stop completely the long-term mdeication these patients have to take.
This study is funded by the European Commission.
Aims and Objectives
Renal transplantation can revolutionise the quality of life and life expectancy of patients with end stage renal failure. However, such patients are required to take immunosuppressive medication for the rest of their lives. These drugs have a significant incidence of adverse effects, including infection and malignancy, which may be life-threatening. In addition, these drugs are very expensive.
However, there are anecdotal reports of occasional patients who have discontinued their immunosuppressive drugs without loosing their transplants. These patients are described as being “tolerant” of their grafts. Unfortunately, there has been no reliable way of differentiating these individuals from the majority who have discontinued their medication and subsequently rejected their grafts.
Recent advances in basic immunology have permitted the development of targeted, ex vivo tests of immunological reactivity whose clinical applicability has been demonstrated in a number of contexts. However, there remains a “validation gap” to be bridged which will allow these tests to be transformed into tests appropriate for the routine prospective management of transplant patients.
There are two ways in which this project will bridge that gap. First, it will bring together a range of several different ex vivo approaches to the analysis of immunological tolerance in carefully defined patients. Second, by applying these tests, to spontaneously tolerant patients who are taking no immunosuppressive drugs, it will be using a group of patients who are ideal to address this question but who are too rare to be studied in anything other than a large multi-centre project such as this.
The use of these tests in this group of patients will lead to the validation of the concept of an “immunological fingerprint” of the tolerant state. So successful has recent progress in transplant immunotherapy been that there is now a realistic expectation of being able to manipulate the immune response towards immunological tolerance. Hence, our demonstration of the validity of these tests in identifying the spontaneously tolerant state will also allow us to use them to identify potentially successful therapeutic manipulations that will generate tolerance. Real clinical advantage will accrue when these tests can be applied prospectively to patients, to identify those in whom discontinuation of immunosuppressive medication will not result in rejection.
Once the
blood samples have been collected and sent to the relevant centres
the following tests will be carried out:
• The frequency of cells specific for donor antigen, using three distinct tests: limiting dilution analysis, ELISPOT and CFSE proliferation,
• Donor-reactivity in a trans-vivo delayed type hypersensitivity assay
• Frequency of T cell receptor gene usage and length polymorphism,
• Expression of activation markers and transcription of cytokine genes using real-time PCR and
• Transcription of immune-related genes by cDNA array chip analysts.
All these assays will be performed in parallel on samples from control non-tolerant patients. Not all the tests will be carried out in the same centre: each lab will perform individual testing and the results will be collated at King's College . This information will then be integrated with a view to defining an “immunological fingerprint” of transplantation tolerance. This will then be disseminated to propagate awareness of and progress in applicability of these assays amongst interested groups. As a result of this study, we hope to undertake a trial of drug withdrawal in patients deemed to be tolerant.
The project started mid-2003 and will run for three years during which patients will be continuously recruited and information disseminated. Progress this project can be monitored through this website
Indices of Tolerance 2004 | |
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