Mechanisms of DiseaseNon-HLA transplantation immunity revealed by lymphocytotoxic antibodies
Introduction
Terasaki and colleagues first reported 30 years ago that kidney-transplant recipients whose serum contained lymphocytotoxic antibodies before transplantation were at increased risk of graft rejection.1 Their finding was confirmed in many subsequent studies, and now patients awaiting renal transplantation are routinely tested for lymphocytotoxic panel-reactive antibodies (PRA).2 The lymphocytotoxicity assay has certain drawbacks. There is no binding convention about the size of the cell panel used for testing, although most laboratories use commercial kits with frozen lymphocytes from 56 random donors. There is general acceptance that the results of the test system are suboptimally reproducible. Nevertheless, risk of rejection appears to rise as serum reactivity against the random lymphocyte test panel increases.3, 4 PRA-positive serum samples contain antibodies against HLA antigens on lymphocytes,5, 6 and graft survival in preimmunised recipients is assumed to be lower as the result of insufficient sensitivity in the pretransplant lymphocytotoxic cross-match test against donor lymphocytes. Much effort has therefore been spent on increasing the sensitivity of the cross-match assay so that weak anti-HLA sensitisation can be detected,7, 8 and the use of new techniques for pretransplant antibody testing based on highly sensitive, strictly HLA-specific ELISAs has been encouraged.9, 10, 11 Patients cannot form antibodies against their own HLA antigens; therefore they cannot form anti-HLA against lymphocytes of an HLA-identical sibling donor. In distinction from genetically identical twins, who share all genes and therefore do not require immunosuppression when tissues are transplanted between them, the common definition of HLA-identical siblings is that they are matched for both HLA chromosomes but mismatched at other chromosomes; thus, they can be of different sex, eye colour, and so on, as well as age. Since HLA chromosomes are inherited according to mendelian rules, the likelihood that two siblings will inherit identical HLA chromosomes from their parents is 25%. Although many other factors influence the outcome of kidney transplantation, transplants from HLA-identical sibling donors are recognised as a special category. They have significantly better success rates than transplants from HLA-mismatched donors,12 and they are the standard against which the results of transplantation from other donor sources are compared. However, since rejection of HLA-identical sibling grafts commonly occurs if no immunosuppression is given, these recipients are treated with immunosuppressive drugs, albeit at lower doses than recipients of grafts from cadaver donors. This need for immunosuppressive treatment shows that, aside from HLA, there must be other antigen systems that can cause transplant rejection. HLA-identical sibling transplants do not provide a target for anti-HLA, and PRA reactivity before transplantation should therefore not influence their success rate.
We studied the influence of pretransplant PRA status on the long-term outcome of kidney grafts from HLA-identical sibling donors.
Section snippets
Patients
Kidney transplants reported by 245 centres to the international Collaborative Transplant Study13 were analysed. Transplants were carried out between 1982, the year the study was initiated, and 2002. The centres included in this analysis provided written assurance of compliance with local ethical and consent guidelines and of patients' consent for the use of data for scientific analysis. When consent from patients could not be obtained, care was taken to ensure that all data processing was
Results
The differential effect of PRA on survival of transplants from cadaver donors or HLA-identical sibling donors during the first year after transplantation is shown in figure 1. As expected, a significant effect of PRA on graft survival was evident in cadaver transplants (p<0·0001), but no significant effect was noted in transplants from HLA-identical sibling donors (p=0·0831). PRA reactivity in cadaver-transplant recipients was associated with immunological graft loss rather than death of the
Discussion
This study showed a highly significant association between the presence of lymphocytotoxic antibodies before transplantation and the outcome of kidney grafts from cadaver donors and HLA-identical sibling donors. Such an association was previously known in cadaver kidney transplantation, in which it has been attributed to unrecognised antibody reactivity against mismatched HLA antigens. However, the finding of a similar association for transplantation of organs between HLA-identical siblings was
Glossary
- Panel-reactive antibodies
- Serum of a potential transplant recipient is tested for reaction with a panel of lymphocyte suspensions, generally obtained from random blood donors, in a dye-exclusion assay. The proportion of donors against whose lymphocytes a serum gives positive test reactions is recorded as a general measure of the patient's state of presensitisation.
- Lymphocytotoxicity
- Commonly referred to in clinical transplant immunology as the serological dye-exclusion assay. When human
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