Elsevier

The Lancet

Volume 365, Issue 9470, 30 April–6 May 2005, Pages 1570-1576
The Lancet

Mechanisms of Disease
Non-HLA transplantation immunity revealed by lymphocytotoxic antibodies

https://doi.org/10.1016/S0140-6736(05)66458-6Get rights and content

Summary

Background

The presence of panel-reactive antibodies (PRA) against HLA antigens before transplantation is associated with early rejection of kidney grafts from cadaver donors. Transplants from HLA-identical sibling donors do not provide a target for antibodies to HLA antigens and should therefore not be affected by PRA.

Methods

Data from the Collaborative Transplant Study were used to examine the influence of PRA on graft survival. Uncensored graft survival and death-censored graft survival were calculated, and the data were analysed by multivariate Cox's regression methods.

Findings

Among recipients of HLA-identical sibling transplants, 3001 patients with no PRA had significantly higher 10-year graft survival (72·4% [SE 1·1]) than 803 patients with 1–50% PRA (63·3% [2·5]; p=0·0006) or 244 patients with more than 50% PRA (55·5% [4·0]; p<0·0001). The effect of PRA became apparent after the first post-transplant year and was, therefore, strikingly different from the early steep decline in graft survival during the first year associated with PRA in recipients of cadaver kidneys. We could not discern whether graft loss was a direct effect of non-HLA humoral sensitisation or whether PRA served as an indicator of heightened immunity against non-HLA transplantation antigens.

Interpretation

PRA reactivity is strongly associated with long-term graft loss in kidney transplants from HLA-identical sibling donors.

Relevance to practice

Our findings suggest that non-HLA immunity has a much stronger role in clinical transplantation than previously thought. In contrast to immunity against HLA mediated by antibodies present before transplantation, which leads to early acute graft rejection, non-HLA immunity is associated with chronic graft loss. The possibility of identifying recipients at increased risk of late graft loss before transplantation could be used to devise specific immunosuppressive strategies for these patients.

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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