Non HLA Genetic Factors that Influence Graft Survival

Minor Histocompatibility Antigens

There have only been a small handful of studies into the influence of minor histocompatibility antigens in solid organ transplantation, with most of the available data being based on the HY antigen rather than the autosomal minor histocompatibility antigens. In fully matched kidney transplants, minor histocompatibility antigens are thought to contribute to immune rejection, a process which, along with many other factors, leads eventually to long term graft loss. HY antigens are ubiquitously expressed on renal tubular epithelial cells and thus function as a target for destruction. In one study, HY specific cytolytic T cells were detected in a female patient transplanted with a kidney from her HLA matched brother. In another study, the presence of de novo anti HY antibodies in female patients transplanted with kidneys from male donors correlated with the incidence of acute rejection.


In the largest study of the role of minor histocompatibility antigens in kidney transplantation, Gratwohl et al reviewed over 150,000 deceased donor transplants and found in a multivariate analysis that when compared to all other combinations of sex, transplant of kidneys from male donors into female patients was associated with an increased risk of graft failure at both 1 and 10 years.



Post transplant de novo anti MIC antibodies have been shown to be associated with graft loss in kidney transplantation, with acute rejection episodes in heart transplantation and with chronic rejection in lung transplantation.


In one large retrospective study involving over 1900 transplants, the presence of pre transplant MICA antibodies was found to associate significantly with an increase in graft failure. This was also evident in well matched transplants in patients with no pre-transplant anti HLA antibodies. In another smaller study, anti MICA antibodies were eluted from kidneys which had been lost due to acute as well as chronic rejection. These antibodies were eluted with and without anti HLA antibodies. Where donor material was available, the study could identify the possible immunising donor MICA epitope.


In one study of the relevance of MICA in heart transplantation the presence of MICA antibodies was significantly higher in those patients with severe acute rejection than those without rejection. The study found that in most cases the appearance of the MICA antibodies preceded the development of acute rejection. Histological evidence showed an upregulation in MICA.


Studies of the role of MICA and MICB in lung transplantation have shown that the development of antibodies to either MICA alone or to MICA and HLA together, correlated significantly with the development of bronchiolitis obliterans syndrome in chronic rejection.



In solid organ transplantation, NK cells are known to infiltrate allograft, suggesting that activation of NK cells may be critical in the immediate post transplant period. However, one recent study found that there was no associated between KIR ligand mismatch and the incidence of acute rejection though they did find that certain KIR receptor-HLA class I ligand combinations were more frequent in patients with stable grafts when compared to patients with acute rejection. This reflects the outcome of a much larger CTS study involving over 2,700 deceased donor kidney transplants which also found no effect of ligand matching on graft survival. 

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