Anti-Idiotypes to HLA and their Role in Transplantation

Abstract

The network theory proposed by Jerne is based on the finding that variable regions of T and B cell antigen receptors are structurally diverse and express unique variable region determinants. We have postulated that idiotypes present on the V region of the anti-HLA antibody molecule (Ab1) can elicit the production of anti-anti-HLA antibodies or Ab2 and that such Ab2 may play a role in the suppression of anti-HLA antibody responses. We first tested the validity of this concept in pregnancy, natures most perfect model of allogeneic tolerance. Our studies revealed that anti-Id antibodies were present during pregnancy at times when HLA antibodies had disappeared from the circulation (1,2). This inverse correlation between Ab1 and Ab2 suggested that Ab2 suppresses the production of Ab1. Once the validity of this concept was substantiated in the model of pregnancy, we tried to determine whether anti-Id antibodies to HLA also play a role in the down regulation of the alloimmune response to transfusions and transplantation. For this, we monitored patients for the development of anti-anti-HLA antibodies following donor specific blood transfusion (3). We found that most patients developed Ab2 to the mismatched HLA class II antigens of the blood donor two weeks following transfusion and were associated with successful transplantation. Furthermore, we found a positive correlation between the presence of anti-anti-HLA antibodies and tolerance to the graft in patients with a history of presensitization to HLA antigens of the donor (4). The role of anti-Id antibodies to HLA was also evaluated in renal and heart transplantation (5,6,7). In these studies, patients were monitored following transplantation for the production of Ab2. We found that 5 year actuarial survival of heart and kidney allografts was significantly higher in patients developing Ab2, compared to patients without Ab2. Taken together, our data suggest that anti-Id antibodies to HLA play an important role in suppressing the immune response to HLA and that such anti-Id may be of therapeutic interest in transplantation.