During the past two decades, renal allograft transplantation has emerged as the desired treatment of children with end stage renal disease (ESRD). Despite increasingly sophisticated methods of HLA-typing and efforts to transplant well matched kidneys, allograft rejection continues to be the major cause of allograft failure and treatment of rejection a cause of patient morbidity. This would imply that factors other than HLA antigens may play a role in the determination of allograft rejection. One of the major factors that improves allograft survival is pre-transplant blood transfusions (BT). The exact mechanism(s) responsible for this enhancing effect remain unknown. It has been suggested that (BT) induce enhancement or an active immunologic unresponsiveness to donor antigens. Two (BT) protocols are now operational at UCLA. In PROTOCOL I, potential cadaver transplant recipients will be randomized to either a group receiving 20 small-dose transfusions (2.5 cc/kg) over 5 months or a group receiving 5 full transfusions (10 cc/kg) over the same time period. In PROTOCOL II, ESRD patients with greater than 70% HLA antibodies will be transfused from known donors to determine if the high titer HLA antibodies can be reduced. Preliminary data generated in our laboratory shows that post-BT patients generate blocking factors which inhibit anti-HLA antibodies specific for donor/recipient discrepant HLA antigens. Within the framework of the outlined protocols, we plan to evaluate post-BT serum samples for the presence of blocking factors (antiidiotypic antibody) using techniques developed in our laboratory. Briefly, post-BT sera will be evaluated every two weeks for circulating immune complexes (CICs), and lymphocytotoxic antibody (LCA). Patients will be categorized according to immune responses; (i.e., CIC(+)/LCA(+), CIC(+)/LCA(-), etc.). Analysis of sera (both IC(+)/IC(-), for anti-F(ab')2 and anti-IgG antibodies and for specific antiidiotypic antibodies, (i.e. anti-anti-HLA) will be done. By ELISA techniques, Gel filtration and affinity chromatography analysis of sera will be carried out to confirm the antibody nature of demonstrated blocking factors. Another group of non-HLA antigens (endothelial antigens, E-antigens) are important targets in certain types of allograft rejection. BTs inhibit E-antibody formation. We will investigate the possibility that post-BT inhibition of E-antibody formation is related to antiidiotypic antibody formation (i.e. anti-anti-E-antibody). It is anticipated that these investigations will provide data on the mechanism(s) responsible for the known allograft enhancing effect of BTs. This information will allow us to isolate specific allograft-enhancing factors and develop new approaches to the prevention and treatment of allograft rejection.
