The association of enhancement of renal allograft survival by donor-specific blood transfusion with host MHC-linked inhibition of IgG anti-donor class I alloantibody responses

Donor-specific blood transfusion (DSBT) in animals and humans can either promote subsequent renal graft survival or lead to sensitization and graft rejection. Using a rat renal allograft model, we have examined whether the effects of DSBT on renal allograft outcome and IgG alloantibody responses are linked to the host MHC. In F1 rats produced by mating PVG (RT1c), a low IgG alloantibody responder to transfused ACI (RT1a) blood, with 3 different high-IgG responders [W/F (RT1u), LOU (RT1u), and LEW (RT11)], high IgG alloantibody production was found to be inherited as a dominant trait and associated with acute rejection of ACI renal allografts. DSBT given to offspring of (PVG±W/F)F1 rats backcrossed to W/F with either RT1u//e (u/c) or RT1u/u) (u/u) phenotype induced high-IgG-alloantibody responses that were associated with acute renal allograft rejection. Likewise, offspring of (PVG±W/F)F1 rats backcrossed to PVG expressing the u/c phenotype had high IgG responses to ACI DSBT associated with acute renal allograft rejection. In contrast, DSBT given to backcrossed recipients expressing the RT1c/c (c/c) phenotype elicited a transient IgM response that switched to a very low IgG response and was associated with renal allograft acceptance. Analysis of IgG isotypes demonstrated that DSBT prevented production of IgGl and IgG2a, and to a lesser extent IgG2b and IgG2c alloantibodies in c/c but not u/c renal allograft recipients. The differences in the level and isotype of IgG alloantibody responses found in sera of DSBT-pretreated backcross rats of u/c and c/c phenotypes were also present in allograft eluates and splenocyte cultures. Likewise, DSBT-pretreated renal allograft recipients of the c/c phenotype produced lower levels of alloantibodies directed to class I RT1.Aa antigens compared with their u/c counterparts; in contrast, no difference was found in alloantibody responses to class II RT1.Ba antigens. These findings demonstrate that the variable ability of DSBT to enhance renal allograft survival correlates with the inhibition of antidonor class I alloantibody responses of all IgG subclasses by a mechanism that is linked to host MHC.