Different patterns of sensitization following renal allograft rejection in an inbred rat strain combination

Exposure to MHC antigens by kidney transplantation can result in long-term sensitization or tolerance. In order to characterize immune responses to an acutely rejected renal allograft, ACI (RT1^a) kidneys were transplanted into untreated male PVG (RT1^e) recipients and allowed to reject while one native kidney remained in situ for host survival. Two distinct patterns of recipient sensitization were found based on early IgM responses to RT1.A^a following rejection, with “weakly sensitized” and “strongly sensitized” groups comprising approximately 40% and 60%, respectively, of the recipients. Serum taken from strongly versus weakly sensitized animals at the time of peak IgM responses (7 days post-transplantation) showed greater ability to block binding of anti-RT1.A^a mAb (R2/15S, R2/10P, or YR1/100) to PVG.1A (RT1^a class I and II on a PVG background) lymph node target cells. Sera obtained from strongly sensitized recipients during peak IgG responses (4 weeks after kidney transplantation) demonstrated significantly higher IgG2a and IgG2b alloantibody levels than weakly sensitized rats at all serum dilutions (1:4-1:1024). Allografts harvested 10 days after transplantation from strongly sensitized recipients (strong R2/10P-blocking serum, n=9) had a vascular pattern of rejection characterized primarily by extensive vascular endothelial damage, glomerular and cortical necrosis, and gross infarction of the graft. In contrast, grafts harvested from weakly sensitized recipients at 10 days, 21 days, or >6 months (n=6, 10, and 6, respectively) posttransplantation showed a significantly different pattern of rejection, with moderate interstitial lymphocytic infiltrates but substantial preservation of the general kidney architecture. When challenged 13 weeks posttransplantation, strongly sensitized animals rejected RT1.A^a class I-disparate PVG.R1 skin grafts in an accelerated fashion, whereas such grafts survived indefinitely on weakly sensitized recipients. These findings indicate that two patterns of renal allograft rejection can occur between a fixed strain disparity, one of which results in long-term sensitization and the other with partial tolerance to donor class IMHC antigens, as evidenced by (1) decreased production of IgM, IgG2a and IgG2b isotype alloantibody to donor class I MHC antigen epitopes after kidney rejection and (2) acceptance of donor class I-disparate skin grafts.