Rat Cytomegalovirus Infection Interferes with Anti‐CD4 mAb‐(RIB 5/2) Mediated Tolerance and Induces Chronic Allograft Damage

In order to assess the role of heterologous immunity on tolerance induction (TI) by signal 1 modification, the influence of rat cytomegalovirus infection (RCMVI) on TI by a non‐depleting monoclonal anti‐CD4 mAb (monoclonal antibody) (RIB 5/2) in a rat kidney transplant (KTx) model was investigated. Orthotopic rat KTx (Dark Agouty (DA) → Lewis (LEW)) was performed after TI with RIB 5/2 [10 mg/kg body weight (BW); day –1, 0, 1, 2, 3; i.p. (intraperitoneal route)]. RCMVI (5 × 10E5 Plaque forming units [PFU] i.p.) was simultaneously conducted to KTx, 50 days after KTx, and 14 days before and after KTx. RIB 5/2 induced robust allograft tolerance even across the high‐responder strain barrier. RCMVI broke RIB 5/2‐induced tolerance regardless of the time of RCMVI but did not induce acute graft failure during the 120 days follow‐up. RCMVI induced a significant chronic deterioration of allograft function (p < 0.01) and enhanced morphological signs of chronic allograft damage (p < 0.05). Cellular infiltrates and major histo‐compatibility complex (MHC)‐expression were more pronounced (p < 0.05) in the infected groups. RCMVI induced not only RCMV‐specific T‐cell response but also enhanced the frequency of alloreactive T cells. RCMV interferes with anti‐CD4 mAb‐induced tolerance and leads to chronic allograft damage. The data we presented suggest a potentially important role of viral infections and their prophylaxis in clinical TI protocols. In a protocol using a monoclonal anti‐CD4 antibody that produces robust allograft survival, rat cytomegalovirus infection interfered with long‐term survival, with deterioration of function and morphology, indicating that CMV infection may interfere with favorable immunologic changes induced by anti‐CD4 antibody.