Anti-CD4 monoclonal antibody-induced allograft tolerance in rats despite persistence of donor-reactive T cells

• Published in: Transplantation Vol. 64; no. 8; p. 1181
• Main Authors: Lehmann, M, Graser, E, Risch, K, Hancock, W W, Müller, A, Kuttler, B, Hahn, H J, Kupiec-Weglinski, J W, Brock, J, Volk, H D
• Format: Journal Article
• Language: English
• Published: United States 27.10.1997
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; CD4-Positive T-Lymphocytes - immunology; Cytokines - genetics; Gene Expression; Graft Survival - drug effects; Immune Tolerance - drug effects; Immune Tolerance - immunology; Immunosuppression; Kidney Transplantation - immunology; Lymphocyte Depletion; Male; Polymerase Chain Reaction - methods; Rats; Rats, Inbred Lew; Rats, Inbred WF; RNA-Directed DNA Polymerase; Th1 Cells - physiology; Th2 Cells - physiology; Transplantation, Homologous - immunology
• ISSN: 0041-1337
• DOI: 10.1097/00007890-199710270-00017

Although CD4-targeted therapy abrogates acute rejection and may induce permanent graft acceptance in rodents, little is known about the mechanisms of long-term graft survival in these models. Recently, we have shown that treatment with a nondepleting anti-CD4 monoclonal antibody (mAb) (RIB-5/2) induces long-term survival of renal, heart, and skin allografts in strong major histocompatibility complex I/II incompatible rat strains. Here, we demonstrate that the development of major histocompatibility complex-specific and tissue-nonspecific tolerance rather than graft adaptation is responsible for long-term anti-CD4 mAb-induced transplant survival. Donor-specific but not third-party heart and pancreatic islet grafts were accepted permanently without adjunctive therapy in long-term kidney allograft recipients, and infusion of naive or alloimmune splenocytes failed to break the tolerant state. Interestingly, alloreactive T cells were not depleted in these long-term survivors, as ex vivo donor-specific mixed lymphocyte reaction was largely unaffected. The reverse transcriptase-polymerase chain reaction analyses of long-term renal allografts before and after donor-specific antigen challenge revealed no changes in CD3 mRNA level, but showed up-regulation of CD25, interleukin (IL) 2, interferon (IFN) gamma, IL-4, and IL-10 mRNA in the early phase, suggesting the presence of alloreactive T cells in tolerant rats. At later time points, the expression of IFN-gamma declined rapidly, whereas IL-4 persisted, resulting in a reversal of IFN-gamma/IL-4 ratio. Our data demonstrate the stability of anti-CD4 mAb-induced tolerance despite persistence of alloreactive T cells, suggesting the role of active tolerance-maintaining mechanisms. The T helper (Th) 1/Th2 shift may be involved in this regulatory process, as anti-CD4 mAb prevents acute graft-deteriorating rejection by effectively blocking Th1 responses, and well-functioning grafts may tolerize themselves by inducing regulatory cells.