Anti-CD4 monoclonal antibody-induced allograft tolerance in rats despite persistence of donor-reactive T cells.
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.
Lehmann
M
M
Institute of Medical Biochemistry, University of Rostock, Germany.
Graser
E
E
Risch
K
K
Hancock
W W
WW
Müller
A
A
Kuttler
B
B
Hahn
H J
HJ
Kupiec-Weglinski
J W
JW
Brock
J
J
Volk
H D
HD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000235:genetics; D015870:Gene Expression; D006085:Graft Survival / Q000187:drug effects; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D007165:Immunosuppression Therapy; D016030:Kidney Transplantation / Q000276:immunology*; D008212:Lymphocyte Depletion; D008297:Male; D016133:Polymerase Chain Reaction / Q000379:methods; D012194:RNA-Directed DNA Polymerase; D051381:Rats; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D018417:Th1 Cells / Q000502:physiology; D018418:Th2 Cells / Q000502:physiology; D014184:Transplantation, Homologous / Q000276:immunology
D000911:Antibodies, Monoclonal; D016207:Cytokines; D012194:RNA-Directed DNA Polymerase