Tolerance induction by anti-CD2 plus anti-CD3 monoclonal antibodies: evidence for an IL-4 requirement.
Anti-CD2 mAb plus anti-CD3 mAb induce alloantigen specific tolerance. We sought to determine whether Th2 cytokines are involved in the induction of tolerance in this model. Addition of anti-IL-4 mAb or anti-IL-10 mAb to anti-CD2 plus anti-CD3 treatment abrogated tolerance and resulted in graft survivals of 26+/-4 and 25+/-5 days, respectively. Splenocytes from the anti-IL-4 mAb and anti-IL-10 groups had greater proliferation in response to alloantigen than either tolerant or naive groups. Cytokine analysis of MLR supernatants showed increased IL-10 in the tolerant group and increased IFN-gamma in the anti-IL-4 mAb treated group. Donor-specific alloantibody responses in untreated immune animals had a predominantly Th1 (IgG2a) alloantibody response, while the tolerogenic regimen reduced the ratio of IgG2a:IgG1 titers. The addition of anti-IL-4 mAb to the tolerogenic regimen partly restored the Th1-related IgG2a response. Tolerance did not develop in IL-4 knockout animals treated with anti-CD2 plus anti-CD3 (mean graft survival, 27+/-5 days). Restoration of IL-4 to IL-4 knockout animals by gene transfer with plasmid DNA resulted in prolongation of survival to 46+/-7 days, while adoptive transfer of wild-type splenocytes into IL-4 knockout recipients resulted in indefinite graft survival (>60 days) and indefinite survival of second donor-type grafts. IL-10 gene transfer to IL-4 knockout recipients did not prolong graft survival (28+/-4). These results demonstrate that tolerance in this model is mediated at least in part by Th2-type cells that secrete IL-4, promote IL-10 and IgG1 production, and inhibit alloantigen reactivity.
Department of Surgery, University of Michigan, Ann Arbor 48109, USA.
J D
JD
Punch
T
T
Tono
L
L
Qin
D K
DK
Bishop
J S
JS
Bromberg
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D018801:CD2 Antigens / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D004357:Drug Synergism; D005260:Female; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007275:Injections, Intravenous; D016753:Interleukin-10 / Q000276:immunology; D015847:Interleukin-4 / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D007518:Isoantibodies / Q000096:biosynthesis; D007519:Isoantigens / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D018801:CD2 Antigens; D017252:CD3 Complex; D016207:Cytokines; D007518:Isoantibodies; D007519:Isoantigens; D016753:Interleukin-10; D015847:Interleukin-4