Anti-CD4 monoclonal antibody-induced tolerance to MHC-incompatible cardiac allografts maintained by CD4+ suppressor T cells that are not dependent upon IL-4.
Anti-CD4 mAb-induced tolerance to transplanted tissues has been proposed as due to down-regulation of Thl cells by preferential induction of Th2 cytokines, especially IL-4. This study examined the role of CD4+ cells and cytokines in tolerance to fully allogeneic PVG strain heterotopic cardiac allografts induced in naive DA rats by treatment with MRC Ox38, a nondepleting anti-CD4 mAb. All grafts survived >100 days but had a minor mononuclear cell infiltrate that increased mRNA for the Thl cytokines IL-2, IFN-gamma, and TNF-beta, but not for Th2 cytokines IL-4 and IL-6 or the cytolytic molecules perforin and granzyme A. These hosts accepted PVG skin grafts but rejected third-party grafts, which were not blocked by anti-IL-4 mAb. Cells from these tolerant hosts proliferated in MLC and produced IL-2, IFN-gamma, and IL-4 at levels equivalent to naive cells. Unfractionated and CD4+ T cells, but not CD8+ T cells, transferred specific tolerance to irradiated heart grafted hosts and inhibited reconstitution of rejection by cotransferred naive cells. This transfer of tolerance was associated with normal induction of IL-2 and delayed induction of IFN-gamma, but not with increased IL-4 or IL-10 mRNA. Transfer of tolerance was also not inhibited by anti-IL-4 mAb. This study demonstrated that tolerance induced by a nondepleting anti-CD4 mAb is maintained by a CD4+ suppressor T cell that is not associated with preferential induction of Th2 cytokines or the need for IL-4; nor is it associated with an inability to induce Th1 cytokines or anergy.
Hall
B M
BM
Department of Medicine, University of New South Wales, Liverpool Hospital, New South Wales, Australia. b.hall@unsw.edu.au
Fava
L
L
Chen
J
J
Plain
K M
KM
Boyd
R A
RA
Spicer
S T
ST
Berger
M F
MF
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015704:CD4 Antigens / Q000096:biosynthesis / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D006648:Histocompatibility / Q000276:immunology*; D007108:Immune Tolerance; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D008198:Lymph Nodes / Q000166:cytology / Q000637:transplantation; D017710:Lymphocyte Transfusion; D051379:Mice; D008807:Mice, Inbred BALB C; D011828:Radiation Chimera; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D016038:Skin Transplantation / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000637:transplantation; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D016042:Transplantation, Heterotopic / Q000276:immunology
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D015847:Interleukin-4