Induction of donor specific transplantation tolerance to cardiac allografts following treatment with nondepleting (RIB 5/2) or depleting (OX-38) anti-CD4 mAb plus intrathymic or intravenous donor alloantigen.
The nondepleting monoclonal antirat CD4 antibody, RIB 5/2, has been shown to modulate, but not eliminate, the CD4+ T cells and to prolong survival of rat skin, renal, or cardiac allografts when serially administered after transplantation. In the present study, we compared the efficacy of recipient pretreatment with a single dose of nondepleting RIB 5/2 or depleting OX-38 anti-CD4 monoclonal antibody plus donor alloantigen given intravenously or intrathymically 21 days before transplantation on the survival of completely MHC-mismatched rat cardiac allografts. Intraperitoneal injection of a single dose (20 mg/kg) of RIB 5/2 resulted in a decrease in CD4 surface molecule expression on peripheral CD4+ T cells without cell elimination as shown by FACS analysis. The nonspecific effect of a single dose of RIB 5/2 mAb had resolved by 21 days after treatment as evidenced by the almost complete recovery of normal surface CD4 molecule expression. Cardiac allografts transplanted immediately or 21 days after a single dose of RIB 5/2 alone were uniformly acutely rejected. On the other hand, recipients treated with depleting anti-CD4 OX-38 (20 mg/kg) acutely rejected cardiac allografts transplanted 21 days later, but indefinitely accepted all grafts transplanted on the same day. In contrast, combined treatment with i.v. donor splenocytes (25 x 10(6)) plus nondepleting RIB 5/2, but not with depleting anti-CD4 mAb, OX-38, resulted in survival for more than 100 days in 75% of recipients of donor specific, but not third party, cardiac allografts transplanted 21 days later. Irradiation (3000 rads) of the i.v. donor splenocytes combined with RIB 5/2 abrogated their tolerizing effect. When donor antigen was given intrathymically, both RIB 5/2 and OX-38 resulted in indefinite tolerance to cardiac allografts transplanted 21 days later. The failure of exogenous administration of high dose (180,000 IU/injection) rIL-2 for 10 days to reverse the unresponsiveness of i.v. SC plus RIB 5/2 pretreatment suggests that this tolerant state is not due to a deficiency of IL-2. In vitro studies showed marked inhibition of MLC responsiveness and cytolytic T cell activity in tolerant recipients that cannot be reversed by the addition of IL-2. Thus, pretransplant intravenous donor alloantigen combined with a dose of nondepleting anti-CD4 mAb, RIB 5/2, which alone has no significant effect, induced donor specific cardiac allograft tolerance.
Arima
T
T
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
Lehmann
M
M
Flye
M W
MW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015704:CD4 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D007165:Immunosuppression Therapy / Q000379:methods*; D007376:Interleukin-2 / Q000494:pharmacology; D007519:Isoantigens / Q000008:administration & dosage / Q000627:therapeutic use*; D008212:Lymphocyte Depletion; D008297:Male; D051381:Rats; D011912:Rats, Inbred ACI; D011914:Rats, Inbred BN; D011915:Rats, Inbred BUF; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013950:Thymus Gland; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D007376:Interleukin-2; D007519:Isoantigens; D011994:Recombinant Proteins