title: Induction of donor-specific unresponsiveness to cardiac allografts in rats by pretransplant anti-CD4 monoclonal antibody therapy.
abstract: In the present report a monoclonal antibody designated OX-38 directed against the rat CD4 molecule was tested for its ability to prolong the survival of heterotopic vascularized rat heart allografts transplanted across major histocompatibility barriers. Fluorescence-activated cell-sorter analysis showed that administration of OX-38 selectively depleted 80-95% of CD4+ cells from peripheral blood of treated rats. The immunosuppressive effects of OX-38 in vivo were verified by suppression of an antibody response against OX-38 itself as a heterologous protein immunogen. Recipient rats received OX-38 antibody as a single agent given in pretransplant regimens. Nine of 12 treated rats have maintained heterotopic abdominal heart allografts for greater than 175 days. Control rats that did not receive antibody therapy rejected their grafts within 14 days. Rats that maintained heart allografts for greater than 100 days accepted second donor strain hearts but rejected third-party heart grafts transplanted into the femoral space. Anti-CD4-induced allograft unresponsiveness persisted for at least 90 days following surgical removal of donor tissue and retransplantation of a second donor-matched heart. These results indicated that transient, pretransplant therapy with monoclonal antibodies directed against the CD4+ lymphocyte induced specific, long-lasting unresponsiveness to fully MHC-mismatched cardiac allografts in rats without additional immunosuppression.
authors.affiliation: Department of Medicine, Stanford University Medical Center, California 94305.
authors.forename: J A
authors.initials: JA
authors.lastname: Shizuru
authors.forename: K B
authors.initials: KB
authors.lastname: Seydel
authors.forename: T F
authors.initials: TF
authors.lastname: Flavin
authors.forename: A P
authors.initials: AP
authors.lastname: Wu
authors.forename: C C
authors.initials: CC
authors.lastname: Kong
authors.forename: E G
authors.initials: EG
authors.lastname: Hoyt
authors.forename: N
authors.initials: N
authors.lastname: Fujimoto
authors.forename: M E
authors.initials: ME
authors.lastname: Billingham
authors.forename: V A
authors.initials: VA
authors.lastname: Starnes
authors.forename: C G
authors.initials: CG
authors.lastname: Fathman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000917:Antibody Formation / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology; D015704:CD4 Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016827:CD8 Antigens; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D006649:Histocompatibility Antigens / Q000276:immunology; D007165:Immunosuppression Therapy; D008212:Lymphocyte Depletion; D008297:Male; D051381:Rats; D011912:Rats, Inbred ACI; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D000945:Antigens, Differentiation, T-Lymphocyte; D015704:CD4 Antigens; D016827:CD8 Antigens; D006649:Histocompatibility Antigens