Synergy between subtherapeutic doses of cyclosporine and immunobiological manipulations in rat heart graft recipients.
Cyclosporine in combination with other chemical or biological immunosuppressive modalities has been useful in clinical and experimental organ transplantation. In these studies, the efficacy of adjunctive subtherapeutic doses of CsA given to immunologically enhanced heart graft recipients or to animals treated with an anti-IL-2 receptor monoclonal antibody (ART18) are described. Individually, the treatment entities are only partially effective. In rats undergoing active and passive enhancement alone, heart allograft survival was increased to 25 +/- 12 days in two-thirds, indefinitely in one-third. After ART18 treatment, grafts survive 21 +/- 1 days. Grafts are accepted permanently in animals receiving full-dose CsA (15 mg/kg X 7), but are rejected acutely (c. 7 days) when subtherapeutic doses (1.5 mg/kg X 7) are used. However, when subtherapeutic doses of CsA are given in combination with immunological enhancement or with interleukin-2-receptor-targeted therapy, graft survival increases dramatically, with permanent or markedly prolonged engraftment occurring in all instances. In the early phases of host unresponsiveness, both enhancement and IL-2R-targeted therapy, graft survival increases dramatically, with permanent or markedly prolonged engraftment occurring in all instances. In the early phases of host unresponsiveness, both enhancement and IL-2R-targeted therapy spare selectively T cells with suppressor activity in vivo; in enhanced animals, the W3/25+ subset is responsible for prolonged graft survival, the OX8+ fraction is responsible in ART18-treated animals and in CsA-treated animals. Both subpopulations show suppressor activity in the later stages of combination treatment. IL-3 production is increased significantly in these states of unresponsiveness, an observation also noted during maintenance CsA treatment; this seems to correlate with suppressor activity. Immunoperoxidase studies of the graft infiltrates emphasize the synergistic effects of combination treatments. Thus, subtherapeutic doses of CsA plus biologic host manipulations produce greatly increased graft survival by affecting selectively different host immune mechanisms.
Tilney
N L
NL
Surgical Research Laboratory, Harvard Medical School, Boston, Massachusetts.
Padberg
W M
WM
Lord
R H
RH
Araneda
D
D
Strom
T B
TB
Kupiec-Weglinski
J W
JW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000943:Antigens, Differentiation / Q000032:analysis; D003524:Cyclosporins / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D006085:Graft Survival; D016027:Heart Transplantation; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D007114:Immunization; D007116:Immunization, Passive; D007376:Interleukin-2 / Q000378:metabolism; D007377:Interleukin-3 / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011971:Receptors, Immunologic / Q000276:immunology*; D015375:Receptors, Interleukin-2; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; D003524:Cyclosporins; D000949:Histocompatibility Antigens Class II; D007376:Interleukin-2; D007377:Interleukin-3; D011971:Receptors, Immunologic; D015375:Receptors, Interleukin-2