Long-term acceptance of major histocompatibility complex-mismatched cardiac allograft induced by a low dose of CTLA4IgM plus FK506.
The immunosuppressant FK506 prolongs allograft survival. However, at therapeutic doses it has significant side effects. A fusion protein consisting of the extracellular portion of CTLA4 and the Fc portion of human IgG (CTLA4IgG) also prolongs allograft survival, but large doses of CTLA4IgG are required for the induction of cardiac allograft acceptance. Therefore, we constructed a pentameric form of a new CTLA4 fusion protein, CTLA4IgM. We tested whether low doses of CTLA4IgG or CTLA4IgM in combination with subtherapeutic doses of FK506 can prolong allograft survival in a synergistic fashion. C57BL/6 (H-2b) neonatal hearts were transplanted to CBA/J (H-2b) mice in a heterotopic, nonvascularized cardiac allograft model. The findings demonstrate that a combination of low doses of FK506 plus a pentameric form of CTLA4Ig, CTLA4IgM, leads to significant graft survival, while a combination of FK506 plus CTLA4IgG does not.
Yamada
A
A
Section of Immunopathogenesis, Hokkaido University, Japan.
Murakami
M
M
Ijima
K
K
Yagita
H
H
Okumura
K
K
Komatsu
S
S
Uede
T
T
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000494:pharmacology*; D060908:CTLA-4 Antigen; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006085:Graft Survival / Q000187:drug effects*; D006183:H-2 Antigens; D016027:Heart Transplantation / Q000276:immunology* / Q000401:mortality; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007959:Lymphocyte Culture Test, Mixed; D008285:Major Histocompatibility Complex / Q000276:immunology*; D051379:Mice; D008808:Mice, Inbred CBA; D016019:Survival Analysis; D016559:Tacrolimus / Q000494:pharmacology*; D014184:Transplantation, Homologous
D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D006183:H-2 Antigens; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D000069594:Abatacept; D016559:Tacrolimus