Prolonged allograft survival in cynomolgus monkeys treated with a monoclonal antibody to the human type I interferon receptor and low doses of cyclosporine.
A monoclonal antibody (mAb) directed against the extracellular domain of the IFNAR1 chain of the human interferon-alpha (IFN-alpha) receptor (IFN-alphaR), which inhibits activation of the Jak-Stat signal transduction pathway, administered together with a subeffective dose of cyclosporine induced prolonged survival of skin allografts in major histocompatibility complex (MHC) divergent cynomolgus monkeys. Skin biopsies from animals treated with anti-IFN-alphaR mAb and cyclosporine revealed very low levels of MHC class I and class II antigen expression and the absence of histologic signs of rejection. Monkey antibodies (IgG) to the mouse antihuman IFN-alphaR mAb were not detected in the serum of any of the animals treated with the anti-IFN-alphaR mAb either alone or together with cyclosporine. The anti-IFN-alphaR mAb abrogated activation of the Jak-Stat signal transduction pathway in IFN-treated cells. These results, which show that selective and long-lasting immunosuppression can be obtained by short-term administration of an IFN-alpha antagonist together with a subeffective dose of cyclosporine, may have important implications for the therapy of human allograft rejection.
Benizri
E
E
Laboratoire de Recherches Chirurgicales, Université de Nice Sophia-Antipolis, France.
Gugenheim
J
J
Lasfar
A
A
Eid
P
P
Blanchard
B
B
Lallemand
C
C
Tovey
M G
MG
D000818:Animals; D000911:Antibodies, Monoclonal; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006085:Graft Survival; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects; D008252:Macaca fascicularis; D008565:Membrane Proteins; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D016038:Skin Transplantation; D013997:Time Factors; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; C507964:IFNAR1 protein, human; C508032:Ifnar1 protein, mouse; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D017471:Receptors, Interferon; D053633:Receptor, Interferon alpha-beta; D016572:Cyclosporine