Modulation of antigen-specific T cell response by a non-mitogenic anti-CD3 antibody.
Suppression of T cell response is the key to enhance graft survival and control autoimmune diseases. A mitogenic anti-CD3 monoclonal antibody (mAb), OKT3, has been used for decades to control acute rejection in organ transplantation. Although effective, the clinical use was limited by its side effects, such as cytokine release mediated by T cell activation. A low mitogenic humanized OKT3 with reduced FcR-binding (hgammaOKT3 Ala-Ala) was generated and tested in several clinical studies. Although hgammaOKT3 Ala-Ala demonstrated maintained efficacy and better safety it still activated T cells. To investigate if a non-mitogenic anti-CD3 mAb can be equally effective in immune suppression, a chimeric non-FcR-binding anti-mouse CD3 mAb (anti-CD3 IgG2a Ala-Ala) was generated. Unlike the hgammaOKT3 Ala-Ala, the mouse IgG2a Ala-Ala anti-CD3 mAb did not induce T cell activation as measured by proliferation, cytokine production and apoptosis. Nevertheless, the IgG2a Ala-Ala anti-CD3 mAb was equally effective in the inhibition of antigen-specific CD4+ T cell activation in vitro to that of the mitogenic anti-CD3 mAb (Anti-CD3 IgG2a). In vivo, the IgG2a Ala-Ala anti-CD3 mAb only induced transient reduction of peripheral and spleen T cells and did not trigger detectable cytokine release. Nonetheless, this non-mitogenic anti-CD3 mAb significantly prolonged islet graft survival as effectively as the mitogenic anti-CD3 mAb in an allogenic islet transplantation model. These results demonstrated that a non-mitogenic anti-CD3 mAb could be used as an effective immune modulator. It may also indicate that a true non-mitogenic version of OKT3 could further improve its safety profile for clinical use.
Li
Jian
J
Centocor Inc., 200 Great Valley Parkway, Malvern, PA 19355, United States. lli14@cntus.jnj.com
Davis
Janet
J
Bracht
Michelle
M
Carton
Jill
J
Armstrong
Jennifer
J
Gao
Wei
W
Scallon
Bernie
B
Fung
Ramie
R
Emmell
Eva
E
Zimmerman
Mark
M
Griswold
Don E
DE
Li
Li
L
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000601:surgery; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016853:Muromonab-CD3 / Q000494:pharmacology; D011485:Protein Binding; D011961:Receptors, Fc / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D020298:U937 Cells; D019014:fas Receptor / Q000378:metabolism
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D016207:Cytokines; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D016853:Muromonab-CD3; D011961:Receptors, Fc; D019014:fas Receptor