Increased in vivo mitogenicity of anti-TCR/CD3 monoclonal antibody through reduced interaction with Fcgamma receptors.
Since its initial clinical use in 1980, anti-TCR/CD3 monoclonal antibody (mAb) has been shown to be a potent immunosuppressive agent in the prevention of renal allograft rejections. However, toxic side effects caused by release of cytokines, predominantly from activated CD4+ T-cells, remain a major problem with the use of these reagents. Previous work has shown that this activation is mediated via antibody binding to Fcgamma receptors (FcgammaR) on host effector cells. In the present study, we have demonstrated in an in vivo mouse model that the anti-TCR/CD3 mouse mAb 7D6, as well as that from rat (17A2) and hamster (H57-597), induce a gradual depletion of host CD4+ T-cells without any apparent proliferative effects on the cells. In contrast, when treatment with these mAbs was combined with a mAb (2.4G2) that blocks the low-affinity Fcgamma receptors (FcgammaRII/III), we found that the in vivo actions of the anti-TCR/CD3 mAbs resulted in a significant expansion, rather than depletion, of CD4+ cells. The ability of 2.4G2 to reduce mAb 7D6-FcgammaR interaction was directly demonstrated in an in vitro assay system in which 2.4G2 partially suppressed 7D6-mediated T-cell responses. Taken together, our results have shown that some so-called "nonmitogenic" anti-TCR/CD3 mAbs in fact possess potent activating properties and that their mitogenic potential can be exposed by reducing their interaction with FcgammaR on host effector cells.
Kummer
U
U
GSF Institute of Molecular Immunology, Marchioninistr 25, D-81377, Munich, Germany. kummer@gsf.de
Zengerle
U
U
Pischel
J
J
Trautmann
B
B
Mailhammer
R
R
Sidell
N
N
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism* / Q000494:pharmacology*; D000961:Antilymphocyte Serum / Q000378:metabolism / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D005260:Female; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008212:Lymphocyte Depletion; D051379:Mice; D008808:Mice, Inbred CBA; D008934:Mitogens / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D017452:Receptors, IgG / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D000961:Antilymphocyte Serum; D017252:CD3 Complex; D007166:Immunosuppressive Agents; D008934:Mitogens; D011948:Receptors, Antigen, T-Cell; D017452:Receptors, IgG