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Differential functional effects of a humanized anti‐CD4 antibody on resting and activated human T cells
Author(s) -
BRETT S. J.,
ROWAN W.,
SMITH M.,
BARTHOLOMEW M.,
TITE J. P.
Publication year - 1997
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1046/j.1365-2567.1997.00265.x
Subject(s) - antibody , antigen , humanized antibody , microbiology and biotechnology , monoclonal antibody , biology , t cell receptor , t cell , immunology , immune system
A fully humanized immunoglobulin G1 (IgG1) anti‐CD4 monoclonal antibody is currently being evaluated in phase I/II clinical trials for rheumatoid arthritis. In order to understand the mode of action of this antibody in vivo , we have carried out a detailed functional analysis in vitro of the effects of this antibody on T‐cell activation. The anti‐CD4 antibody was found to inhibit both antigen‐specific responses involving recognition of human leucocyte antigen (HLA) class II and processed antigenic peptides as well as non‐class II dependent responses via anti‐CD3 antibodies. The antibody did not cause total blockade of T‐cell proliferation, but rather induced a shift in the dose–response curve, decreasing the sensitivity of cells to antigen or anti‐CD3‐mediated stimulation. The antibody appears to allow at least a partial early signal into the T cell as it does not inhibit the increase in tyrosine phosphorylation induced by anti‐CD3 antibodies. A comparison of the intact antibody with that of either the F(ab′) 2 fragment or an engineered non‐Fc receptor (FcR) binding form revealed that the intact antibody was the most effective at inhibiting proliferation of resting peripheral blood CD4 + T cells. However, this difference was only apparent when excess antibody was removed from culture prior to antigen or anti‐CD3 mediated stimulation. The intact antibody induced both CD4 down‐modulation and increases in CD4‐associated tyrosine phosphorylation of resting CD4 + T cells, which were not seen with the non‐FcR binding versions, which may account for the enhanced potency of the intact antibody at inhibiting T‐cell activation. Interestingly, the anti‐CD4 antibody induced a differential effect on activated CD4 + T cell clones compared with resting CD4 + T cells with respect to degree of CD4 cross‐linking required to induce functional effects in the T cell. Both intact and non‐FcR binding antibodies were equally effective at inhibiting T‐cell proliferation of activated T‐cell clones. In addition CD4 down‐modulation and increased CD4‐associated tyrosine phosphorylation were observed with T‐cell clones in the absence of secondary cross‐linking. Such observations may be of relevance when studying the effects of the antibody at sites of inflammation, where there will be CD4 + T cells of differing activation states as well as varying numbers of FcR positive cells.