Clonal deletion and clonal anergy mediated by antibodies to the human CD4 protein

Abstract

Monoclonal antibodies (mAbs) to the CD4 protein are potent immunosuppressive agents which were shown to induce long term survival of skin, heart and pancreatic islet allografts in murine models and to delay the rejection of skin and kidney allografts in monkeys (1). Treatment with anti-CD4 antibodies was also reported to prevent the progression of several spontaneous auto-immune diseases in mice (e.g. diabetes in the NOD mouse, lupus-like disease of NZB/NZW, BxSB and MLR/lpr strains). One remarkable effect of anti-CD4 antibodies is their capacity to induce long term tolerance to their own antigens and to foreign antigens presented during their administration (2–5). For all these reasons, numerous preliminary clinical trials have been initiated with murine or chimeric anti-CD4 antibodies in auto-immune or chronic inflammatory diseases such as psoriasis, inflammatory bowel diseases, multiple sclerosis, rheumatoid arthritis, vasculitis or polychondritis (6,7). Although nearly all these trials were not placebo-controled, some beneficial clinical effects were suggested and the side effects were reported to be minimal. However, in several recent trials, a very short course of humanized anti-CD4 antibodies was shown to induce long lasting profond CD4+ lymphocyte depletion, especially in patients who were treated with low doses of methotrexate or corticosteroids. Such side effect carries a risk of severe iatrogenic immunodeficiency which should not be acceptable in most clinical situations. Furthermore in some reports, CD4+ lymphocyte depletion was not associated with clinical improvement. Conversely, several murine mAbs were shown to induce clinical remissions without depleting circulating CD4+ cells. The efficacy of these non-depleting treatments have been extensively demonstrated in animal models (2, 8–10) but their mechanisms of action are still poorly understood. We therefore re-examined the effect of anti-CD4 mAbs on in vitro responses of normal peripheral blood lymphocytes to various stimuli, including allogeneic B cells in mixed lymphocyte cultures (MLC) and the superantigen staphylococcal enterotoxin B (SEB).