title: Human CD4 modulation in vivo induced by antibody treatment.
abstract: Clinical improvement after treatment with anti-CD4 antibodies has been documented in patients suffering from rheumatoid arthritis. This observation has stimulated the interest in effects induced by the in vivo application of anti-CD4 antibodies. Here, we have investigated features of CD4 modulation during and after anti-CD4 therapy with the monoclonal anti-body MAX.16H5. Depletion of circulating helper T cells was accompanied by modulation of the CD4 molecule down to 30% of the initial antigen density 1 hr after antibody infusion. However, despite the reappearance of CD4+ cells in the circulation CD4 remained down-modulated for up to 28 days without a significant residual anti-CD4 binding. Depletion of CD4+ cells as well as CD4 modulation were observed to a similar extent both in responders and non-responders to anti-CD4 therapy. Modulation of CD4 was more effective in vivo than in vitro with a mean reduction of CD4 density down to 46% in vitro. It was induced in varying degrees by all anti-CD4 antibodies investigated except for OKT4 and required viable monocytes in the case of MAX.16H5 and most of the anti-CD4 antibodies investigated. Supernatants from LPS-activated monocytes or the addition of monocytes that were freeze-fractioned or fixed monocytes did not substitute for this requirement. The effect was Fc-receptor dependent since F(ab)2 fragments of MAX.16H5 did not induce CD4 modulation. No significant co-modulation was found for a variety of T-cell surface antigens including CD2, CD3, CD8, CD45R, CD45RO, CD25, CDw29, and HLA-DR. In order to test functional effects, the influence of CD4 modulation on the increase of free cytosolic Ca2+ concentration ([Ca2+]i) stimulated via the T-cell receptor complex by an anti-CD3 antibody was studied. A significant inhibition was observed upon direct binding of anti-CD4 to its ligand. However, a diminished CD4 density alone as induced by in vivo modulation did not reduce, but rather enhanced the T cell receptor-mediated mobilization of [Ca2+]i in T cells of the patients. Taken together, no evidence was found that CD4 modulation per se could explain the beneficial effects of anti-CD4 therapy.
authors.affiliation: Institut für Klinische Immunologie und Rheumatologie, Universität of Erlangen-Nürnberg, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Horneff
authors.forename: A H
authors.initials: AH
authors.lastname: Guse
authors.forename: H
authors.initials: H
authors.lastname: Schulze-Koops
authors.forename: J R
authors.initials: JR
authors.lastname: Kalden
authors.forename: G R
authors.initials: GR
authors.lastname: Burmester
authors.forename: F
authors.initials: F
authors.lastname: Emmrich
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000906:Antibodies / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000628:therapy; D017252:CD3 Complex / Q000494:pharmacology; D015704:CD4 Antigens / Q000032:analysis / Q000276:immunology*; D002118:Calcium / Q000032:analysis / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008212:Lymphocyte Depletion; D009000:Monocytes / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000906:Antibodies; D017252:CD3 Complex; D015704:CD4 Antigens; D002118:Calcium