title: Treatment with nonmitogenic anti-CD3 monoclonal antibody induces CD4+ T cell unresponsiveness and functional reversal of established experimental autoimmune encephalomyelitis.
abstract: In vivo administration of anti-CD3 Ab induces both immune tolerance and undesirable side-effects resulting from nonspecific proinflammatory cytokine production. In the current study, we investigated the therapeutic potential of two structurally altered forms of the anti-CD3 Ab in ameliorating established experimental autoimmune encephalomyelitis. Administration of either a chimeric (NM-IgG3) or digestion product (NM-F(ab')2) form of the anti-CD3 Ab during established experimental autoimmune encephalomyelitis conferred significant protection from clinical disease progression and was associated with decreased Ag-specific T cell proliferation, cytokine production, and CNS inflammation. Interestingly, while this protection correlated with an increase in the frequency of CD4(+)CD25(+) regulatory T cells, neither prior depletion of regulatory T cells nor anti-TGF-beta treatment abrogated the treatment's efficacy. Importantly, both treatments induced normal levels of intracellular Ca(2+)-flux, but significantly diminished levels of TCR signaling. Consequent to this decreased level of TCR-mediated signaling were alterations in the level of apoptosis and CD4+ T cell trafficking resulting in a profound lymphopenia. Collectively, these results indicate that nonmitogenic anti-CD3 directly induces a state of immune unresponsiveness in primed pathogenic autoreactive effector cells via mechanisms that may involve the induction of T cell tolerance, apoptosis, and/or alterations in cell trafficking.
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Northwestern University Medical School, Chicago, IL 60611, USA.
authors.forename: Adam P
authors.initials: AP
authors.lastname: Kohm
authors.forename: Julie S
authors.initials: JS
authors.lastname: Williams
authors.forename: Allison L
authors.initials: AL
authors.lastname: Bickford
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: McMahon
authors.forename: Lucienne
authors.initials: L
authors.lastname: Chatenoud
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Bach
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Bluestone
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Miller
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000627:therapeutic use*; D017252:CD3 Complex / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020013:Calcium Signaling; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D005260:Female; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D016207:Cytokines; D011993:Recombinant Fusion Proteins