title: Oral administration of myelin induces antigen-specific TGF-beta 1 secreting T cells in patients with multiple sclerosis.
abstract: Oral administration of antigen is a long-recognized method of inducing systemic immune tolerance. In animals with experimental autoimmune disease, a major mechanism of oral tolerance involves the induction of regulatory T cells that mediate active suppression by secreting the cytokine TGF-beta 1. Multiple sclerosis (MS) is a presumed T cell-mediated Th1 type autoimmune disease. In this paper we investigated, in patients with MS, whether oral myelin treatment (myelin containing both MBP and PLP) induced antigen-specific MBP- or PLP-reactive T cells that were either Th2-like (secreted IL-4 or TGF-beta 1), or alternatively whether Th1 type sensitization occurred as measured by IFN-gamma secretion. Specifically, 4,860 short-term T cell lines were generated to either MBP, PLP or TT from 34 relapsing-remitting patients with MS; 17 were orally treated with bovine myelin daily for a minimum of two years as compared to 17 non-treated patients. We found a marked increase in the relative frequencies of both MBP- and PLP-specific TGF-beta 1 secreting T cell lines in the myelin-treated MS patients as compared to non-treated MS patients (MBP, p < 0.001; PLP, p < 0.003). In contrast, no changes in the frequency of MBP- or PLP-specific IFN-gamma or TT-specific TGF-beta 1 secreting T cells were observed. These results suggest that the oral administration of antigens generates antigen-specific TGF-beta 1 secreting T cells of presumed mucosal origin that may represent a distinct cytokine-secreting lineage of T cells (Th3). Since, in animal models, antigen-specific TGF-beta 1 secreting cells localize to the target organ and then suppress inflammation in the local microenvironment, oral tolerization with self-antigens may provide a therapeutic approach for the treatment of cell-mediated autoimmune disease which does not depend upon knowledge of the antigen specificity of the original T cell clone triggering the autoimmune cascade.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. hafler@CND.BWH.Harvard.edu
authors.forename: D A
authors.initials: DA
authors.lastname: Hafler
authors.forename: S C
authors.initials: SC
authors.lastname: Kent
authors.forename: M J
authors.initials: MJ
authors.lastname: Pietrusewicz
authors.forename: S J
authors.initials: SJ
authors.lastname: Khoury
authors.forename: H L
authors.initials: HL
authors.lastname: Weiner
authors.forename: H
authors.initials: H
authors.lastname: Fukaura
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000941:Antigens / Q000032:analysis; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology; D004676:Myelin Basic Protein / Q000008:administration & dosage*; D018991:Myelin Proteolipid Protein / Q000008:administration & dosage*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000276:immunology* / Q000378:metabolism
chemical_list: D000941:Antigens; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D007371:Interferon-gamma