Sub-Areas to Oral Tolerization:
(Journal Article): Antigen-specific TGF-beta1 secretion with bovine myelin oral tolerization in multiple sclerosis.
Fukaura H, Kent SC, Pietrusewicz MJ, Khoury SJ, Weiner HL, Hafler DA (Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.)
IN:
Ann N Y Acad Sci
1996; 778:251-257
Impact Factor(s) of Ann N Y Acad Sci: 1.789 (2004), 1.892 (2003), 1.682 (2002), 1.593 (2001)
ABSTRACT: Multiple sclerosis is a presumed autoimmune disease, associated with inflammation in the CNS white matter, mediated by autoreactive T cells. We previously reported that oral myelin tolerization of relapsing-remitting MS patients resulted in fewer attacks, as compared to a placebo-fed group. Here, we examined whether oral tolerization with bovine myelin resulted in altered autoreactive T-cell populations or altered T-cell fraction. We generated 4,620 T-cell lines from 34 relapsing-remitting MS patients (17 were fed bovine myelin daily), and each line was examined for proliferation to MBP, PLP, and TT and for secretion of IL-4, IFN-gamma, and TGF-beta1. The frequency of TGF-beta1-secreting T-cell lines after MBP and PLP stimulation in fed patients was greater than that of nonfed patients. These experiments demonstrate that oral tolerization with autoantigen results in altered cytokine secretion in a human autoimmune disease with the generation of TGF-beta1-secreting T cells that may regulate the inflammatory response at the site of the demyelinating lesions in multiple sclerosis. These data provide the first evidence of antigen-specific modification of cytokine secretion in a human autoimmune disease.
TYPE OF PUBLICATION: Original article
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(Journal Article): Oral administration of myelin induces antigen-specific TGF-beta 1 secreting T cells in patients with multiple sclerosis.
Hafler DA, Kent SC, Pietrusewicz MJ, Khoury SJ, Weiner HL, Fukaura H (Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.,
hafler@CND.BWH.Harvard.edu
)
IN:
Ann N Y Acad Sci
1997; 835:120-131
Impact Factor(s) of Ann N Y Acad Sci: 1.789 (2004), 1.892 (2003), 1.682 (2002), 1.593 (2001)
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.
TYPE OF PUBLICATION: Original article
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(Journal Article): Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis.
Chen Y, Kuchroo VK, Inobe J, Hafler DA, Weiner HL (Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.)
IN:
Science
1994; 265(5176):1237-1240
Impact Factor(s) of Science: 30.927 (2005), 31.853 (2004), 29.162 (2003), 26.682 (2002), 23.329 (2001)
ABSTRACT: Experimental autoimmune encephalomyelitis (EAE) is a cell-mediated autoimmune disease that serves as an animal model for multiple sclerosis. Oral administration of myelin basic protein (MBP) suppresses EAE by inducing peripheral tolerance. T cell clones were isolated from the mesenteric lymph nodes of SJL mice that had been orally tolerized to MBP. These clones were CD4+ and were structurally identical to T helper cell type 1 (TH1) encephalitogenic CD4+ clones in T cell receptor usage, major histocompatibility complex restriction, and epitope recognition. However, they produced transforming growth factor-beta with various amounts of interleukin-4 and interleukin-10 and suppressed EAE induced with either MBP or proteolipid protein. Thus, mucosally derived TH2-like clones induced by oral antigen can actively regulate immune responses in vivo and may represent a different subset of T cells.
TYPE OF PUBLICATION: Original article
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