Search tips
Search criteria 


Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. 1996 July 1; 98(1): 70–77.
PMCID: PMC507402

Induction of circulating myelin basic protein and proteolipid protein-specific transforming growth factor-beta1-secreting Th3 T cells by oral administration of myelin in multiple sclerosis patients.


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 triggered by oral administration of antigen 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. Here, we investigated whether in MS patients oral myelin treatment, containing both myelin basic protein (MBP) and proteolipid protein (PLP), induced antigen specific MBP or PLP reactive T cells that either secreted IL4, TGF-beta1, or alternatively did Th1 type sensitization occur as measured by IFN-gamma secretion. Specifically, 4,860 short-term T cell lines were generated to either MBP, PLP, or tetanus toxoid (TT) from 34 relapsing-remitting MS patients: 17 orally treated with bovine myelin daily for a minimum of 2 yr as compared to 17 nontreated patients. We found a marked increase in the relative frequencies of both MBP and PLP specific TGF-beta1-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 change in the frequency of MBP or PLP specific IFN-gamma or TT specific TGF-beta1 secreting T cells were observed. These results suggest that the oral administration of antigens generates antigen specific TGF-beta1 secreting Th3 cells of presumed mucosal origin that represent a distinct lineage of T cells. Since antigen-specific TGF-beta1 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.

Full Text

The Full Text of this article is available as a PDF (233K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • McFarlin DE, McFarland HF. Multiple sclerosis (first of two parts). N Engl J Med. 1982 Nov 4;307(19):1183–1188. [PubMed]
  • Hafler DA, Weiner HL. Immunologic mechanisms and therapy in multiple sclerosis. Immunol Rev. 1995 Apr;144:75–107. [PubMed]
  • Zamvil S, Nelson P, Trotter J, Mitchell D, Knobler R, Fritz R, Steinman L. T-cell clones specific for myelin basic protein induce chronic relapsing paralysis and demyelination. Nature. 317(6035):355–358. [PubMed]
  • Tuohy VK, Sobel RA, Lees MB. Myelin proteolipid protein-induced experimental allergic encephalomyelitis. Variations of disease expression in different strains of mice. J Immunol. 1988 Mar 15;140(6):1868–1873. [PubMed]
  • Linington C, Berger T, Perry L, Weerth S, Hinze-Selch D, Zhang Y, Lu HC, Lassmann H, Wekerle H. T cells specific for the myelin oligodendrocyte glycoprotein mediate an unusual autoimmune inflammatory response in the central nervous system. Eur J Immunol. 1993 Jun;23(6):1364–1372. [PubMed]
  • Khoury SJ, Hancock WW, Weiner HL. Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with downregulation of inflammatory cytokines and differential upregulation of transforming growth factor beta, interleukin 4, and prostaglandin E expression in the brain. J Exp Med. 1992 Nov 1;176(5):1355–1364. [PMC free article] [PubMed]
  • Higgins PJ, Weiner HL. Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein and its fragments. J Immunol. 1988 Jan 15;140(2):440–445. [PubMed]
  • Bitar DM, Whitacre CC. Suppression of experimental autoimmune encephalomyelitis by the oral administration of myelin basic protein. Cell Immunol. 1988 Apr 1;112(2):364–370. [PubMed]
  • Thompson HS, Staines NA. Gastric administration of type II collagen delays the onset and severity of collagen-induced arthritis in rats. Clin Exp Immunol. 1986 Jun;64(3):581–586. [PubMed]
  • Nagler-Anderson C, Bober LA, Robinson ME, Siskind GW, Thorbecke GJ. Suppression of type II collagen-induced arthritis by intragastric administration of soluble type II collagen. Proc Natl Acad Sci U S A. 1986 Oct;83(19):7443–7446. [PubMed]
  • Zhang ZY, Lee CS, Lider O, Weiner HL. Suppression of adjuvant arthritis in Lewis rats by oral administration of type II collagen. J Immunol. 1990 Oct 15;145(8):2489–2493. [PubMed]
  • Nussenblatt RB, Caspi RR, Mahdi R, Chan CC, Roberge F, Lider O, Weiner HL. Inhibition of S-antigen induced experimental autoimmune uveoretinitis by oral induction of tolerance with S-antigen. J Immunol. 1990 Mar 1;144(5):1689–1695. [PubMed]
  • Zhang ZJ, Davidson L, Eisenbarth G, Weiner HL. Suppression of diabetes in nonobese diabetic mice by oral administration of porcine insulin. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10252–10256. [PubMed]
  • Chen Y, Inobe J, Marks R, Gonnella P, Kuchroo VK, Weiner HL. Peripheral deletion of antigen-reactive T cells in oral tolerance. Nature. 1995 Jul 13;376(6536):177–180. [PubMed]
  • Whitacre CC, Gienapp IE, Orosz CG, Bitar DM. Oral tolerance in experimental autoimmune encephalomyelitis. III. Evidence for clonal anergy. J Immunol. 1991 Oct 1;147(7):2155–2163. [PubMed]
  • Friedman A, Weiner HL. Induction of anergy or active suppression following oral tolerance is determined by antigen dosage. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6688–6692. [PubMed]
  • Miller A, Lider O, Weiner HL. Antigen-driven bystander suppression after oral administration of antigens. J Exp Med. 1991 Oct 1;174(4):791–798. [PMC free article] [PubMed]
  • Chen Y, Kuchroo VK, Inobe J, Hafler DA, Weiner HL. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science. 1994 Aug 26;265(5176):1237–1240. [PubMed]
  • Chen Y, Inobe J, Kuchroo VK, Baron JL, Janeway CA, Jr, Weiner HL. Oral tolerance in myelin basic protein T-cell receptor transgenic mice: suppression of autoimmune encephalomyelitis and dose-dependent induction of regulatory cells. Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):388–391. [PubMed]
  • Weiner HL, Mackin GA, Matsui M, Orav EJ, Khoury SJ, Dawson DM, Hafler DA. Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis. Science. 1993 Feb 26;259(5099):1321–1324. [PubMed]
  • Trentham DE, Dynesius-Trentham RA, Orav EJ, Combitchi D, Lorenzo C, Sewell KL, Hafler DA, Weiner HL. Effects of oral administration of type II collagen on rheumatoid arthritis. Science. 1993 Sep 24;261(5129):1727–1730. [PubMed]
  • Hohol MJ, Khoury SJ, Cook SL, Orav EJ, Hafler DA, Weiner HL. Three-year open protocol continuation study of oral tolerization with myelin antigens in multiple sclerosis and design of a phase III pivotal trial. Ann N Y Acad Sci. 1996 Feb 13;778:243–250. [PubMed]
  • Chou FC, Chou CH, Shapira R, Kibler RF. Basis of microheterogeneity of myelin basic protein. J Biol Chem. 1976 May 10;251(9):2671–2679. [PubMed]
  • Bizzozero OA, Zuñiga G, Lees MB. Fatty acid composition of human myelin proteolipid protein in peroxisomal disorders. J Neurochem. 1991 Mar;56(3):872–878. [PubMed]
  • Miller A, Lider O, Roberts AB, Sporn MB, Weiner HL. Suppressor T cells generated by oral tolerization to myelin basic protein suppress both in vitro and in vivo immune responses by the release of transforming growth factor beta after antigen-specific triggering. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):421–425. [PubMed]
  • Lebman DA, Lee FD, Coffman RL. Mechanism for transforming growth factor beta and IL-2 enhancement of IgA expression in lipopolysaccharide-stimulated B cell cultures. J Immunol. 1990 Feb 1;144(3):952–959. [PubMed]
  • Wahl SM, McCartney-Francis N, Mergenhagen SE. Inflammatory and immunomodulatory roles of TGF-beta. Immunol Today. 1989 Aug;10(8):258–261. [PubMed]
  • Weiner HL, Friedman A, Miller A, Khoury SJ, al-Sabbagh A, Santos L, Sayegh M, Nussenblatt RB, Trentham DE, Hafler DA. Oral tolerance: immunologic mechanisms and treatment of animal and human organ-specific autoimmune diseases by oral administration of autoantigens. Annu Rev Immunol. 1994;12:809–837. [PubMed]
  • Husby S, Mestecky J, Moldoveanu Z, Holland S, Elson CO. Oral tolerance in humans. T cell but not B cell tolerance after antigen feeding. J Immunol. 1994 May 1;152(9):4663–4670. [PubMed]
  • Kojima K, Berger T, Lassmann H, Hinze-Selch D, Zhang Y, Gehrmann J, Reske K, Wekerle H, Linington C. Experimental autoimmune panencephalitis and uveoretinitis transferred to the Lewis rat by T lymphocytes specific for the S100 beta molecule, a calcium binding protein of astroglia. J Exp Med. 1994 Sep 1;180(3):817–829. [PMC free article] [PubMed]
  • Lehmann PV, Forsthuber T, Miller A, Sercarz EE. Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature. 1992 Jul 9;358(6382):155–157. [PubMed]
  • Zhang J, Markovic-Plese S, Lacet B, Raus J, Weiner HL, Hafler DA. Increased frequency of interleukin 2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. J Exp Med. 1994 Mar 1;179(3):973–984. [PMC free article] [PubMed]
  • Mosmann TR, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996 Mar;17(3):138–146. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation