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. 1996 Jul 1;98(1):70–77. doi: 10.1172/JCI118779

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.

H Fukaura 1, S C Kent 1, M J Pietrusewicz 1, S J Khoury 1, H L Weiner 1, D A Hafler 1
PMCID: PMC507402  PMID: 8690806

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 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.

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Selected References

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  1. Bitar D. M., Whitacre C. C. Suppression of experimental autoimmune encephalomyelitis by the oral administration of myelin basic protein. Cell Immunol. 1988 Apr 1;112(2):364–370. doi: 10.1016/0008-8749(88)90305-x. [DOI] [PubMed] [Google Scholar]
  2. Bizzozero O. A., Zuñiga G., Lees M. B. Fatty acid composition of human myelin proteolipid protein in peroxisomal disorders. J Neurochem. 1991 Mar;56(3):872–878. doi: 10.1111/j.1471-4159.1991.tb02003.x. [DOI] [PubMed] [Google Scholar]
  3. Chen Y., Inobe J., Kuchroo V. K., Baron J. L., Janeway C. A., Jr, Weiner H. L. 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. doi: 10.1073/pnas.93.1.388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chen Y., Inobe J., Marks R., Gonnella P., Kuchroo V. K., Weiner H. L. Peripheral deletion of antigen-reactive T cells in oral tolerance. Nature. 1995 Jul 13;376(6536):177–180. doi: 10.1038/376177a0. [DOI] [PubMed] [Google Scholar]
  5. Chen Y., Kuchroo V. K., Inobe J., Hafler D. A., Weiner H. L. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science. 1994 Aug 26;265(5176):1237–1240. doi: 10.1126/science.7520605. [DOI] [PubMed] [Google Scholar]
  6. Chou F. C., Chou C. H., Shapira R., Kibler R. F. Basis of microheterogeneity of myelin basic protein. J Biol Chem. 1976 May 10;251(9):2671–2679. [PubMed] [Google Scholar]
  7. Friedman A., Weiner H. L. 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. doi: 10.1073/pnas.91.14.6688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hafler D. A., Weiner H. L. Immunologic mechanisms and therapy in multiple sclerosis. Immunol Rev. 1995 Apr;144:75–107. doi: 10.1111/j.1600-065x.1995.tb00066.x. [DOI] [PubMed] [Google Scholar]
  9. Higgins P. J., Weiner H. L. 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] [Google Scholar]
  10. Hohol M. J., Khoury S. J., Cook S. L., Orav E. J., Hafler D. A., Weiner H. L. 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. doi: 10.1111/j.1749-6632.1996.tb21132.x. [DOI] [PubMed] [Google Scholar]
  11. Husby S., Mestecky J., Moldoveanu Z., Holland S., Elson C. O. Oral tolerance in humans. T cell but not B cell tolerance after antigen feeding. J Immunol. 1994 May 1;152(9):4663–4670. [PubMed] [Google Scholar]
  12. Khoury S. J., Hancock W. W., Weiner H. L. 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. doi: 10.1084/jem.176.5.1355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. 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. doi: 10.1084/jem.180.3.817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Lebman D. A., Lee F. D., Coffman R. L. 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] [Google Scholar]
  15. Lehmann P. V., Forsthuber T., Miller A., Sercarz E. E. Spreading of T-cell autoimmunity to cryptic determinants of an autoantigen. Nature. 1992 Jul 9;358(6382):155–157. doi: 10.1038/358155a0. [DOI] [PubMed] [Google Scholar]
  16. Linington C., Berger T., Perry L., Weerth S., Hinze-Selch D., Zhang Y., Lu H. C., 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. doi: 10.1002/eji.1830230627. [DOI] [PubMed] [Google Scholar]
  17. McFarlin D. E., McFarland H. F. Multiple sclerosis (first of two parts). N Engl J Med. 1982 Nov 4;307(19):1183–1188. doi: 10.1056/NEJM198211043071905. [DOI] [PubMed] [Google Scholar]
  18. Miller A., Lider O., Roberts A. B., Sporn M. B., Weiner H. L. 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. doi: 10.1073/pnas.89.1.421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Miller A., Lider O., Weiner H. L. Antigen-driven bystander suppression after oral administration of antigens. J Exp Med. 1991 Oct 1;174(4):791–798. doi: 10.1084/jem.174.4.791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Mosmann T. R., Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more. Immunol Today. 1996 Mar;17(3):138–146. doi: 10.1016/0167-5699(96)80606-2. [DOI] [PubMed] [Google Scholar]
  21. Nagler-Anderson C., Bober L. A., Robinson M. E., Siskind G. W., Thorbecke G. J. 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. doi: 10.1073/pnas.83.19.7443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Nussenblatt R. B., Caspi R. R., Mahdi R., Chan C. C., Roberge F., Lider O., Weiner H. L. 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] [Google Scholar]
  23. Thompson H. S., Staines N. A. 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. [PMC free article] [PubMed] [Google Scholar]
  24. Trentham D. E., Dynesius-Trentham R. A., Orav E. J., Combitchi D., Lorenzo C., Sewell K. L., Hafler D. A., Weiner H. L. Effects of oral administration of type II collagen on rheumatoid arthritis. Science. 1993 Sep 24;261(5129):1727–1730. doi: 10.1126/science.8378772. [DOI] [PubMed] [Google Scholar]
  25. Tuohy V. K., Sobel R. A., Lees M. B. 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] [Google Scholar]
  26. Wahl S. M., McCartney-Francis N., Mergenhagen S. E. Inflammatory and immunomodulatory roles of TGF-beta. Immunol Today. 1989 Aug;10(8):258–261. doi: 10.1016/0167-5699(89)90136-9. [DOI] [PubMed] [Google Scholar]
  27. Weiner H. L., Friedman A., Miller A., Khoury S. J., al-Sabbagh A., Santos L., Sayegh M., Nussenblatt R. B., Trentham D. E., Hafler D. A. 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. doi: 10.1146/annurev.iy.12.040194.004113. [DOI] [PubMed] [Google Scholar]
  28. Weiner H. L., Mackin G. A., Matsui M., Orav E. J., Khoury S. J., Dawson D. M., Hafler D. A. Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis. Science. 1993 Feb 26;259(5099):1321–1324. doi: 10.1126/science.7680493. [DOI] [PubMed] [Google Scholar]
  29. Whitacre C. C., Gienapp I. E., Orosz C. G., Bitar D. M. Oral tolerance in experimental autoimmune encephalomyelitis. III. Evidence for clonal anergy. J Immunol. 1991 Oct 1;147(7):2155–2163. [PubMed] [Google Scholar]
  30. 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. 1985 Sep 26-Oct 2Nature. 317(6035):355–358. doi: 10.1038/317355a0. [DOI] [PubMed] [Google Scholar]
  31. Zhang J., Markovic-Plese S., Lacet B., Raus J., Weiner H. L., Hafler D. A. 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. doi: 10.1084/jem.179.3.973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Zhang Z. J., Davidson L., Eisenbarth G., Weiner H. L. 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. doi: 10.1073/pnas.88.22.10252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Zhang Z. Y., Lee C. S., Lider O., Weiner H. L. Suppression of adjuvant arthritis in Lewis rats by oral administration of type II collagen. J Immunol. 1990 Oct 15;145(8):2489–2493. [PubMed] [Google Scholar]

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