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. 1991 Oct 1;174(4):791–798. doi: 10.1084/jem.174.4.791

Antigen-driven bystander suppression after oral administration of antigens

PMCID: PMC2118953  PMID: 1717632

Abstract

Suppression of experimental autoimmune encephalomyelitis (EAE) in Lewis rats by the oral administration of myelin basic protein (MBP) is mediated by CD8+ T cells that can be isolated from the spleens of MBP- fed animals. These cells adoptively transfer protection to naive animals subsequently immunized with MBP and complete Freund's adjuvant (CFA) and suppress in vitro MBP proliferative responses. Using a transwell system in which the modulator spleen cells from MBP-fed animals are separated by a semipermeable membrane from responder cells, MBP, or OVA-specific T cell lines, we have found that cell contact is not required for in vitro suppression to occur. In vitro suppression is dependent, however, upon antigen-specific triggering of modulator T cells. Once antigen-specific triggering occurs, suppression across the transwell is mediated by an antigen-nonspecific soluble factor that equally suppresses an MBP line or an ovalbumin (OVA) line. This phenomenon of antigen-driven bystander suppression was also demonstrated in vivo. Specifically, Lewis rats fed OVA which were then immunized with MBP/CFA plus OVA given separately subcutaneously were protected from EAE. Animals fed OVA and then immunized with MBP/CFA without OVA given subcutaneously were not protected. The protective effect of feeding OVA could be adoptively transferred by CD8+ T cells from OVA-fed animals into MBP/CFA plus OVA-injected animals. Feeding bovine serum albumin (BSA) or keyhole limpet hemocyanin did not suppress EAE in animals immunized with MBP/CFA plus OVA. EAE was suppressed, however, if BSA was fed and animals then immunized with MBP/CFA plus BSA given subcutaneously. Antigen-driven bystander suppression appears to be an important mechanism by which antigen- driven peripheral tolerance after oral administration of antigen is mediated, and presumably occurs in the microenvironment accounting for the antigen specificity of suppression generated by oral tolerization to antigens.

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Selected References

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  1. Aoki I., Usui M., Minami M., Dorf M. E. A genetically restricted suppressor factor that requires interaction with two distinct targets. J Immunol. 1984 Apr;132(4):1735–1740. [PubMed] [Google Scholar]
  2. Balkwill F. R., Burke F. The cytokine network. Immunol Today. 1989 Sep;10(9):299–304. doi: 10.1016/0167-5699(89)90085-6. [DOI] [PubMed] [Google Scholar]
  3. Ben-Nun A., Wekerle H., Cohen I. R. The rapid isolation of clonable antigen-specific T lymphocyte lines capable of mediating autoimmune encephalomyelitis. Eur J Immunol. 1981 Mar;11(3):195–199. doi: 10.1002/eji.1830110307. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Brackertz D., Mitchell G. F., Mackay I. R. Antigen-induced arthritis in mice. I. Induction of arthritis in various strains of mice. Arthritis Rheum. 1977 Apr;20(3):841–850. doi: 10.1002/art.1780200314. [DOI] [PubMed] [Google Scholar]
  6. Brackertz D., Mitchell G. F., Vadas M. A., Mackay I. R. Studies on antigen-induced arthritis in mice. III. Cell and serum transfer experiments. J Immunol. 1977 May;118(5):1645–1648. [PubMed] [Google Scholar]
  7. Brod S. A., al-Sabbagh A., Sobel R. A., Hafler D. A., Weiner H. L. Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin antigens: IV. Suppression of chronic relapsing disease in the Lewis rat and strain 13 guinea pig. Ann Neurol. 1991 Jun;29(6):615–622. doi: 10.1002/ana.410290608. [DOI] [PubMed] [Google Scholar]
  8. Cruikshank W. W., Berman J. S., Theodore A. C., Bernardo J., Center D. M. Lymphokine activation of T4+ T lymphocytes and monocytes. J Immunol. 1987 Jun 1;138(11):3817–3823. [PubMed] [Google Scholar]
  9. DUMONDE D. C., GLYNN L. E. The production of arthritis in rabbits by an immunological reaction to fibrin. Br J Exp Pathol. 1962 Aug;43:373–383. [PMC free article] [PubMed] [Google Scholar]
  10. Deibler G. E., Martenson R. E., Kies M. W. Large scale preparation of myelin basic protein from central nervous tissue of several mammalian species. Prep Biochem. 1972;2(2):139–165. doi: 10.1080/00327487208061467. [DOI] [PubMed] [Google Scholar]
  11. Dorf M. E., Benacerraf B. Suppressor cells and immunoregulation. Annu Rev Immunol. 1984;2:127–157. doi: 10.1146/annurev.iy.02.040184.001015. [DOI] [PubMed] [Google Scholar]
  12. Gautam A. M., Glynn P. Competition between foreign and self proteins in antigen presentation. Ovalbumin can inhibit activation of myelin basic protein-specific T cells. J Immunol. 1990 Feb 15;144(4):1177–1180. [PubMed] [Google Scholar]
  13. Gershon R. K., Kondo K. Infectious immunological tolerance. Immunology. 1971 Dec;21(6):903–914. [PMC free article] [PubMed] [Google Scholar]
  14. 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]
  15. Kappler J. W., Roehm N., Marrack P. T cell tolerance by clonal elimination in the thymus. Cell. 1987 Apr 24;49(2):273–280. doi: 10.1016/0092-8674(87)90568-x. [DOI] [PubMed] [Google Scholar]
  16. Kennedy M. K., Dal Canto M. C., Trotter J. L., Miller S. D. Specific immune regulation of chronic-relapsing experimental allergic encephalomyelitis in mice. J Immunol. 1988 Nov 1;141(9):2986–2993. [PubMed] [Google Scholar]
  17. Khoury S. J., Lider O., al-Sabbagh A., Weiner H. L. Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein. III. Synergistic effect of lipopolysaccharide. Cell Immunol. 1990 Dec;131(2):302–310. doi: 10.1016/0008-8749(90)90256-q. [DOI] [PubMed] [Google Scholar]
  18. Levine S., Sowinski R., Kies M. W. Treatment of experimental allergic encephalomyelitis with encephalitogenic basic proteins. Proc Soc Exp Biol Med. 1972 Feb;139(2):506–510. doi: 10.3181/00379727-139-36174. [DOI] [PubMed] [Google Scholar]
  19. Lider O., Santos L. M., Lee C. S., Higgins P. J., Weiner H. L. Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein. II. Suppression of disease and in vitro immune responses is mediated by antigen-specific CD8+ T lymphocytes. J Immunol. 1989 Feb 1;142(3):748–752. [PubMed] [Google Scholar]
  20. 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]
  21. 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]
  22. Rammensee H. G., Kroschewski R., Frangoulis B. Clonal anergy induced in mature V beta 6+ T lymphocytes on immunizing Mls-1b mice with Mls-1a expressing cells. Nature. 1989 Jun 15;339(6225):541–544. doi: 10.1038/339541a0. [DOI] [PubMed] [Google Scholar]
  23. Ramsdell F., Lantz T., Fowlkes B. J. A nondeletional mechanism of thymic self tolerance. Science. 1989 Nov 24;246(4933):1038–1041. doi: 10.1126/science.2511629. [DOI] [PubMed] [Google Scholar]
  24. Salgame P., Modlin R., Bloom B. R. On the mechanism of human T cell suppression. Int Immunol. 1989;1(2):121–129. doi: 10.1093/intimm/1.2.121. [DOI] [PubMed] [Google Scholar]
  25. Sriram S., Schwartz G., Steinman L. Administration of myelin basic protein-coupled spleen cells prevents experimental allergic encephalitis. Cell Immunol. 1983 Feb 1;75(2):378–382. doi: 10.1016/0008-8749(83)90335-0. [DOI] [PubMed] [Google Scholar]
  26. Tada T., Asano Y., Sano K. Present understanding of suppressor T cells. Res Immunol. 1989 Mar-Apr;140(3):291–345. doi: 10.1016/0923-2494(89)90064-3. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. Wisniewski H. M., Bloom B. R. Primary demyelination as a nonspecific consequence of a cell-mediated immune reaction. J Exp Med. 1975 Feb 1;141(2):346–359. doi: 10.1084/jem.141.2.346. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. 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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