Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1994 Oct;94(4):1668–1672. doi: 10.1172/JCI117511

Interleukin-2 treatment potentiates induction of oral tolerance in a murine model of autoimmunity.

L V Rizzo 1, N E Miller-Rivero 1, C C Chan 1, B Wiggert 1, R B Nussenblatt 1, R R Caspi 1
PMCID: PMC295329  PMID: 7929845

Abstract

The present study addresses the feasibility of potentiating oral tolerance by immunomanipulation, using the murine model of experimental autoimmune uveoretinitis (EAU) induced by immunization with the retinal antigen interphotoreceptor retinoid binding protein (IRBP). Three feedings of 0.2 mg IRBP every other day before immunization did not protect against EAU, whereas a similar regimen of five doses was protective. However, supplementing the nonprotective 3x regimen with as little as one injection of 1,000 U of human recombinant interleukin-2 (IL-2) resulted in disease suppression that was equal to that of the protective 5x regimen. The protective effect was maintained across a range of IL-2 doses and times of administration; none of the IL-2 regimens tested resulted in disease enhancement. Peyer's Patch cells of 3x-fed and IL-2-treated mice showed greatly increased production of TGF-beta, IL-4, and IL-10 compared with animals given the nonprotective 3x regimen and to animals given the protective 5x regimen. We propose that IL-2 treatment enhances protection from EAU at least in part by stimulating production of antiinflammatory cytokines by regulatory cells in Payer's Patches. Moreover, the observed lymphokine production patterns suggest that whereas protection induced by the 3x + IL-2 regimen is likely to involve antiinflammatory cytokines, protection induced by the 5x regimen might involve anergy or deletion of the uveitogenic T cells. These results could have practical implications for use of IL-2 as a safe and effective way of potentiating oral tolerance.

Full text

PDF
1668

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Caspi R. R., Roberge F. G., Chan C. C., Wiggert B., Chader G. J., Rozenszajn L. A., Lando Z., Nussenblatt R. B. A new model of autoimmune disease. Experimental autoimmune uveoretinitis induced in mice with two different retinal antigens. J Immunol. 1988 Mar 1;140(5):1490–1495. [PubMed] [Google Scholar]
  2. Caspi R. R., Roberge F. G., McAllister C. G., el-Saied M., Kuwabara T., Gery I., Hanna E., Nussenblatt R. B. T cell lines mediating experimental autoimmune uveoretinitis (EAU) in the rat. J Immunol. 1986 Feb 1;136(3):928–933. [PubMed] [Google Scholar]
  3. Gregerson D. S., Obritsch W. F., Donoso L. A. Oral tolerance in experimental autoimmune uveoretinitis. Distinct mechanisms of resistance are induced by low dose vs high dose feeding protocols. J Immunol. 1993 Nov 15;151(10):5751–5761. [PubMed] [Google Scholar]
  4. 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]
  5. Lamont A. G., Bruce M. G., Watret K. C., Ferguson A. Suppression of an established DTH response to ovalbumin in mice by feeding antigen after immunization. Immunology. 1988 May;64(1):135–139. [PMC free article] [PubMed] [Google Scholar]
  6. Melamed D., Friedman A. Direct evidence for anergy in T lymphocytes tolerized by oral administration of ovalbumin. Eur J Immunol. 1993 Apr;23(4):935–942. doi: 10.1002/eji.1830230426. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. 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]
  9. Redmond T. M., Wiggert B., Robey F. A., Nguyen N. Y., Lewis M. S., Lee L., Chader G. J. Isolation and characterization of monkey interphotoreceptor retinoid-binding protein, a unique extracellular matrix component of the retina. Biochemistry. 1985 Jan 29;24(3):787–793. doi: 10.1021/bi00324a038. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. 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]
  12. Weiner H. L. Treatment of autoimmune diseases by oral tolerance to autoantigens. Autoimmunity. 1993;15 (Suppl):6–7. doi: 10.3109/08916939309008850. [DOI] [PubMed] [Google Scholar]
  13. 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]

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

RESOURCES