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Proc Natl Acad Sci U S A. Jul 5, 1994; 91(14): 6688–6692.

Induction of anergy or active suppression following oral tolerance is determined by antigen dosage.


Oral tolerance was generated to hen egg white lysozyme in the mouse or to guinea pig myelin basic protein in the rat by a low-dose (1 mg) or a high-dose (5-20 mg) feeding regimen. High doses of antigen induced tolerance characterized by anergy with little or no active suppression and increased secretion of interleukin 4 (IL-4). Anergy was shown by an increase in frequency of IL-2-secreting cells following culture in recombinant IL-2. Low doses of antigen induced tolerance characterized by antigen-driven active suppression with increased secretion of transforming growth factor beta (TGF-beta) and IL-4 and minimal anergy. Without further immunization, spleen cells from animals orally tolerized by both regimens secreted increased levels of IL-4 and TGF-beta in an antigen-specific manner. Animals fed high doses secreted more IL-4 and less TGF-beta, whereas those fed low doses secreted more TGF-beta and less IL-4. These results demonstrate that the two feeding regimens induced cell populations that differed in their cytokine secretion profile and their capacity to actively suppress in vitro and to induce anergy. Our results provide a basis for distinguishing different forms of antigen-driven peripheral tolerance and have important implications for orally induced antigen-specific modulation of human autoimmune diseases.

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  • 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]
  • 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]
  • 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]
  • Challacombe SJ, Tomasi TB., Jr Systemic tolerance and secretory immunity after oral immunization. J Exp Med. 1980 Dec 1;152(6):1459–1472. [PMC free article] [PubMed]
  • Melamed D, Friedman A. Modification of the immune response by oral tolerance: antigen requirements and interaction with immunogenic stimuli. Cell Immunol. 1993 Feb;146(2):412–420. [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]
  • 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. [PMC free article] [PubMed]
  • Miller A, al-Sabbagh A, Santos LM, Das MP, Weiner HL. Epitopes of myelin basic protein that trigger TGF-beta release after oral tolerization are distinct from encephalitogenic epitopes and mediate epitope-driven bystander suppression. J Immunol. 1993 Dec 15;151(12):7307–7315. [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]
  • 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. [PubMed]
  • Taswell C. Limiting dilution assays for the determination of immunocompetent cell frequencies. I. Data analysis. J Immunol. 1981 Apr;126(4):1614–1619. [PubMed]
  • Nossal GJ. Immunologic tolerance: collaboration between antigen and lymphokines. Science. 1989 Jul 14;245(4914):147–153. [PubMed]
  • Gahring LC, Weigle WO. The regulatory effects of cytokines on the induction of a peripheral immunologic tolerance in mice. J Immunol. 1990 Sep 1;145(5):1318–1323. [PubMed]
  • Gregerson DS, Obritsch WF, Donoso LA. 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]
  • Mowat AM, Strobel S, Drummond HE, Ferguson A. Immunological responses to fed protein antigens in mice. I. Reversal of oral tolerance to ovalbumin by cyclophosphamide. Immunology. 1982 Jan;45(1):105–113. [PMC free article] [PubMed]
  • Hanson DG, Miller SD. Inhibition of specific immune responses by feeding protein antigens. V. Induction of the tolerant state in the absence of specific suppressor T cells. J Immunol. 1982 May;128(5):2378–2381. [PubMed]
  • Mattingly JA, Waksman BH. Immunologic suppression after oral administration of antigen. I. Specific suppressor cells formed in rat Peyer's patches after oral administration of sheep erythrocytes and their systemic migration. J Immunol. 1978 Nov;121(5):1878–1883. [PubMed]
  • Peng HJ, Turner MW, Strobel S. The generation of a 'tolerogen' after the ingestion of ovalbumin is time-dependent and unrelated to serum levels of immunoreactive antigen. Clin Exp Immunol. 1990 Sep;81(3):510–515. [PMC free article] [PubMed]
  • Bruce MG, Ferguson A. Oral tolerance induced by gut-processed antigen. Adv Exp Med Biol. 1987;216A:721–731. [PubMed]
  • Burstein HJ, Shea CM, Abbas AK. Aqueous antigens induce in vivo tolerance selectively in IL-2- and IFN-gamma-producing (Th1) cells. J Immunol. 1992 Jun 15;148(12):3687–3691. [PubMed]
  • Burstein HJ, Abbas AK. In vivo role of interleukin 4 in T cell tolerance induced by aqueous protein antigen. J Exp Med. 1993 Feb 1;177(2):457–463. [PMC free article] [PubMed]
  • Miller A, Zhang ZJ, Sobel RA, al-Sabbagh A, Weiner HL. Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein. VI. Suppression of adoptively transferred disease and differential effects of oral vs. intravenous tolerization. J Neuroimmunol. 1993 Jul;46(1-2):73–82. [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]
  • Peterson JD, Karpus WJ, Clatch RJ, Miller SD. Split tolerance of Th1 and Th2 cells in tolerance to Theiler's murine encephalomyelitis virus. Eur J Immunol. 1993 Jan;23(1):46–55. [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]
  • 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]
  • McCarron RM, Fallis RJ, McFarlin DE. Alterations in T cell antigen specificity and class II restriction during the course of chronic relapsing experimental allergic encephalomyelitis. J Neuroimmunol. 1990 Sep-Oct;29(1-3):73–79. [PubMed]
  • Cross AH, Tuohy VK, Raine CS. Development of reactivity to new myelin antigens during chronic relapsing autoimmune demyelination. Cell Immunol. 1993 Feb;146(2):261–269. [PubMed]
  • Harrison LC. Islet cell antigens in insulin-dependent diabetes: Pandora's box revisited. Immunol Today. 1992 Sep;13(9):348–352. [PubMed]

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