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. 1995 Aug 1;182(2):335–344. doi: 10.1084/jem.182.2.335

Prevention of experimental allergic encephalomyelitis in rats by targeting autoantigen to B cells: evidence that the protective mechanism depends on changes in the cytokine response and migratory properties of the autoantigen-specific T cells

PMCID: PMC2192149  PMID: 7543135

Abstract

Previous experiments from this laboratory have shown that Lewis rats were protected from experimental allergic encephalomyelitis (EAE) induced by the injection of myelin basic protein (MBP) in Freund's complete adjuvant if they were treated with the encephalitogenic peptide of MBP covalently linked to mouse anti-rat immunoglobulin (Ig) D. It was suggested that this protection developed because the antibody- peptide conjugate targeted the peptide to B cells and that this mode of presentation induced a Th2-like T cell response that controlled the concomitant encephalitogenic Th1 reaction to the autoantigen. The current experiments were carried out to test this hypothesis and to examine the alternative explanation for the protective effect of the conjugate pretreatment, namely that it induced a state of nonresponsiveness in the autoantigenspecific T cells. It was shown that EAE induction was suppressed in Lewis rats when the antibody-peptide conjugate was injected intravenously 14 and 7 d before immunization with MBP in adjuvant, but that anti-MBP antibody titers were at least as high in these animals as in controls that were not pretreated with the conjugate before immunization. Lymph node cells from these pretreated animals, while proliferating in vitro to MBP as vigorously as those from controls, produced less interferon gamma and were very inferior in their ability to transfer disease after this in vitro activation. In contrast, these same lymph node cells from protected rats generated markedly increased levels of messenger RNA for interleukin (IL)-4 and IL-13. When these in vitro experiments were repeated using the encephalitogenic peptide rather than MBP as the stimulus, the proliferative response of lymph node cells from pretreated donors was less than that from controls but was still readily detectable in the majority of experiments. Furthermore, the cytokine expression induced by the peptide was similar to that elicited by whole MBP. While these results support the original hypothesis that the anti-IgD-peptide conjugate pretreatment protected rats from EAE by inducing a Th2-type cytokine response, a totally unexpected finding was that this pretreatment greatly reduced the level of leukocyte infiltration into the central nervous system. This result provides a direct explanation for the protective effect of the pretreatment, but it raises questions regarding migratory and homing patterns of leukocytes activated by different immunological stimuli.

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Selected References

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  1. Ando D. G., Clayton J., Kono D., Urban J. L., Sercarz E. E. Encephalitogenic T cells in the B10.PL model of experimental allergic encephalomyelitis (EAE) are of the Th-1 lymphokine subtype. Cell Immunol. 1989 Nov;124(1):132–143. doi: 10.1016/0008-8749(89)90117-2. [DOI] [PubMed] [Google Scholar]
  2. Barclay A. N. The localization of populations of lymphocytes defined by monoclonal antibodies in rat lymphoid tissues. Immunology. 1981 Apr;42(4):593–600. [PMC free article] [PubMed] [Google Scholar]
  3. Brideau R. J., Carter P. B., McMaster W. R., Mason D. W., Williams A. F. Two subsets of rat T lymphocytes defined with monoclonal antibodies. Eur J Immunol. 1980 Aug;10(8):609–615. doi: 10.1002/eji.1830100807. [DOI] [PubMed] [Google Scholar]
  4. Chatelain R., Varkila K., Coffman R. L. IL-4 induces a Th2 response in Leishmania major-infected mice. J Immunol. 1992 Feb 15;148(4):1182–1187. [PubMed] [Google Scholar]
  5. Cher D. J., Mosmann T. R. Two types of murine helper T cell clone. II. Delayed-type hypersensitivity is mediated by TH1 clones. J Immunol. 1987 Jun 1;138(11):3688–3694. [PubMed] [Google Scholar]
  6. Day M. J., Tse A. G., Puklavec M., Simmonds S. J., Mason D. W. Targeting autoantigen to B cells prevents the induction of a cell-mediated autoimmune disease in rats. J Exp Med. 1992 Mar 1;175(3):655–659. doi: 10.1084/jem.175.3.655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dijkstra C. D., Döpp E. A., Joling P., Kraal G. The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in the rat recognized by monoclonal antibodies ED1, ED2 and ED3. Immunology. 1985 Mar;54(3):589–599. [PMC free article] [PubMed] [Google Scholar]
  8. Eynon E. E., Parker D. C. Parameters of tolerance induction by antigen targeted to B lymphocytes. J Immunol. 1993 Sep 15;151(6):2958–2964. [PubMed] [Google Scholar]
  9. Eynon E. E., Parker D. C. Small B cells as antigen-presenting cells in the induction of tolerance to soluble protein antigens. J Exp Med. 1992 Jan 1;175(1):131–138. doi: 10.1084/jem.175.1.131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Finkelman F. D., Ohara J., Goroff D. K., Smith J., Villacreses N., Mond J. J., Paul W. E. Production of BSF-1 during an in vivo, T-dependent immune response. J Immunol. 1986 Nov 1;137(9):2878–2885. [PubMed] [Google Scholar]
  11. Finkelman F. D., Snapper C. M., Mountz J. D., Katona I. M. Polyclonal activation of the murine immune system by a goat antibody to mouse IgD. IX. Induction of a polyclonal IgE response. J Immunol. 1987 May 1;138(9):2826–2830. [PubMed] [Google Scholar]
  12. Fiorentino D. F., Bond M. W., Mosmann T. R. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med. 1989 Dec 1;170(6):2081–2095. doi: 10.1084/jem.170.6.2081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gajewski T. F., Fitch F. W. Differential activation of murine TH1 and TH2 clones. Res Immunol. 1991 Jan;142(1):19–23. doi: 10.1016/0923-2494(91)90005-4. [DOI] [PubMed] [Google Scholar]
  14. Gajewski T. F., Pinnas M., Wong T., Fitch F. W. Murine Th1 and Th2 clones proliferate optimally in response to distinct antigen-presenting cell populations. J Immunol. 1991 Mar 15;146(6):1750–1758. [PubMed] [Google Scholar]
  15. Gajewski T. F., Schell S. R., Nau G., Fitch F. W. Regulation of T-cell activation: differences among T-cell subsets. Immunol Rev. 1989 Oct;111:79–110. doi: 10.1111/j.1600-065x.1989.tb00543.x. [DOI] [PubMed] [Google Scholar]
  16. Gillis S., Ferm M. M., Ou W., Smith K. A. T cell growth factor: parameters of production and a quantitative microassay for activity. J Immunol. 1978 Jun;120(6):2027–2032. [PubMed] [Google Scholar]
  17. Hashim G. A. Myelin basic protein: structure, function and antigenic determinants. Immunol Rev. 1978;39:60–107. doi: 10.1111/j.1600-065x.1978.tb00397.x. [DOI] [PubMed] [Google Scholar]
  18. Hinrichs D. J., Roberts C. M., Waxman F. J. Regulation of paralytic experimental allergic encephalomyelitis in rats: susceptibility to active and passive disease reinduction. J Immunol. 1981 May;126(5):1857–1862. [PubMed] [Google Scholar]
  19. Hsiung L., Barclay A. N., Brandon M. R., Sim E., Porter R. R. Purification of human C3b inactivator by monoclonal-antibody affinity chromatography. Biochem J. 1982 Apr 1;203(1):293–298. doi: 10.1042/bj2030293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Issekutz T. B., Stoltz J. M., vd Meide P. Lymphocyte recruitment in delayed-type hypersensitivity. The role of IFN-gamma. J Immunol. 1988 May 1;140(9):2989–2993. [PubMed] [Google Scholar]
  21. Lakkis F. G., Cruet E. N. Cloning of rat interleukin-13 (IL-13) cDNA and analysis of IL-13 gene expression in experimental glomerulonephritis. Biochem Biophys Res Commun. 1993 Dec 15;197(2):612–618. doi: 10.1006/bbrc.1993.2523. [DOI] [PubMed] [Google Scholar]
  22. MacPhee I. A., Antoni F. A., Mason D. W. Spontaneous recovery of rats from experimental allergic encephalomyelitis is dependent on regulation of the immune system by endogenous adrenal corticosteroids. J Exp Med. 1989 Feb 1;169(2):431–445. doi: 10.1084/jem.169.2.431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mason D. Genetic variation in the stress response: susceptibility to experimental allergic encephalomyelitis and implications for human inflammatory disease. Immunol Today. 1991 Feb;12(2):57–60. doi: 10.1016/0167-5699(91)90158-P. [DOI] [PubMed] [Google Scholar]
  24. McKnight A. J., Barclay A. N., Mason D. W. Molecular cloning of rat interleukin 4 cDNA and analysis of the cytokine repertoire of subsets of CD4+ T cells. Eur J Immunol. 1991 May;21(5):1187–1194. doi: 10.1002/eji.1830210514. [DOI] [PubMed] [Google Scholar]
  25. McMaster W. R., Williams A. F. Identification of Ia glycoproteins in rat thymus and purification from rat spleen. Eur J Immunol. 1979 Jun;9(6):426–433. doi: 10.1002/eji.1830090603. [DOI] [PubMed] [Google Scholar]
  26. Morris S. C., Lees A., Finkelman F. D. In vivo activation of naive T cells by antigen-presenting B cells. J Immunol. 1994 Apr 15;152(8):3777–3785. [PubMed] [Google Scholar]
  27. Mosmann T. R., Coffman R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045. [DOI] [PubMed] [Google Scholar]
  28. Pezzella F., Tse A. G., Cordell J. L., Pulford K. A., Gatter K. C., Mason D. Y. Expression of the bcl-2 oncogene protein is not specific for the 14;18 chromosomal translocation. Am J Pathol. 1990 Aug;137(2):225–232. [PMC free article] [PubMed] [Google Scholar]
  29. Powrie F., Menon S., Coffman R. L. Interleukin-4 and interleukin-10 synergize to inhibit cell-mediated immunity in vivo. Eur J Immunol. 1993 Nov;23(11):3043–3049. doi: 10.1002/eji.1830231147. [DOI] [PubMed] [Google Scholar]
  30. Racke M. K., Bonomo A., Scott D. E., Cannella B., Levine A., Raine C. S., Shevach E. M., Röcken M. Cytokine-induced immune deviation as a therapy for inflammatory autoimmune disease. J Exp Med. 1994 Nov 1;180(5):1961–1966. doi: 10.1084/jem.180.5.1961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Raine C. S. Biology of disease. Analysis of autoimmune demyelination: its impact upon multiple sclerosis. Lab Invest. 1984 Jun;50(6):608–635. [PubMed] [Google Scholar]
  32. Sadick M. D., Heinzel F. P., Holaday B. J., Pu R. T., Dawkins R. S., Locksley R. M. Cure of murine leishmaniasis with anti-interleukin 4 monoclonal antibody. Evidence for a T cell-dependent, interferon gamma-independent mechanism. J Exp Med. 1990 Jan 1;171(1):115–127. doi: 10.1084/jem.171.1.115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Scott P., Pearce E., Cheever A. W., Coffman R. L., Sher A. Role of cytokines and CD4+ T-cell subsets in the regulation of parasite immunity and disease. Immunol Rev. 1989 Dec;112:161–182. doi: 10.1111/j.1600-065x.1989.tb00557.x. [DOI] [PubMed] [Google Scholar]
  34. Sedgwick J. D., Mason D. W. The mechanism of inhibition of experimental allergic encephalomyelitis in the rat by monoclonal antibody against CD4. J Neuroimmunol. 1986 Dec;13(2):217–232. doi: 10.1016/0165-5728(86)90066-4. [DOI] [PubMed] [Google Scholar]
  35. Sedgwick J., Brostoff S., Mason D. Experimental allergic encephalomyelitis in the absence of a classical delayed-type hypersensitivity reaction. Severe paralytic disease correlates with the presence of interleukin 2 receptor-positive cells infiltrating the central nervous system. J Exp Med. 1987 Apr 1;165(4):1058–1075. doi: 10.1084/jem.165.4.1058. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Swain S. L., Bradley L. M., Croft M., Tonkonogy S., Atkins G., Weinberg A. D., Duncan D. D., Hedrick S. M., Dutton R. W., Huston G. Helper T-cell subsets: phenotype, function and the role of lymphokines in regulating their development. Immunol Rev. 1991 Oct;123:115–144. doi: 10.1111/j.1600-065x.1991.tb00608.x. [DOI] [PubMed] [Google Scholar]
  37. Williams A. F., Galfrè G., Milstein C. Analysis of cell surfaces by xenogeneic myeloma-hybrid antibodies: differentiation antigens of rat lymphocytes. Cell. 1977 Nov;12(3):663–673. doi: 10.1016/0092-8674(77)90266-5. [DOI] [PubMed] [Google Scholar]
  38. Zurawski G., de Vries J. E. Interleukin 13, an interleukin 4-like cytokine that acts on monocytes and B cells, but not on T cells. Immunol Today. 1994 Jan;15(1):19–26. doi: 10.1016/0167-5699(94)90021-3. [DOI] [PubMed] [Google Scholar]
  39. van der Veen R. C., Kapp J. A., Trotter J. L. Fine-specificity differences in the recognition of an encephalitogenic peptide by T helper 1 and 2 cells. J Neuroimmunol. 1993 Nov-Dec;48(2):221–226. doi: 10.1016/0165-5728(93)90195-5. [DOI] [PubMed] [Google Scholar]

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