Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1991 Apr 1;173(4):899–912. doi: 10.1084/jem.173.4.899

Induction of severe granulomatous experimental autoimmune thyroiditis in mice by effector cells activated in the presence of anti-interleukin 2 receptor antibody

PMCID: PMC2190797  PMID: 1672546

Abstract

Spleen cells from CBA/J mice immunized with mouse thyroglobulin (MTg) and the adjuvant lipopolysaccharide induce experimental autoimmune thyroiditis (EAT) after transfer to recipient mice if they are first activated in vitro with MTg. EAT induced by cells cultured with MTg is generally moderate in severity and is characterized by a thyroid infiltration consisting primarily of mononuclear cells. Addition of the anti-interleukin 2 receptor (IL-2R) monoclonal antibodies (mAbs) M7/20, 3C7, or 7D4 to spleen cell cultures with MTg resulted in a cell population capable of inducing a more severe type of EAT characterized by extensive follicular destruction, granuloma formation, and the presence of multinucleated giant cells. Recipients of cells cultured with MTg and anti-IL-2R mAb also had higher anti-MTg autoantibody responses than recipients of cells cultured with MTg alone. Activation of cells capable of transferring severe granulomatous EAT and increased anti-MTg autoantibody responses required both MTg and M7/20 in culture and required addition of M7/20 within the first 8 h of the 72-h culture period. CD4+ T cells were required for the expression of both the severe granulomatous EAT lesions and the mononuclear cell infiltrates typically observed in murine EAT. The increased anti-MTg autoantibody responses in recipients of cells cultured with MTg and anti-IL-2R mAbs were not restricted to a particular immunoglobulin G (IgG) subclass and included antibody of the IgG1, IgG2A, and IgG2B subclasses. These results suggest that a subset of CD4+ T cells capable of inducing severe granulomatous EAT and increased anti-MTg autoantibody responses is preferentially activated when cells are cultured in the presence of anti-IL-2R mAb. Anti-IL-2R mAb may either prevent activation of cells that induce classical lymphocytic EAT or prevent activation of cells that normally function to downregulate EAT effector T cell activity.

Full Text

The Full Text of this article is available as a PDF (1.7 MB).

Selected References

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

  1. Abbas A. K., Urioste S., Collins T. L., Boom W. H. Heterogeneity of helper/inducer T lymphocytes. IV. Stimulation of resting and activated B cells by Th1 and Th2 clones. J Immunol. 1990 Mar 15;144(6):2031–2037. [PubMed] [Google Scholar]
  2. Betz M., Fox B. S. Regulation and development of cytochrome c-specific IL-4-producing T cells. J Immunol. 1990 Aug 15;145(4):1046–1052. [PubMed] [Google Scholar]
  3. Braley-Mullen H., Johnson M., Sharp G. C., Kyriakos M. Induction of experimental autoimmune thyroiditis in mice with in vitro activated splenic T cells. Cell Immunol. 1985 Jun;93(1):132–143. doi: 10.1016/0008-8749(85)90394-6. [DOI] [PubMed] [Google Scholar]
  4. Charreire J. Immune mechanisms in autoimmune thyroiditis. Adv Immunol. 1989;46:263–334. doi: 10.1016/s0065-2776(08)60656-2. [DOI] [PubMed] [Google Scholar]
  5. Cohen S. B., Diamantstein T., Weetman A. P. The effect of T cell subset depletion on autoimmune thyroiditis in the Buffalo strain rat. Immunol Lett. 1990 Feb;23(4):263–268. doi: 10.1016/0165-2478(90)90070-7. [DOI] [PubMed] [Google Scholar]
  6. Daynes R. A., Araneo B. A. Contrasting effects of glucocorticoids on the capacity of T cells to produce the growth factors interleukin 2 and interleukin 4. Eur J Immunol. 1989 Dec;19(12):2319–2325. doi: 10.1002/eji.1830191221. [DOI] [PubMed] [Google Scholar]
  7. Diamantstein T., Eckert R., Volk H. D., Kupier-Weglinski J. W. Reversal by interferon-gamma of inhibition of delayed-type hypersensitivity induction by anti-CD4 or anti-interleukin 2 receptor (CD25) monoclonal antibodies. Evidence for the physiological role of the CD4+ TH1+ subset in mice. Eur J Immunol. 1988 Dec;18(12):2101–2103. doi: 10.1002/eji.1830181237. [DOI] [PubMed] [Google Scholar]
  8. Fernandez-Botran R., Sanders V. M., Mosmann T. R., Vitetta E. S. Lymphokine-mediated regulation of the proliferative response of clones of T helper 1 and T helper 2 cells. J Exp Med. 1988 Aug 1;168(2):543–558. doi: 10.1084/jem.168.2.543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Flynn J. C., Conaway D. H., Cobbold S., Waldmann H., Kong Y. C. Depletion of L3T4+ and Lyt-2+ cells by rat monoclonal antibodies alters the development of adoptively transferred experimental autoimmune thyroiditis. Cell Immunol. 1989 Sep;122(2):377–390. doi: 10.1016/0008-8749(89)90085-3. [DOI] [PubMed] [Google Scholar]
  10. Hahn H. J., Gerdes J., Lucke S., Liepe L., Kauert C., Volk H. D., Wacker H. H., Brocke S., Stein H., Diamantstein T. Phenotypical characterization of the cells invading pancreatic islets of diabetic BB/OK rats: effect of interleukin 2 receptor-targeted immunotherapy. Eur J Immunol. 1988 Dec;18(12):2037–2042. doi: 10.1002/eji.1830181225. [DOI] [PubMed] [Google Scholar]
  11. Hayosh N. S., Swanborg R. H. Autoimmune effector cells. IX. Inhibition of adoptive transfer of autoimmune encephalomyelitis with a monoclonal antibody specific for interleukin 2 receptors. J Immunol. 1987 Jun 1;138(11):3771–3775. [PubMed] [Google Scholar]
  12. Imahori S. C., Vladutiu A. O. Autoimmune granulomatous thyroiditis in inbred mice: resemblance to subacute (de Quervain's) thyroiditis in man. Proc Soc Exp Biol Med. 1983 Jul;173(3):408–416. doi: 10.3181/00379727-173-41664. [DOI] [PubMed] [Google Scholar]
  13. Imahori S. C., Vladutiu A. O. Evolution and host-dependent lesions in autoimmune thyroiditis: experimental study in inbred mice. Clin Immunol Immunopathol. 1984 Oct;33(1):87–98. doi: 10.1016/0090-1229(84)90295-2. [DOI] [PubMed] [Google Scholar]
  14. Janeway C. A., Jr, Carding S., Jones B., Murray J., Portoles P., Rasmussen R., Rojo J., Saizawa K., West J., Bottomly K. CD4+ T cells: specificity and function. Immunol Rev. 1988 Jan;101:39–80. doi: 10.1111/j.1600-065x.1988.tb00732.x. [DOI] [PubMed] [Google Scholar]
  15. Killar L., MacDonald G., West J., Woods A., Bottomly K. Cloned, Ia-restricted T cells that do not produce interleukin 4(IL 4)/B cell stimulatory factor 1(BSF-1) fail to help antigen-specific B cells. J Immunol. 1987 Mar 15;138(6):1674–1679. [PubMed] [Google Scholar]
  16. Kurt-Jones E. A., Hamberg S., Ohara J., Paul W. E., Abbas A. K. Heterogeneity of helper/inducer T lymphocytes. I. Lymphokine production and lymphokine responsiveness. J Exp Med. 1987 Dec 1;166(6):1774–1787. doi: 10.1084/jem.166.6.1774. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Ledbetter J. A., Herzenberg L. A. Xenogeneic monoclonal antibodies to mouse lymphoid differentiation antigens. Immunol Rev. 1979;47:63–90. doi: 10.1111/j.1600-065x.1979.tb00289.x. [DOI] [PubMed] [Google Scholar]
  18. Maron R., Zerubavel R., Friedman A., Cohen I. R. T lymphocyte line specific for thyroglobulin produces or vaccinates against autoimmune thyroiditis in mice. J Immunol. 1983 Nov;131(5):2316–2322. [PubMed] [Google Scholar]
  19. Mosmann T. R., Coffman R. L. Heterogeneity of cytokine secretion patterns and functions of helper T cells. Adv Immunol. 1989;46:111–147. doi: 10.1016/s0065-2776(08)60652-5. [DOI] [PubMed] [Google Scholar]
  20. Ortega G., Robb R. J., Shevach E. M., Malek T. R. The murine IL 2 receptor. I. Monoclonal antibodies that define distinct functional epitopes on activated T cells and react with activated B cells. J Immunol. 1984 Oct;133(4):1970–1975. [PubMed] [Google Scholar]
  21. Romball C. G., Weigle W. O. Transfer of experimental autoimmune thyroiditis with T cell clones. J Immunol. 1987 Feb 15;138(4):1092–1098. [PubMed] [Google Scholar]
  22. Rose N. R., Kong Y. C., Okayasu I., Giraldo A. A., Beisel K., Sundick R. S. T-cell regulation in autoimmune thyroiditis. Immunol Rev. 1981;55:299–314. doi: 10.1111/j.1600-065x.1981.tb00346.x. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Scott P., Natovitz P., Coffman R. L., Pearce E., Sher A. Immunoregulation of cutaneous leishmaniasis. T cell lines that transfer protective immunity or exacerbation belong to different T helper subsets and respond to distinct parasite antigens. J Exp Med. 1988 Nov 1;168(5):1675–1684. doi: 10.1084/jem.168.5.1675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Shizuru J. A., Taylor-Edwards C., Banks B. A., Gregory A. K., Fathman C. G. Immunotherapy of the nonobese diabetic mouse: treatment with an antibody to T-helper lymphocytes. Science. 1988 Apr 29;240(4852):659–662. doi: 10.1126/science.2966437. [DOI] [PubMed] [Google Scholar]
  26. Snapper C. M., Paul W. E. Interferon-gamma and B cell stimulatory factor-1 reciprocally regulate Ig isotype production. Science. 1987 May 22;236(4804):944–947. doi: 10.1126/science.3107127. [DOI] [PubMed] [Google Scholar]
  27. Springer T., Galfrè G., Secher D. S., Milstein C. Monoclonal xenogeneic antibodies to murine cell surface antigens: identification of novel leukocyte differentiation antigens. Eur J Immunol. 1978 Aug;8(8):539–551. doi: 10.1002/eji.1830080802. [DOI] [PubMed] [Google Scholar]
  28. Sriram S., Ranges G. E. Immunotherapy of autoimmune disease with T cell subset specific antibodies. Concepts Immunopathol. 1987;4:275–286. [PubMed] [Google Scholar]
  29. Sriram S., Steinman L. Anti I-A antibody suppresses active encephalomyelitis: treatment model for diseases linked to IR genes. J Exp Med. 1983 Oct 1;158(4):1362–1367. doi: 10.1084/jem.158.4.1362. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Steinman L., Waldor M. K., Zamvil S. S., Lim M., Herzenberg L., Herzenberg L., McDevitt H. O., Mitchell D., Sriram S. Therapy of autoimmune diseases with antibody to immune response gene products or to T-cell surface markers. Ann N Y Acad Sci. 1986;475:274–284. doi: 10.1111/j.1749-6632.1986.tb20876.x. [DOI] [PubMed] [Google Scholar]
  31. Stevens T. L., Bossie A., Sanders V. M., Fernandez-Botran R., Coffman R. L., Mosmann T. R., Vitetta E. S. Regulation of antibody isotype secretion by subsets of antigen-specific helper T cells. Nature. 1988 Jul 21;334(6179):255–258. doi: 10.1038/334255a0. [DOI] [PubMed] [Google Scholar]
  32. Stull S. J., Kyriakos M., Sharp G. C., Braley-Mullen H. Prevention and reversal of experimental autoimmune thyroiditis (EAT) in mice by administration of anti-L3T4 monoclonal antibody at different stages of disease development. Cell Immunol. 1988 Nov;117(1):188–198. doi: 10.1016/0008-8749(88)90087-1. [DOI] [PubMed] [Google Scholar]
  33. Stünkel K. G., Theisen P., Mouzaki A., Diamantstein T., Schlumberger H. D. Monitoring of interleukin-2 receptor (IL-2R) expression in vivo and studies on an IL-2R-directed immunosuppressive therapy of active and adoptive adjuvant-induced arthritis in rats. Immunology. 1988 Aug;64(4):683–689. [PMC free article] [PubMed] [Google Scholar]
  34. Tite J. P., Foellmer H. G., Madri J. A., Janeway C. A., Jr Inverse Ir gene control of the antibody and T cell proliferative responses to human basement membrane collagen. J Immunol. 1987 Nov 1;139(9):2892–2898. [PubMed] [Google Scholar]
  35. Waldmann H. Manipulation of T-cell responses with monoclonal antibodies. Annu Rev Immunol. 1989;7:407–444. doi: 10.1146/annurev.iy.07.040189.002203. [DOI] [PubMed] [Google Scholar]
  36. Waldor M. K., Sriram S., Hardy R., Herzenberg L. A., Herzenberg L. A., Lanier L., Lim M., Steinman L. Reversal of experimental allergic encephalomyelitis with monoclonal antibody to a T-cell subset marker. Science. 1985 Jan 25;227(4685):415–417. doi: 10.1126/science.3155574. [DOI] [PubMed] [Google Scholar]
  37. Williams W. V., Kyriakos M., Sharp G. C., Braley-Mullen H. Augmentation of transfer of experimental autoimmune thyroiditis (EAT) in mice by irradiation of recipients. Cell Immunol. 1987 Oct 15;109(2):397–406. doi: 10.1016/0008-8749(87)90322-4. [DOI] [PubMed] [Google Scholar]
  38. Wofsy D., Seaman W. E. Reversal of advanced murine lupus in NZB/NZW F1 mice by treatment with monoclonal antibody to L3T4. J Immunol. 1987 May 15;138(10):3247–3253. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES