Skip to main content
NCBI home page
Immunology logoLink to Immunology
. 1997 Mar;90(3):421–426. doi: 10.1111/j.1365-2567.1997.00421.x

Suppression of murine thyroiditis via blockade of the CD40-CD40L interaction.

G Carayanniotis 1, S R Masters 1, R J Noelle 1
PMCID: PMC1456613  PMID: 9155650

Abstract

The CD40 ligand (gp39) is transiently expressed on activated CD4+ T cells and mediates cognate helper function by interacting with CD40 on B cells. Increasing evidence suggests, however, critical involvement of gp39 not only in antibody-mediated responses but also in the development of effector T cells. Here, we have investigated the effect of in vivo gp39 blockade on the induction of murine experimental autoimmune thyroiditis (EAT), a T-cell-mediated disease. Over a 5-week period, EAT was induced in SJL mice with thyroglobulin (Tg) and adjuvant. Concomitantly, mice received intraperitoneal (i.p.) injections of MR1, a gp39-specific hamster monoclonal antibody (mAb), at 4-day intervals. Control mice were challenged with Tg but received equivalent doses of hamster immunoglobulin (HIg). It was observed that the control mice developed severe thyroiditis whereas the MR1-treated mice exhibited very low levels of infiltration that were mostly focal in nature. Blockade of gp39 was effective since the Tg-specific IgG titres were low or undetectable in all MR1-treated animals compared with the controls. In addition, upon restimulation with Tg in vitro, lymph node cells (LNC) from Tg-primed, MR1-treated mice proliferated less strongly and secreted significantly lower amounts of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) than LNC from untreated or HIg-treated controls. These results strongly suggest that in vivo blockade of gp39 suppresses EAT by inhibiting the priming of inflammatory Tg-specific T-helper type 1 cells.

Full text

PDF
421

Images in this article

422Figure 1
on p.422

Selected References

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

  1. Banchereau J., Bazan F., Blanchard D., Brière F., Galizzi J. P., van Kooten C., Liu Y. J., Rousset F., Saeland S. The CD40 antigen and its ligand. Annu Rev Immunol. 1994;12:881–922. doi: 10.1146/annurev.iy.12.040194.004313. [DOI] [PubMed] [Google Scholar]
  2. 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]
  3. Caux C., Massacrier C., Vanbervliet B., Dubois B., Van Kooten C., Durand I., Banchereau J. Activation of human dendritic cells through CD40 cross-linking. J Exp Med. 1994 Oct 1;180(4):1263–1272. doi: 10.1084/jem.180.4.1263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chronopoulou E., Carayanniotis G. Identification of a thyroiditogenic sequence within the thyroglobulin molecule. J Immunol. 1992 Aug 1;149(3):1039–1044. [PubMed] [Google Scholar]
  5. Dugas B., Mossalayi M. D., Damais C., Kolb J. P. Nitric oxide production by human monocytes: evidence for a role of CD23. Immunol Today. 1995 Dec;16(12):574–580. doi: 10.1016/0167-5699(95)80080-8. [DOI] [PubMed] [Google Scholar]
  6. Durie F. H., Aruffo A., Ledbetter J., Crassi K. M., Green W. R., Fast L. D., Noelle R. J. Antibody to the ligand of CD40, gp39, blocks the occurrence of the acute and chronic forms of graft-vs-host disease. J Clin Invest. 1994 Sep;94(3):1333–1338. doi: 10.1172/JCI117453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Durie F. H., Fava R. A., Foy T. M., Aruffo A., Ledbetter J. A., Noelle R. J. Prevention of collagen-induced arthritis with an antibody to gp39, the ligand for CD40. Science. 1993 Sep 3;261(5126):1328–1330. doi: 10.1126/science.7689748. [DOI] [PubMed] [Google Scholar]
  8. Durie F. H., Foy T. M., Masters S. R., Laman J. D., Noelle R. J. The role of CD40 in the regulation of humoral and cell-mediated immunity. Immunol Today. 1994 Sep;15(9):406–411. doi: 10.1016/0167-5699(94)90269-0. [DOI] [PubMed] [Google Scholar]
  9. Foy T. M., Laman J. D., Ledbetter J. A., Aruffo A., Claassen E., Noelle R. J. gp39-CD40 interactions are essential for germinal center formation and the development of B cell memory. J Exp Med. 1994 Jul 1;180(1):157–163. doi: 10.1084/jem.180.1.157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Foy T. M., Shepherd D. M., Durie F. H., Aruffo A., Ledbetter J. A., Noelle R. J. In vivo CD40-gp39 interactions are essential for thymus-dependent humoral immunity. II. Prolonged suppression of the humoral immune response by an antibody to the ligand for CD40, gp39. J Exp Med. 1993 Nov 1;178(5):1567–1575. doi: 10.1084/jem.178.5.1567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Grewal I. S., Flavell R. A. A central role of CD40 ligand in the regulation of CD4+ T-cell responses. Immunol Today. 1996 Sep;17(9):410–414. doi: 10.1016/0167-5699(96)10030-x. [DOI] [PubMed] [Google Scholar]
  12. Hollenbaugh D., Mischel-Petty N., Edwards C. P., Simon J. C., Denfeld R. W., Kiener P. A., Aruffo A. Expression of functional CD40 by vascular endothelial cells. J Exp Med. 1995 Jul 1;182(1):33–40. doi: 10.1084/jem.182.1.33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hutchings P. R., Cooke A., Dawe K., Champion B. R., Geysen M., Valerio R., Roitt I. M. A thyroxine-containing peptide can induce murine experimental autoimmune thyroiditis. J Exp Med. 1992 Mar 1;175(3):869–872. doi: 10.1084/jem.175.3.869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jenkins M. K. The ups and downs of T cell costimulation. Immunity. 1994 Sep;1(6):443–446. doi: 10.1016/1074-7613(94)90086-8. [DOI] [PubMed] [Google Scholar]
  15. Karmann K., Hughes C. C., Schechner J., Fanslow W. C., Pober J. S. CD40 on human endothelial cells: inducibility by cytokines and functional regulation of adhesion molecule expression. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4342–4346. doi: 10.1073/pnas.92.10.4342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kennedy M. K., Mohler K. M., Shanebeck K. D., Baum P. R., Picha K. S., Otten-Evans C. A., Janeway C. A., Jr, Grabstein K. H. Induction of B cell costimulatory function by recombinant murine CD40 ligand. Eur J Immunol. 1994 Jan;24(1):116–123. doi: 10.1002/eji.1830240118. [DOI] [PubMed] [Google Scholar]
  17. Kennedy M. K., Picha K. S., Fanslow W. C., Grabstein K. H., Alderson M. R., Clifford K. N., Chin W. A., Mohler K. M. CD40/CD40 ligand interactions are required for T cell-dependent production of interleukin-12 by mouse macrophages. Eur J Immunol. 1996 Feb;26(2):370–378. doi: 10.1002/eji.1830260216. [DOI] [PubMed] [Google Scholar]
  18. Khoruts A., Miller S. D., Jenkins M. K. Neuroantigen-specific Th2 cells are inefficient suppressors of experimental autoimmune encephalomyelitis induced by effector Th1 cells. J Immunol. 1995 Nov 15;155(10):5011–5017. [PubMed] [Google Scholar]
  19. Kong Y. C., McCormick D. J., Wan Q., Motte R. W., Fuller B. E., Giraldo A. A., David C. S. Primary hormonogenic sites as conserved autoepitopes on thyroglobulin in murine autoimmune thyroiditis. Secondary role of iodination. J Immunol. 1995 Dec 15;155(12):5847–5854. [PubMed] [Google Scholar]
  20. Kuchroo V. K., Das M. P., Brown J. A., Ranger A. M., Zamvil S. S., Sobel R. A., Weiner H. L., Nabavi N., Glimcher L. H. B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: application to autoimmune disease therapy. Cell. 1995 Mar 10;80(5):707–718. doi: 10.1016/0092-8674(95)90349-6. [DOI] [PubMed] [Google Scholar]
  21. Larsen C. P., Alexander D. Z., Hollenbaugh D., Elwood E. T., Ritchie S. C., Aruffo A., Hendrix R., Pearson T. C. CD40-gp39 interactions play a critical role during allograft rejection. Suppression of allograft rejection by blockade of the CD40-gp39 pathway. Transplantation. 1996 Jan 15;61(1):4–9. doi: 10.1097/00007890-199601150-00002. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Mohan C., Shi Y., Laman J. D., Datta S. K. Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis. J Immunol. 1995 Feb 1;154(3):1470–1480. [PubMed] [Google Scholar]
  24. Noelle R. J., Roy M., Shepherd D. M., Stamenkovic I., Ledbetter J. A., Aruffo A. A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells. Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6550–6554. doi: 10.1073/pnas.89.14.6550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Noelle R. J. The role of gp39 (CD40L) in immunity. Clin Immunol Immunopathol. 1995 Sep;76(3 Pt 2):S203–S207. doi: 10.1016/s0090-1229(95)90234-1. [DOI] [PubMed] [Google Scholar]
  26. Okayasu I. Transfer of experimental autoimmune thyroiditis to normal syngeneic mice by injection of mouse thyroglobulin-sensitized T lymphocytes after activation with concanavalin A. Clin Immunol Immunopathol. 1985 Jul;36(1):101–109. doi: 10.1016/0090-1229(85)90043-1. [DOI] [PubMed] [Google Scholar]
  27. Ranheim E. A., Kipps T. J. Activated T cells induce expression of B7/BB1 on normal or leukemic B cells through a CD40-dependent signal. J Exp Med. 1993 Apr 1;177(4):925–935. doi: 10.1084/jem.177.4.925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rao V. P., Balasa B., Carayanniotis G. Mapping of thyroglobulin epitopes: presentation of a 9mer pathogenic peptide by different mouse MHC class II isotypes. Immunogenetics. 1994;40(5):352–359. doi: 10.1007/BF01246676. [DOI] [PubMed] [Google Scholar]
  29. Romball C. G., Weigle W. O. T cell competence to heterologous and homologous thyroglobulins during the induction of experimental autoimmune thyroiditis. Eur J Immunol. 1984 Oct;14(10):887–893. doi: 10.1002/eji.1830141005. [DOI] [PubMed] [Google Scholar]
  30. 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]
  31. Roy M., Aruffo A., Ledbetter J., Linsley P., Kehry M., Noelle R. Studies on the interdependence of gp39 and B7 expression and function during antigen-specific immune responses. Eur J Immunol. 1995 Feb;25(2):596–603. doi: 10.1002/eji.1830250243. [DOI] [PubMed] [Google Scholar]
  32. Scott P. IL-12: initiation cytokine for cell-mediated immunity. Science. 1993 Apr 23;260(5107):496–497. doi: 10.1126/science.8097337. [DOI] [PubMed] [Google Scholar]
  33. Shu U., Kiniwa M., Wu C. Y., Maliszewski C., Vezzio N., Hakimi J., Gately M., Delespesse G. Activated T cells induce interleukin-12 production by monocytes via CD40-CD40 ligand interaction. Eur J Immunol. 1995 Apr;25(4):1125–1128. doi: 10.1002/eji.1830250442. [DOI] [PubMed] [Google Scholar]
  34. Simon L. L., Krco C. J., David C. S., Kong Y. M. Characterization of the in vitro murine T-cell proliferative responses to murine and human thyroglobulins in thyroiditis-susceptible and -resistant mice. Cell Immunol. 1985 Aug;94(1):243–253. doi: 10.1016/0008-8749(85)90101-7. [DOI] [PubMed] [Google Scholar]
  35. Stuber E., Strober W., Neurath M. Blocking the CD40L-CD40 interaction in vivo specifically prevents the priming of T helper 1 cells through the inhibition of interleukin 12 secretion. J Exp Med. 1996 Feb 1;183(2):693–698. doi: 10.1084/jem.183.2.693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Tang H., Mignon-Godefroy K., Meroni P. L., Garotta G., Charreire J., Nicoletti F. The effects of a monoclonal antibody to interferon-gamma on experimental autoimmune thyroiditis (EAT): prevention of disease and decrease of EAT-specific T cells. Eur J Immunol. 1993 Jan;23(1):275–278. doi: 10.1002/eji.1830230143. [DOI] [PubMed] [Google Scholar]
  37. Texier B., Bédin C., Tang H., Camoin L., Laurent-Winter C., Charreire J. Characterization and sequencing of a 40-amino-acid peptide from human thyroglobulin inducing experimental autoimmune thyroiditis. J Immunol. 1992 Jun 1;148(11):3405–3411. [PubMed] [Google Scholar]
  38. Tomazic V., Rose N. R. Autoimmune murine thyroiditis VII: induction of the thyroid lesions by passive transfer of immune serum. Clin Immunol Immunopathol. 1975 Nov;4(4):511–518. doi: 10.1016/0090-1229(75)90092-6. [DOI] [PubMed] [Google Scholar]
  39. Van den Eertwegh A. J., Noelle R. J., Roy M., Shepherd D. M., Aruffo A., Ledbetter J. A., Boersma W. J., Claassen E. In vivo CD40-gp39 interactions are essential for thymus-dependent humoral immunity. I. In vivo expression of CD40 ligand, cytokines, and antibody production delineates sites of cognate T-B cell interactions. J Exp Med. 1993 Nov 1;178(5):1555–1565. doi: 10.1084/jem.178.5.1555. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Vladutiu A. O., Rose N. R. Cellular basis of the genetic control of immune responsiveness to murine thyroglobulin in mice. Cell Immunol. 1975 May;17(1):106–113. doi: 10.1016/s0008-8749(75)80010-4. [DOI] [PubMed] [Google Scholar]
  41. Vladutiu A. O., Rose N. R. Transfer of experimental autoimmune thyroiditis of the mouse by serum. J Immunol. 1971 Apr;106(4):1139–1142. [PubMed] [Google Scholar]
  42. Weetman A. P., McGregor A. M. Autoimmune thyroid disease: further developments in our understanding. Endocr Rev. 1994 Dec;15(6):788–830. doi: 10.1210/edrv-15-6-788. [DOI] [PubMed] [Google Scholar]
  43. Wu Y., Xu J., Shinde S., Grewal I., Henderson T., Flavell R. A., Liu Y. Rapid induction of a novel costimulatory activity on B cells by CD40 ligand. Curr Biol. 1995 Nov 1;5(11):1303–1311. doi: 10.1016/s0960-9822(95)00257-0. [DOI] [PubMed] [Google Scholar]

Articles from Immunology are provided here courtesy of British Society for Immunology

RESOURCES