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. 1998 Sep;95(1):1–7. doi: 10.1046/j.1365-2567.1998.00580.x

Disease-protected major histocompatibility complex Ea-transgenic non-obese diabetic (NOD) mice show interleukin-4 production not seen in susceptible Ea-transgenic and non-transgenic NOD mice.

N Brenden 1, J Böhme 1
PMCID: PMC1364369  PMID: 9767450

Abstract

The non-obese diabetic (NOD) mouse is an animal model for insulin-dependent diabetes that has many similarities to the human disease. NOD mice transgenic for the Ea gene, allowing expression of the E molecule, are protected from diabetes and rarely develop insulitis. An Ea transgene mutated in the promoter region, (DeltaY) lacks E expression on most B cells, thymic medullary epithelium and primary antigen-presenting cells, and confers no protection whatsoever. We have used these transgenic NOD mice, together with non-transgenic NOD mice, to study the correlation of E expression and production of interleukin-4 (IL-4) and interferon-gamma (IFN-gamma). We show that protected E-transgenic NOD mice have elevated levels of IL-4 compared with non-transgenic mice, both in the thymus and in the periphery. However, susceptible DeltaY-transgenic mice have elevated thymic IL-4 levels, but express almost as little IL-4 as non-transgenic NOD mice in the periphery. This drop in peripheral IL-4 production seen in DeltaY-transgenic mice thus correlates with the decreased E expression in the periphery of DeltaY-transgenic NOD mice. In contrast, there were no differences in IFN-gamma production between the three NOD lines. We suggest that Ea-transgenic NOD mice have E-selected regulatory T cells producing IL-4, which are subsequently activated by E-expressing primary antigen-presenting cells in the periphery. This activation would then be instrumental for the E-mediated protection from disease in NOD mice. Such a process would explain the total absence of protection in DeltaY-transgenic NOD mice, despite their widespread E expression.

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Selected References

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

  1. Acha-Orbea H., McDevitt H. O. The first external domain of the nonobese diabetic mouse class II I-A beta chain is unique. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2435–2439. doi: 10.1073/pnas.84.8.2435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alonso S., Minty A., Bourlet Y., Buckingham M. Comparison of three actin-coding sequences in the mouse; evolutionary relationships between the actin genes of warm-blooded vertebrates. J Mol Evol. 1986;23(1):11–22. doi: 10.1007/BF02100994. [DOI] [PubMed] [Google Scholar]
  3. Bendelac A., Carnaud C., Boitard C., Bach J. F. Syngeneic transfer of autoimmune diabetes from diabetic NOD mice to healthy neonates. Requirement for both L3T4+ and Lyt-2+ T cells. J Exp Med. 1987 Oct 1;166(4):823–832. doi: 10.1084/jem.166.4.823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bendelac A., Schwartz R. H. Th0 cells in the thymus: the question of T-helper lineages. Immunol Rev. 1991 Oct;123:169–188. doi: 10.1111/j.1600-065x.1991.tb00610.x. [DOI] [PubMed] [Google Scholar]
  5. Boitard C., Yasunami R., Dardenne M., Bach J. F. T cell-mediated inhibition of the transfer of autoimmune diabetes in NOD mice. J Exp Med. 1989 May 1;169(5):1669–1680. doi: 10.1084/jem.169.5.1669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bruce J., Symington F. W., McKearn T. J., Sprent J. A monoclonal antibody discriminating between subsets of T and B cells. J Immunol. 1981 Dec;127(6):2496–2501. [PubMed] [Google Scholar]
  7. Böhme J., Schuhbaur B., Kanagawa O., Benoist C., Mathis D. MHC-linked protection from diabetes dissociated from clonal deletion of T cells. Science. 1990 Jul 20;249(4966):293–295. doi: 10.1126/science.2115690. [DOI] [PubMed] [Google Scholar]
  8. Carrasco-Marin E., Shimizu J., Kanagawa O., Unanue E. R. The class II MHC I-Ag7 molecules from non-obese diabetic mice are poor peptide binders. J Immunol. 1996 Jan 15;156(2):450–458. [PubMed] [Google Scholar]
  9. Castaño L., Eisenbarth G. S. Type-I diabetes: a chronic autoimmune disease of human, mouse, and rat. Annu Rev Immunol. 1990;8:647–679. doi: 10.1146/annurev.iy.08.040190.003243. [DOI] [PubMed] [Google Scholar]
  10. Ceredig R., Lowenthal J. W., Nabholz M., MacDonald H. R. Expression of interleukin-2 receptors as a differentiation marker on intrathymic stem cells. Nature. 1985 Mar 7;314(6006):98–100. doi: 10.1038/314098a0. [DOI] [PubMed] [Google Scholar]
  11. Fox C. J., Danska J. S. IL-4 expression at the onset of islet inflammation predicts nondestructive insulitis in nonobese diabetic mice. J Immunol. 1997 Mar 1;158(5):2414–2424. [PubMed] [Google Scholar]
  12. Hanson M. S., Cetkovic-Cvrlje M., Ramiya V. K., Atkinson M. A., Maclaren N. K., Singh B., Elliott J. F., Serreze D. V., Leiter E. H. Quantitative thresholds of MHC class II I-E expressed on hemopoietically derived antigen-presenting cells in transgenic NOD/Lt mice determine level of diabetes resistance and indicate mechanism of protection. J Immunol. 1996 Aug 1;157(3):1279–1287. [PubMed] [Google Scholar]
  13. Haskins K., Portas M., Bradley B., Wegmann D., Lafferty K. T-lymphocyte clone specific for pancreatic islet antigen. Diabetes. 1988 Oct;37(10):1444–1448. doi: 10.2337/diab.37.10.1444. [DOI] [PubMed] [Google Scholar]
  14. Hattori M., Buse J. B., Jackson R. A., Glimcher L., Dorf M. E., Minami M., Makino S., Moriwaki K., Kuzuya H., Imura H. The NOD mouse: recessive diabetogenic gene in the major histocompatibility complex. Science. 1986 Feb 14;231(4739):733–735. doi: 10.1126/science.3003909. [DOI] [PubMed] [Google Scholar]
  15. Katz J. D., Benoist C., Mathis D. T helper cell subsets in insulin-dependent diabetes. Science. 1995 May 26;268(5214):1185–1188. doi: 10.1126/science.7761837. [DOI] [PubMed] [Google Scholar]
  16. Katz J. D., Wang B., Haskins K., Benoist C., Mathis D. Following a diabetogenic T cell from genesis through pathogenesis. Cell. 1993 Sep 24;74(6):1089–1100. doi: 10.1016/0092-8674(93)90730-e. [DOI] [PubMed] [Google Scholar]
  17. Kikutani H., Makino S. The murine autoimmune diabetes model: NOD and related strains. Adv Immunol. 1992;51:285–322. doi: 10.1016/s0065-2776(08)60490-3. [DOI] [PubMed] [Google Scholar]
  18. Leo O., Foo M., Sachs D. H., Samelson L. E., Bluestone J. A. Identification of a monoclonal antibody specific for a murine T3 polypeptide. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1374–1378. doi: 10.1073/pnas.84.5.1374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Lowenthal J. W., Castle B. E., Christiansen J., Schreurs J., Rennick D., Arai N., Hoy P., Takebe Y., Howard M. Expression of high affinity receptors for murine interleukin 4 (BSF-1) on hemopoietic and nonhemopoietic cells. J Immunol. 1988 Jan 15;140(2):456–464. [PubMed] [Google Scholar]
  20. Montgomery R. A., Dallman M. J. Analysis of cytokine gene expression during fetal thymic ontogeny using the polymerase chain reaction. J Immunol. 1991 Jul 15;147(2):554–560. [PubMed] [Google Scholar]
  21. Mueller R., Krahl T., Sarvetnick N. Pancreatic expression of interleukin-4 abrogates insulitis and autoimmune diabetes in nonobese diabetic (NOD) mice. J Exp Med. 1996 Sep 1;184(3):1093–1099. doi: 10.1084/jem.184.3.1093. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Nakano N., Kikutani H., Nishimoto H., Kishimoto T. T cell receptor V gene usage of islet beta cell-reactive T cells is not restricted in non-obese diabetic mice. J Exp Med. 1991 May 1;173(5):1091–1097. doi: 10.1084/jem.173.5.1091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Nishimoto H., Kikutani H., Yamamura K., Kishimoto T. Prevention of autoimmune insulitis by expression of I-E molecules in NOD mice. 1987 Jul 30-Aug 5Nature. 328(6129):432–434. doi: 10.1038/328432a0. [DOI] [PubMed] [Google Scholar]
  24. Pilström B., Björk L., Böhme J. Demonstration of a TH1 cytokine profile in the late phase of NOD insulitis. Cytokine. 1995 Nov;7(8):806–814. doi: 10.1006/cyto.1995.0097. [DOI] [PubMed] [Google Scholar]
  25. Pilström B., Böhme J. Alleviation of insulitis in NOD mice is associated with expression of transgenic MHC E molecules on primary antigen-presenting cells. Immunology. 1997 Apr;90(4):483–488. doi: 10.1046/j.1365-2567.1997.00194.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. 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]
  27. Rapoport M. J., Jaramillo A., Zipris D., Lazarus A. H., Serreze D. V., Leiter E. H., Cyopick P., Danska J. S., Delovitch T. L. Interleukin 4 reverses T cell proliferative unresponsiveness and prevents the onset of diabetes in nonobese diabetic mice. J Exp Med. 1993 Jul 1;178(1):87–99. doi: 10.1084/jem.178.1.87. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sarmiento M., Glasebrook A. L., Fitch F. W. IgG or IgM monoclonal antibodies reactive with different determinants on the molecular complex bearing Lyt 2 antigen block T cell-mediated cytolysis in the absence of complement. J Immunol. 1980 Dec;125(6):2665–2672. [PubMed] [Google Scholar]
  29. Singer S. M., Tisch R., Yang X. D., McDevitt H. O. An Abd transgene prevents diabetes in nonobese diabetic mice by inducing regulatory T cells. Proc Natl Acad Sci U S A. 1993 Oct 15;90(20):9566–9570. doi: 10.1073/pnas.90.20.9566. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Slattery R. M., Miller J. F., Heath W. R., Charlton B. Failure of a protective major histocompatibility complex class II molecule to delete autoreactive T cells in autoimmune diabetes. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10808–10810. doi: 10.1073/pnas.90.22.10808. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Todd J. A., Bell J. I., McDevitt H. O. HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature. 1987 Oct 15;329(6140):599–604. doi: 10.1038/329599a0. [DOI] [PubMed] [Google Scholar]
  32. van Ewijk W., Ron Y., Monaco J., Kappler J., Marrack P., Le Meur M., Gerlinger P., Durand B., Benoist C., Mathis D. Compartmentalization of MHC class II gene expression in transgenic mice. Cell. 1988 May 6;53(3):357–370. doi: 10.1016/0092-8674(88)90156-0. [DOI] [PubMed] [Google Scholar]

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