Inhibition of insulitis and prevention of diabetes in nonobese diabetic mice by blocking L-selectin and very late antigen 4 adhesion receptors (original) (raw)

Abstract

Leukocyte adhesion to the endothelial venules in the pancreatic islets is thought to be one of the initial steps in the development of insulin-dependent diabetes mellitus. It has been suggested that leukocyte adhesion to endothelium is a sequential multistep process involving various different homing receptors. We report here that blocking different homing receptors--namely, L-selectin and very late antigen 4 (VLA-4)--which function during different stages of the adhesion process, by specific monoclonal antibodies inhibits insulitis and prevents diabetes in mice. Moreover, leukocyte attachment to the inflamed vessels within pancreatic sections could be inhibited by anti-L-selectin and anti-VLA-4 antibodies. Interestingly, anti-L-selectin or anti-VLA-4 antibody did not appear to influence the autoimmune response to a panel of pancreatic beta-cell autoantigens. These data suggest that L-selectin and VLA-4 receptors are involved in mediating leukocyte homing to the islets and that intervention of these two adhesion pathways may provide a novel approach for treatment of autoimmune diseases such as insulin-dependent diabetes mellitus.

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Selected References

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  1. Baekkeskov S., Aanstoot H. J., Christgau S., Reetz A., Solimena M., Cascalho M., Folli F., Richter-Olesen H., De Camilli P., Camilli P. D. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature. 1990 Sep 13;347(6289):151–156. doi: 10.1038/347151a0. [DOI] [PubMed] [Google Scholar]
  2. Baron J. L., Madri J. A., Ruddle N. H., Hashim G., Janeway C. A., Jr Surface expression of alpha 4 integrin by CD4 T cells is required for their entry into brain parenchyma. J Exp Med. 1993 Jan 1;177(1):57–68. doi: 10.1084/jem.177.1.57. [DOI] [PMC free article] [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. Boitard C., Villa M. C., Becourt C., Gia H. P., Huc C., Sempe P., Portier M. M., Bach J. F. Peripherin: an islet antigen that is cross-reactive with nonobese diabetic mouse class II gene products. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):172–176. doi: 10.1073/pnas.89.1.172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bu D. F., Erlander M. G., Hitz B. C., Tillakaratne N. J., Kaufman D. L., Wagner-McPherson C. B., Evans G. A., Tobin A. J. Two human glutamate decarboxylases, 65-kDa GAD and 67-kDa GAD, are each encoded by a single gene. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2115–2119. doi: 10.1073/pnas.89.6.2115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Butcher E. C. Leukocyte-endothelial cell recognition: three (or more) steps to specificity and diversity. Cell. 1991 Dec 20;67(6):1033–1036. doi: 10.1016/0092-8674(91)90279-8. [DOI] [PubMed] [Google Scholar]
  7. 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]
  8. Castaño L., Russo E., Zhou L., Lipes M. A., Eisenbarth G. S. Identification and cloning of a granule autoantigen (carboxypeptidase-H) associated with type I diabetes. J Clin Endocrinol Metab. 1991 Dec;73(6):1197–1201. doi: 10.1210/jcem-73-6-1197. [DOI] [PubMed] [Google Scholar]
  9. Damle N. K., Aruffo A. Vascular cell adhesion molecule 1 induces T-cell antigen receptor-dependent activation of CD4+T lymphocytes. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6403–6407. doi: 10.1073/pnas.88.15.6403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Elias D., Markovits D., Reshef T., van der Zee R., Cohen I. R. Induction and therapy of autoimmune diabetes in the non-obese diabetic (NOD/Lt) mouse by a 65-kDa heat shock protein. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1576–1580. doi: 10.1073/pnas.87.4.1576. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Elices M. J., Osborn L., Takada Y., Crouse C., Luhowskyj S., Hemler M. E., Lobb R. R. VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site. Cell. 1990 Feb 23;60(4):577–584. doi: 10.1016/0092-8674(90)90661-w. [DOI] [PubMed] [Google Scholar]
  12. Ferguson T. A., Kupper T. S. Antigen-independent processes in antigen-specific immunity. A role for alpha 4 integrin. J Immunol. 1993 Feb 15;150(4):1172–1182. [PubMed] [Google Scholar]
  13. Ferguson T. A., Mizutani H., Kupper T. S. Two integrin-binding peptides abrogate T cell-mediated immune responses in vivo. Proc Natl Acad Sci U S A. 1991 Sep 15;88(18):8072–8076. doi: 10.1073/pnas.88.18.8072. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gallatin W. M., Weissman I. L., Butcher E. C. A cell-surface molecule involved in organ-specific homing of lymphocytes. Nature. 1983 Jul 7;304(5921):30–34. doi: 10.1038/304030a0. [DOI] [PubMed] [Google Scholar]
  15. Hemler M. E. VLA proteins in the integrin family: structures, functions, and their role on leukocytes. Annu Rev Immunol. 1990;8:365–400. doi: 10.1146/annurev.iy.08.040190.002053. [DOI] [PubMed] [Google Scholar]
  16. Holzmann B., McIntyre B. W., Weissman I. L. Identification of a murine Peyer's patch--specific lymphocyte homing receptor as an integrin molecule with an alpha chain homologous to human VLA-4 alpha. Cell. 1989 Jan 13;56(1):37–46. doi: 10.1016/0092-8674(89)90981-1. [DOI] [PubMed] [Google Scholar]
  17. Hutchings P., Rosen H., O'Reilly L., Simpson E., Gordon S., Cooke A. Transfer of diabetes in mice prevented by blockade of adhesion-promoting receptor on macrophages. Nature. 1990 Dec 13;348(6302):639–642. doi: 10.1038/348639a0. [DOI] [PubMed] [Google Scholar]
  18. Issekutz T. B., Issekutz A. C. T lymphocyte migration to arthritic joints and dermal inflammation in the rat: differing migration patterns and the involvement of VLA-4. Clin Immunol Immunopathol. 1991 Dec;61(3):436–447. doi: 10.1016/s0090-1229(05)80014-5. [DOI] [PubMed] [Google Scholar]
  19. Issekutz T. B., Wykretowicz A. Effect of a new monoclonal antibody, TA-2, that inhibits lymphocyte adherence to cytokine stimulated endothelium in the rat. J Immunol. 1991 Jul 1;147(1):109–116. [PubMed] [Google Scholar]
  20. Jalkanen S. T., Butcher E. C. In vitro analysis of the homing properties of human lymphocytes: developmental regulation of functional receptors for high endothelial venules. Blood. 1985 Sep;66(3):577–582. [PubMed] [Google Scholar]
  21. Lasky L. A. Selectins: interpreters of cell-specific carbohydrate information during inflammation. Science. 1992 Nov 6;258(5084):964–969. doi: 10.1126/science.1439808. [DOI] [PubMed] [Google Scholar]
  22. Leiter E. H., Serreze D. V. Antigen presenting cells and the immunogenetics of autoimmune diabetes in NOD mice. Reg Immunol. 1992 Sep-Oct;4(5):263–273. [PubMed] [Google Scholar]
  23. Nojima Y., Rothstein D. M., Sugita K., Schlossman S. F., Morimoto C. Ligation of VLA-4 on T cells stimulates tyrosine phosphorylation of a 105-kD protein. J Exp Med. 1992 Apr 1;175(4):1045–1053. doi: 10.1084/jem.175.4.1045. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Picker L. J. Mechanisms of lymphocyte homing. Curr Opin Immunol. 1992 Jun;4(3):277–286. doi: 10.1016/0952-7915(92)90077-r. [DOI] [PubMed] [Google Scholar]
  25. Shimizu Y., Newman W., Tanaka Y., Shaw S. Lymphocyte interactions with endothelial cells. Immunol Today. 1992 Mar;13(3):106–112. doi: 10.1016/0167-5699(92)90151-V. [DOI] [PubMed] [Google Scholar]
  26. Spertini O., Luscinskas F. W., Kansas G. S., Munro J. M., Griffin J. D., Gimbrone M. A., Jr, Tedder T. F. Leukocyte adhesion molecule-1 (LAM-1, L-selectin) interacts with an inducible endothelial cell ligand to support leukocyte adhesion. J Immunol. 1991 Oct 15;147(8):2565–2573. [PubMed] [Google Scholar]
  27. Springer T. A. Adhesion receptors of the immune system. Nature. 1990 Aug 2;346(6283):425–434. doi: 10.1038/346425a0. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. Stamper H. B., Jr, Woodruff J. J. Lymphocyte homing into lymph nodes: in vitro demonstration of the selective affinity of recirculating lymphocytes for high-endothelial venules. J Exp Med. 1976 Sep 1;144(3):828–833. doi: 10.1084/jem.144.3.828. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Watson S. R., Fennie C., Lasky L. A. Neutrophil influx into an inflammatory site inhibited by a soluble homing receptor-IgG chimaera. Nature. 1991 Jan 10;349(6305):164–167. doi: 10.1038/349164a0. [DOI] [PubMed] [Google Scholar]
  31. Wicker L. S., Miller B. J., Mullen Y. Transfer of autoimmune diabetes mellitus with splenocytes from nonobese diabetic (NOD) mice. Diabetes. 1986 Aug;35(8):855–860. doi: 10.2337/diab.35.8.855. [DOI] [PubMed] [Google Scholar]
  32. Yednock T. A., Cannon C., Fritz L. C., Sanchez-Madrid F., Steinman L., Karin N. Prevention of experimental autoimmune encephalomyelitis by antibodies against alpha 4 beta 1 integrin. Nature. 1992 Mar 5;356(6364):63–66. doi: 10.1038/356063a0. [DOI] [PubMed] [Google Scholar]