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Departments of
*
Immunology and
Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037; and
Department of Surgery, University of California at San Diego, La Jolla, CA 92037
Migration of CD4 cells into the pancreas represents a
hallmark event in the development of insulin-dependent diabetes
mellitus. Th1, but not Th2, cells are associated with pathogenesis
leading to destruction of islet ß-cells and disease onset. Lymphocyte
extravasation from blood into tissue is regulated by multiple adhesion
receptor/counter-receptor pairs and chemokines. To identify events that
regulate entry of CD4 cells into the pancreas, we transferred Th1 or
Th2 cells induced in vitro from islet-specific TCR transgenic CD4 cells
into immunodeficient (NOD.scid)
recipients. Although both subsets infiltrated the pancreas and elicited
multiple adhesion receptors (peripheral lymph node addressin, mucosal
addressin cell adhesion molecule-1, LFA-1, ICAM-1, and VCAM-1) on
vascular endothelium, entry/accumulation of Th1 cells was more rapid
than that of Th2 cells, and only Th1 cells induced diabetes. In vitro,
Th1 cells were also distinguished from Th2 cells by the capacity to
synthesize several chemokines that included lymphotactin, monocyte
chemoattractant protein-1 (MCP-1), and macrophage inflammatory
protein-1
, whereas both subsets produced macrophage inflammatory
protein-1ß. Some of these chemokines as well as RANTES, MCP-3, MCP-5,
and cytokine-response gene-2 (CRG-2)/IFN-inducible protein-10
(IP-10) were associated with Th1, but not Th2, pancreatic
infiltrates. The data demonstrate polarization of chemokine expression
by Th1 vs Th2 cells, which, within the microenvironment of the
pancreas, accounts for distinctive inflammatory infiltrates that
determine whether insulin-producing ß-cells are protected or
destroyed.
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S. Zhang, N. W. Lukacs, V. A. Lawless, S. L. Kunkel, and M. H. Kaplan Cutting Edge: Differential Expression of Chemokines in Th1 and Th2 Cells Is Dependent on Stat6 But Not Stat4 J. Immunol., July 1, 2000; 165(1): 10 - 14. [Abstract] [Full Text] [PDF]
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C. G. Lerner, M. R. Horton, R. H. Schwartz, and J. D. Powell Distinct Requirements for C-C Chemokine and IL-2 Production by Naive, Previously Activated, and Anergic T Cells J. Immunol., April 15, 2000; 164(8): 3996 - 4002. [Abstract] [Full Text] [PDF]
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M. Poulin and K. Haskins Induction of Diabetes in Nonobese Diabetic Mice by Th2 T Cell Clones from a TCR Transgenic Mouse J. Immunol., March 15, 2000; 164(6): 3072 - 3078. [Abstract] [Full Text] [PDF]
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J. Wang, E. Guan, G. Roderiquez, and M. A. Norcross Inhibition of CCR5 Expression by IL-12 Through Induction of {beta}-Chemokines in Human T Lymphocytes J. Immunol., December 1, 1999; 163(11): 5763 - 5769. [Abstract] [Full Text] [PDF]
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K. Lejon C. and G. Fathman Isolation of Self Antigen-Reactive Cells from Inflamed Islets of Nonobese Diabetic Mice Using CD4high Expression as a Marker J. Immunol., November 15, 1999; 163(10): 5708 - 5714. [Abstract] [Full Text] [PDF]
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B. G. Dorner, A. Scheffold, M. S. Rolph, M. B. Huser, S. H. E. Kaufmann, A. Radbruch, I. E. A. Flesch, and R. A. Kroczek MIP-1alpha , MIP-1beta , RANTES, and ATAC/lymphotactin function together with IFN-gamma as type 1 cytokines PNAS, April 30, 2002; 99(9): 6181 - 6186. [Abstract] [Full Text] [PDF]
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D. L. Radu, N. Noben-Trauth, J. Hu-Li, W. E. Paul, and C. A. Bona A targeted mutation in the IL-4Ralpha gene protects mice against autoimmune diabetes PNAS, November 7, 2000; 97(23): 12700 - 12704. [Abstract] [Full Text] [PDF]
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 I. A. Eaves, L. S. Wicker, G. Ghandour, P. A. Lyons, L. B. Peterson, J. A. Todd, and R. J. Glynne Combining Mouse Congenic Strains and Microarray Gene Expression Analyses to Study a Complex Trait: The NOD Model of Type 1 Diabetes Genome Res., February 1, 2002; 12(2): 232 - 243. [Abstract] [Full Text] [PDF]
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