Diabetes, Vol 38, Issue 4 441-447, Copyright © 1989 by American Diabetes Association

ARTICLES

Cyclophosphamide-induced diabetes in NOD/WEHI mice. Evidence for suppression in spontaneous autoimmune diabetes mellitus

B Charlton, A Bacelj, RM Slattery and TE Mandel
Walter and Eliza Hall Institute of Medical Research, P.O. Royal Melbourne Hospital, Parkville, Victoria, Australia.

Nonobese diabetic (NOD) mice spontaneously develop a lymphocytic infiltration of pancreatic islets (insulitis) that may progress to overt diabetes. Virtually all NOD/WEHI mice develop insulitis, but very few progress to diabetes. However, cyclophosphamide (CY) can promote the onset of diabetes in NOD mice, including the NOD/WEHI strain. The means by which CY produces diabetes was investigated in NOD/WEHI mice, in which it was hypothesized that active suppression mechanisms prevented the progression from insulitis to diabetes. A study of the time course of insulitis in the islets after CY was given showed that insulitis was initially reduced but rapidly increased over 16 days, and T-lymphocytes were predominant in the lesion. This suggested a compression of the normal time course of the disease seen in NOD mice. CY did not produce diabetes in any of 11 non-NOD strains studied. Fetal isografts in NOD mice given CY several days before were subjected to lymphocytic infiltration and beta-cell destruction. These findings suggested that CY was not directly beta-cell toxic and that altered beta-cells were not essential for beta-cell destruction. This was further demonstrated with subdiabetogenic doses of streptozocin, which significantly damaged beta-cells but did not increase the severity of insulitis or induce diabetes as did CY. Most important, the transfer of mononuclear cells from nondiabetic NOD mice to mice given CY prevented diabetes, which indicated that the likely effect of CY was via immunomodulation, possibly by allowing poised effector cells to act on beta-cells.(ABSTRACT TRUNCATED AT 250 WORDS)
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				E. A. Ivakine, S. M. Mortin-Toth, O. M. Gulban, A. Valova, A. Canty, C. Scott, and J. S. Danska The Idd4 Locus Displays Sex-Specific Epistatic Effects on Type 1 Diabetes Susceptibility in Nonobese Diabetic Mice Diabetes, December 1, 2006; 55(12): 3611 - 3619. [Abstract] [Full Text] [PDF]

				S. Brode, T. Raine, P. Zaccone, and A. Cooke Cyclophosphamide-Induced Type-1 Diabetes in the NOD Mouse Is Associated with a Reduction of CD4+CD25+Foxp3+ Regulatory T Cells J. Immunol., November 15, 2006; 177(10): 6603 - 6612. [Abstract] [Full Text] [PDF]

				X. Li, H. Chen, and P. N. Epstein Metallothionein and Catalase Sensitize to Diabetes in Nonobese Diabetic Mice: Reactive Oxygen Species May Have a Protective Role in Pancreatic {beta}-Cells Diabetes, June 1, 2006; 55(6): 1592 - 1604. [Abstract] [Full Text] [PDF]

				E. A. Ivakine, C. J. Fox, A. D. Paterson, S. M. Mortin-Toth, A. Canty, D. S. Walton, K. Aleksa, S. Ito, and J. S. Danska Sex-Specific Effect of Insulin-Dependent Diabetes 4 on Regulation of Diabetes Pathogenesis in the Nonobese Diabetic Mouse J. Immunol., June 1, 2005; 174(11): 7129 - 7140. [Abstract] [Full Text] [PDF]

				T. Pearson, T. G. Markees, D. V. Serreze, M. A. Pierce, M. P. Marron, L. S. Wicker, L. B. Peterson, L. D. Shultz, J. P. Mordes, A. A. Rossini, et al. Genetic Disassociation of Autoimmunity and Resistance to Costimulation Blockade-Induced Transplantation Tolerance in Nonobese Diabetic Mice J. Immunol., July 1, 2003; 171(1): 185 - 195. [Abstract] [Full Text] [PDF]

				S. Winer, I. Astsaturov, R. Gaedigk, D. Hammond-McKibben, M. Pilon, A. Song, V. Kubiak, W. Karges, E. Arpaia, C. McKerlie, et al. ICA69null Nonobese Diabetic Mice Develop Diabetes, but Resist Disease Acceleration by Cyclophosphamide J. Immunol., January 1, 2002; 168(1): 475 - 482. [Abstract] [Full Text] [PDF]

				S. A. W. Greeley, D. J. Moore, H. Noorchashm, L. E. Noto, S. Y. Rostami, A. Schlachterman, H. K. Song, B. Koeberlein, C. F. Barker, and A. Naji Impaired Activation of Islet-Reactive CD4 T Cells in Pancreatic Lymph Nodes of B Cell-Deficient Nonobese Diabetic Mice J. Immunol., October 15, 2001; 167(8): 4351 - 4357. [Abstract] [Full Text] [PDF]

				P. P.L. Chiu, D. V. Serreze, and J. S. Danska Development and Function of Diabetogenic T-cells in B-cell-Deficient Nonobese Diabetic Mice Diabetes, April 1, 2001; 50(4): 763 - 770. [Abstract] [Full Text]

				F. Lepault and M. C. Gagnerault Characterization of Peripheral Regulatory CD4+ T Cells That Prevent Diabetes Onset in Nonobese Diabetic Mice J. Immunol., January 1, 2000; 164(1): 240 - 247. [Abstract] [Full Text] [PDF]

				C. A. Piccirillo, Y. Chang, and G. J. Prud'homme TGF-{beta}1 Somatic Gene Therapy Prevents Autoimmune Disease in Nonobese Diabetic Mice J. Immunol., October 15, 1998; 161(8): 3950 - 3956. [Abstract] [Full Text] [PDF]

				A. Herbelin, J.-M. Gombert, F. Lepault, J.-F. Bach, and L. Chatenoud Mature Mainstream TCR{alpha}{beta}+CD4+ Thymocytes Expressing L-Selectin Mediate ""Active Tolerance"" in the Nonobese Diabetic Mouse J. Immunol., September 1, 1998; 161(5): 2620 - 2628. [Abstract] [Full Text] [PDF]

				A. Hoek, J. Schoemaker, and H. A. Drexhage Premature Ovarian Failure and Ovarian Autoimmunity Endocr. Rev., February 1, 1997; 18(1): 107 - 134. [Abstract] [Full Text]

				J. Salaun, N. Simmenauer, P. Belo, A. Coutinho, and N. M. Le Douarin Grafts of supplementary thymuses injected with allogeneic pancreatic islets protect nonobese diabetic mice against diabetes PNAS, January 22, 2002; 99(2): 874 - 877. [Abstract] [Full Text] [PDF]