The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/10/989/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 7, October 6, 1997 989-997

Articles

Reduced Incidence and Delayed Onset of Diabetes in Perforin-deficient Nonobese Diabetic Mice

David Kägi*, Bernhard Odermatt§, Peter Seiler{ddagger}, Rolf M. Zinkernagel{ddagger}, Tak W. Mak*, and Hans Hengartner{ddagger}

From the * Ontario Cancer Institute, Toronto M5G2M9, Canada; {ddagger} Institute of Experimental Immunology, Department of Pathology, University of Zürich, CH-8091 Zürich, Switzerland; and the § Department of Pathology, University of Zürich, CH-8091 Zürich, Switzerland

To investigate the role of T cell–mediated, perforin-dependent cytotoxicity in autoimmune diabetes, perforin-deficient mice were backcrossed with the nonobese diabetes mouse strain. It was found that the incidence of spontaneous diabetes over a 1 yr period was reduced from 77% in perforin +/+ control to 16% in perforin-deficient mice. Also, the disease onset was markedly delayed (median onset of 39.5 versus 19 wk) in the latter. Insulitis with infiltration of CD4+ and CD8+ T cells occurred similarly in both groups of animals. Lower incidence and delayed disease onset were also evident in perforin-deficient mice when diabetes was induced by cyclophosphamide injection. Thus, perforin-dependent cytotoxicity is a crucial effector mechanism for β cell elimination by cytotoxic T cells in autoimmune diabetes. However, in the absence of perforin chronic inflammation of the islets can lead to diabetogenic β cell loss by less efficient secondary effector mechanisms.

Address correspondence to David Kägi, c/o Professor T.W. Mak, Ontario Cancer Institute, RM 8-622, 610 University Avenue, Toronto, Ontario M5G2M9, Canada. Phone: 416-204-5310; FAX: 416-204-5300; E-mail: dkagi{at}amgen.com

1 Abbreviations used in this paper: GP, glycoprotein; IDDM, insulin-dependent diabetes mellitus; LCMV, lymphocytic choriomeningitis virus; NOD, nonobese diabetic.


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