J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/10/989/09 $2.00
Volume 186, Number 7, October 6, 1997 989-997

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

By David Kägi,^* Bernhard Odermatt,^§ Peter Seiler, Rolf M. Zinkernagel, Tak W. Mak,^* and Hans Hengartner

From the ^* Ontario Cancer Institute, Toronto M5G2M9, Canada;  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  cell elimination by cytotoxic T cells in autoimmune diabetes. However, in the absence of perforin chronic inflammation of the islets can lead to diabetogenic  cell loss by less efficient secondary effector mechanisms.

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