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.
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6 October 1997
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October 06 1997
Reduced Incidence and Delayed Onset of Diabetes in Perforin-deficient Nonobese Diabetic Mice
David Kägi,
David Kägi
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
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Bernhard Odermatt,
Bernhard Odermatt
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
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Peter Seiler,
Peter Seiler
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
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Rolf M. Zinkernagel,
Rolf M. Zinkernagel
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
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Tak W. Mak,
Tak W. Mak
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
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Hans Hengartner
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
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David Kägi
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
Bernhard Odermatt
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
Peter Seiler
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
Rolf M. Zinkernagel
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
Tak W. Mak
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
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
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: [email protected]
1
Abbreviations used in this paper: GP, glycoprotein; IDDM, insulin-dependent diabetes mellitus; LCMV, lymphocytic choriomeningitis virus; NOD, nonobese diabetic.
Received:
March 11 1997
Revision Received:
July 07 1997
Online ISSN: 1540-9538
Print ISSN: 0022-1007
1997
J Exp Med (1997) 186 (7): 989–997.
Article history
Received:
March 11 1997
Revision Received:
July 07 1997
Citation
David Kägi, Bernhard Odermatt, Peter Seiler, Rolf M. Zinkernagel, Tak W. Mak, Hans Hengartner; Reduced Incidence and Delayed Onset of Diabetes in Perforin-deficient Nonobese Diabetic Mice . J Exp Med 6 October 1997; 186 (7): 989–997. doi: https://doi.org/10.1084/jem.186.7.989
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