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PMID: 9314549 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Reduced incidence and delayed onset of diabetes in perforin-deficient nonobese diabetic mice.

The Journal of experimental medicine ·Vol. 186 ·No. 7 ·1997-10-06 ·Pages 989-97

Kägi D, Odermatt B, Seiler P, Zinkernagel RM, Mak TW, Hengartner H

Abstract

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 beta cell elimination by cytotoxic T cells in autoimmune diabetes. However, in the absence of perforin chronic inflammation of the islets can lead to diabetogenic beta cell loss by less efficient secondary effector mechanisms.

MeSH Terms
Animals Autoimmune Diseases/immunology Blood Glucose/metabolism CD4-Positive T-Lymphocytes/immunology CD8-Positive T-Lymphocytes/immunology Crosses, Genetic Cyclophosphamide/pharmacology Diabetes Mellitus, Type 1/genetics,immunology Disease Models, Animal Female Immunosuppressive Agents/pharmacology Islets of Langerhans/immunology Male Membrane Glycoproteins/deficiency,physiology Mice Mice, Inbred NOD Pancreas/cytology,immunology Perforin Pore Forming Cytotoxic Proteins T-Lymphocytes, Cytotoxic/immunology,metabolism
Chemicals
Blood Glucose Immunosuppressive Agents Membrane Glycoproteins Pore Forming Cytotoxic Proteins Perforin Cyclophosphamide
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Kägi D
Ontario Cancer Institute, Toronto M5G2M9, Canada. dkagi@amgen.com
Odermatt B
Seiler P
Zinkernagel R M
Mak T W
Hengartner H
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.186.7.989
Email
dkagi@amgen.com
Published
1997-10-06
Pages
989-97
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2199062
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.186.7.989 PMC Full Text View journal details
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