title: Genetic deletion of granzyme B does not confer resistance to the development of spontaneous diabetes in non-obese diabetic mice.
abstract: Granzyme B (GzmB) and perforin are proteins, secreted mainly by natural killer cells and cytotoxic T lymphocytes that are largely responsible for the induction of apoptosis in target cells. Because type 1 diabetes results from the selective destruction of β cells and perforin deficiency effectively reduces diabetes in non-obese diabetic (NOD) mice, it can be deduced that β cell apoptosis involves the GzmB/perforin pathway. However, the relevance of GzmB remains totally unknown in non-obese diabetic (NOD) mice. In this study we have focused on GzmB and examined the consequence of GzmB deficiency in NOD mice. We found that NOD.GzmB(-/-) mice developed diabetes spontaneously with kinetics similar to those of wild-type NOD (wt-NOD) mice. Adoptive transfer study with regulatory T cell (Treg )-depleted splenocytes (SPCs) into NOD-SCID mice or in-vivo Treg depletion by anti-CD25 antibody at 4 weeks of age comparably induced the rapid progression of diabetes in the NOD.GzmB(-/-) mice and wt-NOD mice. Expression of GzmA and Fas was enhanced in the islets from pre-diabetic NOD.GzmB(-/-) mice. In contrast to spontaneous diabetes, GzmB deficiency suppressed the development of cyclophosphamide-promoted diabetes in male NOD mice. Cyclophosphamide treatment led to a significantly lower percentage of apoptotic CD4(+) , CD8(+) and CD4(+) CD25(+) T cells in SPCs from NOD.GzmB(-/-) mice than those from wt-NOD mice. In conclusion, GzmB, in contrast to perforin, is not essentially involved in the effector mechanisms for β cell destruction in NOD mice.
authors.affiliation: Department of Endocrinology and Metabolism, Unit of Translational Medicine, Graduate School of Biomedical Science, Nagasaki University, Nagasaki, Fukuoka, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kobayashi
authors.forename: C
authors.initials: C
authors.lastname: Kaneko-Koike
authors.forename: N
authors.initials: N
authors.lastname: Abiru
authors.forename: T
authors.initials: T
authors.lastname: Uchida
authors.forename: S
authors.initials: S
authors.lastname: Akazawa
authors.forename: K
authors.initials: K
authors.lastname: Nakamura
authors.forename: G
authors.initials: G
authors.lastname: Kuriya
authors.forename: T
authors.initials: T
authors.lastname: Satoh
authors.forename: H
authors.initials: H
authors.lastname: Ida
authors.forename: E
authors.initials: E
authors.lastname: Kawasaki
authors.forename: H
authors.initials: H
authors.lastname: Yamasaki
authors.forename: Y
authors.initials: Y
authors.lastname: Nagayama
authors.forename: H
authors.initials: H
authors.lastname: Sasaki
authors.forename: A
authors.initials: A
authors.lastname: Kawakami
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D053804:Granzymes / Q000235:genetics*; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics
chemical_list: D019014:fas Receptor; D053804:Granzymes
keywords: NOD mice; apoptosis; transgenic/knock-out mice; type 1 diabetes