title: CXC chemokine ligand 10 neutralization suppresses the occurrence of diabetes in nonobese diabetic mice through enhanced beta cell proliferation without affecting insulitis.
abstract: We have shown that neutralization of IFN-inducible protein 10/CXCL10, a chemokine for Th1 cells, breaks Th1 retention in the draining lymph nodes, resulting in exacerbation in Th1-dominant autoimmune disease models induced by immunization with external Ags. However, there have been no studies on the role of CXCL10 neutralization in Th1-dominant disease models induced by constitutive intrinsic self Ags. So, we have examined the effect of CXCL10 neutralization using a type 1 diabetes model initiated by developmentally regulated presentation of beta cell Ags. CXCL10 neutralization suppressed the occurrence of diabetes after administration with cyclophosphamide in NOD mice, although CXCL10 neutralization did not significantly inhibit insulitis and gave no influence on the trafficking of effector T cells into the islets. Because both CXCL10 and CXCR3 were, unexpectedly, coexpressed on insulin-producing cells, CXCL10 was considered to affect mature and premature beta cells in an autocrine and/or paracrine fashion. In fact, CXCL10 neutralization enhanced proliferative response of beta cells and resultantly increased beta cell mass without inhibiting insulitis. Thus, CXCL10 neutralization can be a new therapeutic target for beta cell survival, not only during the early stage of type 1 diabetes, but also after islet transplantation.
authors.affiliation: Division of Endocrinology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Morimoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yoneyama
authors.forename: Akira
authors.initials: A
authors.lastname: Shimada
authors.forename: Toshikatsu
authors.initials: T
authors.lastname: Shigihara
authors.forename: Satoru
authors.initials: S
authors.lastname: Yamada
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Oikawa
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
authors.forename: Takao
authors.initials: T
authors.lastname: Saruta
authors.forename: Shosaku
authors.initials: S
authors.lastname: Narumi
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D049109:Cell Proliferation; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003520:Cyclophosphamide / Q000008:administration & dosage; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D018450:Disease Progression; D005260:Female; D007165:Immunosuppression Therapy / Q000379:methods; D007274:Injections, Intraperitoneal; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D003520:Cyclophosphamide