title: Small molecule CXCR3 antagonist NIBR2130 has only a limited impact on type 1 diabetes in a virus-induced mouse model.
abstract: CXCL10 is one of the key chemokines involved in trafficking of autoaggressive T cells to the islets of Langerhans during the autoimmune destruction of beta cells in type 1 diabetes (T1D). Blockade of CXCL10 or genetic deletion of its receptor CXCR3 results in a reduction of T1D in animal models. As an alternative to the use of neutralizing monoclonal antibodies to CXCL10 or CXCR3 we evaluated the small molecule CXCR3 antagonist NIBR2130 in a virus-induced mouse model for T1D. We found that the overall frequency of T1D was not reduced in mice administered with NIBR2130. An initial slight delay of diabetes onset was not stable over time, because the mice turned diabetic upon removal of the antagonist. Accordingly, no significant differences were found in the islet infiltration rate and the frequency and activity of islet antigen-specific T cells between protected mice administered with NIBR2130 and control mice. Our data indicate that in contrast to direct inhibition of CXCL10, blockade of CXCR3 with the small molecule antagonist NIBR2130 has no impact on trafficking and/or activation of autoaggressive T cells and is not sufficient to prevent T1D.
authors.affiliation: Pharmazentrum Frankfurt/ZAFES, Klinikum der Goethe Universität, Frankfurt am Main, Germany. christen@med.uni-frankfurt.de
authors.forename: S
authors.initials: S
authors.lastname: Christen
authors.forename: M
authors.initials: M
authors.lastname: Holdener
authors.forename: C
authors.initials: C
authors.lastname: Beerli
authors.forename: G
authors.initials: G
authors.lastname: Thoma
authors.forename: M
authors.initials: M
authors.lastname: Bayer
authors.forename: J M
authors.initials: JM
authors.lastname: Pfeilschifter
authors.forename: E
authors.initials: E
authors.lastname: Hintermann
authors.forename: H-G
authors.initials: HG
authors.lastname: Zerwes
authors.forename: U
authors.initials: U
authors.lastname: Christen
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D054357:Chemokine CXCL10 / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000209:etiology / Q000517:prevention & control* / Q000821:virology; D004195:Disease Models, Animal; D004873:Ergolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D007371:Interferon-gamma / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013154:Spleen / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology
chemical_list: D001786:Blood Glucose; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D004873:Ergolines; D007328:Insulin; D054367:Receptors, CXCR3; D014764:Viral Proteins; D007371:Interferon-gamma