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.
Subject(s)
Diabetes Mellitus, Type 1/prevention & control , Ergolines/therapeutic use , Receptors, CXCR3/antagonists & inhibitors , Animals , Blood Glucose/drug effects , Blood Glucose/metabolism , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/pathology , Cell Movement/drug effects , Cell Movement/immunology , Chemokine CXCL10/pharmacology , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/etiology , Diabetes Mellitus, Type 1/virology , Disease Models, Animal , Ergolines/administration & dosage , Ergolines/pharmacokinetics , Ergolines/pharmacology , Glucose Tolerance Test , Insulin/genetics , Insulin/metabolism , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/pathology , Insulin-Secreting Cells/physiology , Interferon-gamma/metabolism , Islets of Langerhans/drug effects , Islets of Langerhans/pathology , Lymph Nodes/immunology , Lymphocytes/immunology , Lymphocytes/metabolism , Lymphocytes/pathology , Lymphocytic choriomeningitis virus/genetics , Lymphocytic choriomeningitis virus/immunology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Receptors, CXCR3/metabolism , Spleen/immunology , Th1 Cells/cytology , Viral Proteins/genetics , Viral Proteins/immunologyABSTRACT
The prevention of xenograft rejection is substantially dependent on inhibiting antibodies (Ab) produced by B-cells independently of T-cell signals (TI-1). Due to their ubiquitous biochemical mechanisms of action, the immunosuppressants currently employed not only fail to discriminate between B- and T-cells but also have a narrow therapeutic window and, thus, their prolonged use in complex immunosuppressive regimens is problematic. By capitalizing on the target enzyme-bound (DHODH) structure 1b of one of these compounds, leflunomide, and modulating part of its multiple mechanisms of action to gain selectivity, the quinoline-8-carboxamide 3 was designed as a potentially weak enzyme inhibitor but effective immunosuppressant. Compound 3 fulfilled the mechanistic criteria set and had 10-fold B-cell over T-cell selectivity. Its pyridyl analogue 4 was found to be a highly potent and selective B-cell immunosuppressant with a 75-fold selectivity for B- over T-cells (as judged by the MLR data) and no general cytotoxicity at concentrations up to 160-fold higher than those required to inhibit B-cells. In the mouse, 4 effectively blocked TI-1 Ab production and suppressed Ab-mediated xenograft rejection in a xenotransplantation model under a once-daily dosing regimen, with efficacy down to 0.3 mg/kg/day po. These are the first data demonstrating the feasibility of the development of drugs specific for impeding Ab production.
