Acceleration of autoimmune diabetes by cyclophosphamide is associated with an enhanced IFN-gamma secretion pathway.

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Acceleration of autoimmune diabetes by cyclophosphamide is associated with an enhanced IFN-gamma secretion pathway.

J Autoimmun. 1999 Dec;13(4):383-92. Unique Identifier : AIDSLINE MED/20054047
Ablamunits V; Quintana F; Reshef T; Elias D; Cohen IR; Department of Immunology, The Weizmann Institute of Science,; Rehovot, 76100, Israel.

Abstract: Cyclophosphamide (CY), an alkylating cytostatic drug, is known for its ability to accelerate a number of experimental autoimmune diseases including spontaneous diabetes in NOD mice. The mechanism(s) by which CY renders autoreactive lymphocytes more pathogenic is largely unknown, but it has been postulated that the drug preferentially depletes regulatory (suppressor) T cells. It has been suggested that in cell-mediated autoimmune diseases, Th2-like lymphocytes secreting IL-4 and/or IL-10 provide protection, while Th1-like cells secreting IFN-gamma are pathogenic. In this study, we analysed the effects of CY on autoimmune diabetes and cytokines in two mouse models: the spontaneous diabetes of NOD mice and the diabetes induced in C57BL/KsJ mice by multiple injections of low dose streptozotocin (LD-STZ). In both models, CY induced severe lymphopenia and accelerated the progression to hyperglycemia. This was associated with changes in splenic cytokine patterns indicating a shift towards the IFN-gamma-secreting phenotype. We provide here evidence that IFN-gamma producers are relatively resistant to depletion by CY and that Th0 clones can be shifted towards Th1. However, direct exposure of T lymphocytes to CY may not be a necessary condition for exacerbation of diabetes; NOD.scid mice treated with CY before adoptive transfer of NOD splenocytes developed diabetes at a higher rate than did controls. Thus, the acceleration of diabetes by CY seems to be a complex event, which includes the relatively high resistance of IFN-gamma producers to the drug, their rapid reconstitution, and a Th1 shift of surviving T cell clones. Copyright 1999 Academic Press.

Keywords: JOURNAL ARTICLE Animal Cell Differentiation Cyclophosphamide/*PHARMACOLOGY Diabetes Mellitus, Experimental/CHEMICALLY INDUCED Diabetes Mellitus, Insulin-Dependent/*PHYSIOPATHOLOGY Hematopoietic Stem Cells/CYTOLOGY Immunophenotyping Immunosuppressive Agents/*PHARMACOLOGY Interferon Type II/BIOSYNTHESIS/*SECRETION Interleukin-10/SECRETION Interleukin-4/SECRETION Islets of Langerhans/DRUG EFFECTS Mice Mice, Inbred C57BL Mice, Inbred NOD Spleen/CYTOLOGY Streptozocin/PHARMACOLOGY Support, Non-U.S. Gov't Th1 Cells/CYTOLOGY Up-Regulation (Physiology)
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