Acceleration of autoimmune diabetes by cyclophosphamide is associated with an enhanced IFN-gamma secretion pathway.
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.
Ablamunits
V
V
Department of Immunology, The Weizmann Institute of Science, Rehovot, 76100, Israel.
Quintana
F
F
Reshef
T
T
Elias
D
D
Cohen
I R
IR
D000818:Animals; D002454:Cell Differentiation; D003520:Cyclophosphamide / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology*; D006412:Hematopoietic Stem Cells / Q000166:cytology; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D013154:Spleen / Q000166:cytology; D013311:Streptozocin / Q000494:pharmacology; D018417:Th1 Cells / Q000166:cytology; D015854:Up-Regulation
D007166:Immunosuppressive Agents; D016753:Interleukin-10; D015847:Interleukin-4; D013311:Streptozocin; D007371:Interferon-gamma; D003520:Cyclophosphamide