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The Immunosuppressive Agent 15-Deoxyspergualin Functions by Inhibiting Cell Cycle Progression and Cytokine Production Following Naive T Cell Activation¹

Hilda Holcombe^2,*, Ira Mellman^*,,, Charles A. Janeway, Jr.^,, Kim Bottomly and Bonnie N. Dittel^3,,

^* Department of Cell Biology, Section of Immunobiology, and Ludwig Institute for Cancer Research, Yale University School of Medicine, and Howard Hughes Medical Institute, New Haven, CT 06520

Immunosuppressive agents are commonly used in the prevention of graft rejection following transplantation and in the treatment of autoimmunity. In this study, we examined the immunosuppressive mechanism of the drug 15-deoxyspergualin (DSG), which has shown efficacy in the enhancement of graft survival and in the treatment of autoimmunity. Using a murine model of chronic relapsing and remitting experimental autoimmune encephalomyelitis, we were able to demonstrate that DSG both delayed and reduced the severity of experimental autoimmune encephalomyelitis. Subsequent in vitro studies to examine the mechanism of immune suppression showed that DSG was not able to inhibit early activation of naive CD4 T cells, but DSG did effectively inhibit the growth of naive CD4 T cells after activation. An analysis of cell proliferation and cell cycle showed that DSG treatment led to a block in cell cycle progression 2–3 days following Ag stimulation. In addition, DSG treatment inhibited the production of IFN- by Th1 effector T cells. These studies suggest that CD4 T cells are a predominant target for DSG and the immunosuppressive effects of the drug may result from reduced CD4 T cell expansion and decreased polarization into IFN--secreting Th1 effector T cells in the induction of certain autoimmune disorders.

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