title: The immunosuppressive agent 15-deoxyspergualin functions by inhibiting cell cycle progression and cytokine production following naive T cell activation.
abstract: 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-gamma 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-gamma-secreting Th1 effector T cells in the induction of certain autoimmune disorders.
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Hilda
authors.initials: H
authors.lastname: Holcombe
authors.forename: Ira
authors.initials: I
authors.lastname: Mellman
authors.forename: Charles A
authors.initials: CA
authors.lastname: Janeway
authors.forename: Kim
authors.initials: K
authors.lastname: Bottomly
authors.forename: Bonnie N
authors.initials: BN
authors.lastname: Dittel
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects* / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006131:Growth Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006146:Guanidines / Q000494:pharmacology* / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007399:Interphase / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D012720:Severity of Illness Index; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D006131:Growth Inhibitors; D006146:Guanidines; D007166:Immunosuppressive Agents; D004676:Myelin Basic Protein; D010446:Peptide Fragments; C405722:myelin basic protein 1-11; D007371:Interferon-gamma; C037258:gusperimus