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-γ 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-γ-secreting Th1 effector T cells in the induction of certain autoimmune disorders.

Fumonisin B1 alters cell cycle progression and interleukin‐2 synthesis in swine peripheral blood mononuclear cells

“…Sphingoid bases are known to mediate several key biological processes such as cell proliferation or DNA replication [27]. Moreover, cell cycle control, including cell growth and proliferation as well as cell cycle arrest and apoptosis, plays a central role in cellular immune responses [28]. In this context, FB 1 has been shown to alter some lymphocyte functions and to reduce specific antibody production after vaccination with Mycoplasma agalactiae [29,30], to alter cytotoxic functions [31] and to decrease proliferation [32,33].…”

Derivatives of human β-Casein fragments (54–59) exhibit highly potent immunosuppressant activity

“…These peptides showed different immunosuppressive properties compared to commonly used immunosuppressant cyclosporine-A and FK506 which acts by inhibiting production of IL-2 by lymphocytes [27]. These peptides rather act like 15-Deoxyspirogualin (DSG) which suppresses the PFC number, production of IFN-γ and prolongation of skin graft survival [28,29]. The lack of effect of these peptides and DSG on IL-2 production indicates that these peptides must not interfere significantly with the early activation events of the immune response as IL-2 gene activation occurs at early phage of lymphocyte activation.…”

Therapeutics of Wegener's granulomatosis

“…51,52 In two small, openlabel studies, DSG was used to treat patients with Wegener's granulomatosis whose disease was refractory to conventional therapy consisting of cyclophosphamide and glucocorticoids. 53 Schmitt et al 54 showed that all but one patient (n = 7) went into complete or partial remission while taking DSG.…”