Exploiting the Bioenergetics of Disease-Causing Lymphocytes for Selective Immunomodulation.

[摘要] In diseases such as lupus or graft-versus-host disease (GVHD), lymphocytes react against self- or allo-antigen and mediate tissue damage.Current treatments for such diseases rely on non-specific immunosuppression and lead to opportunistic infections.Disease-causing lymphocytes perform numerous energetically demanding processes including proliferation and cytokine synthesis.While activated lymphocytes primarily utilize glycolysis in vitro, little is known regarding the bioenergetics of disease-causing lymphocytes in vivo.Understanding the metabolic pathways used by disease-causing lymphocytes could provide novel therapeutic targets that allow for selective immunomodulation.As such, the goal of this research is to characterize the pathways of cellular metabolism used by pathogenic lymphocytes and to exploit these pathways to treat disease.Splenocytes from NZB/W mice with lupus up-regulate the oxidation of glucose rather than its conversion to lactate.This oxidative phenotype is distinct from acutely-activated T cells, which produce lactate at high rates.However, chronically-stimulated T cells have low rates of lactate production, suggesting that a reliance on oxidative metabolism could be a consequence of chronic stimulation.In the setting of unirradiated GVHD, alloreactive donor T cells up-regulate OXPHOS but have low rates of glycolysis.This bioenergetic phenotype contrasts with control-stimulated T cells and proliferating bone marrow cells, which primarily up-regulate glycolysis.The oxidative phenotype of alloreactive donor T cells is associated with an increased mitochondrial membrane potential, increased levels of superoxide and depleted antioxidants.These bioenergetic abnormalities suggest that GVHD-causing T cells could be sensitive to therapeutic agents that modulate the OXPHOS pathway or induce ROS-dependent apoptosis.Bz-423 is a novel therapeutic that modulates the mitochondrial F1Fo-ATPase, hyperpolarizes m, and induces superoxide-dependent apoptosis.We show that Bz-423 induces mitochondrial membrane potential hyperpolarization, superoxide production and apoptosis in alloreactive donor T cells in vivo.However, Bz-423 does not affect unstimulated T cells or proliferating cells in the bone marrow, which have low rates of OXPHOS and intact antioxidants.Bz-423 treatment reduces tissue damage and mortality in a model of nonirradiated GVHD, but does not inhibit immune reconstitution in fully irradiated syngeneic transplants.Hence, differences in cellular bioenergetics allow Bz-423 to selectively kill GVHD-causing lymphocytes without inducing non-specific immunosuppression.

[发布机构] University of Michigan

[效力级别] GVHD

[关键词] Mitochondria;GVHD;Lymphocyte;Reactive Oxygen Species;Bz-423;Antioxidant;Biological Chemistry;Microbiology and Immunology;Health Sciences;Science;Chemical Biology