Dr. Nitin Karandikar received another 4-year VA Merit Award, entitled “Effector-Regulator Immune Interactions During Autoimmune Demyelinating Disease.” This competitive award was made under the VA’s CSRD (Clinical Science Research and Development) program, which focuses on clinically relevant translational research.
Dr. Karandikar's research focuses on the immune processes that underlie the causation and regulation of multiple sclerosis, an inflammatory demyelinating disease of the central nervous system (CNS). Through studies in human MS as well as its animal model (called EAE), his group was the first to show that CD8+ T cells that are targeted against CNS antigens (CNS-CD8) had the unexpected effect of suppressing disease. His group also was the first to show that CD8+ T cells are responsible for mediating the therapeutic effect of glatiramer acetate, a commonly used treatment for MS.
Dr. Karandikar’s group has shown that the suppressor activity of MS relapse-associated CD8 T-cells can be restored by in vitro pre-treatment with specific cytokines, revealing functional plasticity of these cells and providing a potential avenue for therapeutic intervention. At the same time, severe autoimmune disease is characterized by increased resistance of effector/pathogenic CD4 T-cells to immune regulation. This project addresses this poorly understood but fundamental feature of the immune regulatory apparatus, in the context of MS. The proposal hypothesizes that CD4 T-cells from MS patients have an intrinsically enhanced tendency to develop effector resistance to immune suppression in an inflammatory context, while CD8 T-cells from MS patients have an intrinsically enhanced tendency to develop lower suppressive ability.These phenotypes are plastic and can be modulated by appropriate stimuli. To address these hypotheses, a two-pronged approach will be used that dissects the biology of CD4 resistance, focusing on the novel CD4-intrinsic biology of IL-17 cytokines, and the biology and modulation of CD8 suppression in MS will also be addressed. These studies will provide insights into the immune dysregulation that underlies MS pathogenesis, with implications for treatment approaches in MS and multiple other disease settings.