Autoreactive effector memory (TEM) T lymphocytes are implicated in the pathogenesis of multiple sclerosis (MS), type-1 diabetes mellitus (DM), psoriasis, rheumatoid arthritis and chronic graft-versus-host disease. Recent studies by our group suggest that the voltage-gated Kv1.3 channel is an exciting new target for the therapeutic manipulation of TEM cells. Kv1.3-based therapy for autoimmune disease that target TEM cells would have an advantage over broad and indiscriminate immunosuppression because na'fve/TCM cells would escape inhibition through up-regulation of the calcium-activated IKCal channel, leaving the bulk of the immune response unimpaired. In this proposal, we combine studies on patients with MS and type-1 DM with experiments in an animal model of MS, to establish the intellectual framework for the development of Kv1.3 as a therapeutic and diagnostic target for T cell-mediated autoimmune diseases.
Aim -1 determines if the presence of myelin-specific Kv 1.3high TEM cells in patients with MS is an indicator of disease activity and whether these cells decrease after therapy. We will also screen postmortem brain sections from MS patients for Kv1.3high activated TEM cells to support a role for these cells in pathogenesis.
Aim 2 evaluates the therapeutic effectiveness of Kv 1.3 and IKCal blockers in a rat model of MS that exhibits a chronic relapsing-remitting clinical course similar to MS.
Aim 2. 1 will investigate the channel and cell surface phenotype of T cells infiltrating the CNS during the initial and relapsing phases of disease and identify Kv1.3high TEM cells in inflammatory lesions in the CNS.
Aim 2. 2 will determine if ShK, the most potent Kv1.3 inhibitor, and TRAM-34, a specific IKCal inhibitor, administered alone or in combination, prevent and cure EAE. A successful outcome would pave the way to future trials in primate models of MS and eventually in humans.
Aim 3 examines whether insulin- and GAD65-specific memory T cells that are implicated in disease pathogenesis of type-1 diabetes mellitus, express the Kv1.3high activated TEM phenotype. Functional studies will ascertain whether ShK suppresses antigen-driven proliferation and cytokine production by these cells. If proven true, it would raise the possibility of using a channel-based therapy to ameliorate autoimmune disorders that afflict several million people globally.
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