Aging and T cell Senescence in Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

About This Grant

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is the most common acquired chronic autoimmune neuropathy and occurs more frequently in the aged, with a peak incidence in those 70-79 years of age. How aging predisposes to peripheral nervous system (PNS) autoimmunity, however, is unclear. Early aging-associated changes include the acquisition of T cell immunosenescence, a dysfunctional, pro- inflammatory state that can lead to the spread of senescence to neighboring cell types. Our data demonstrate an increased burden of senescent T cells in patients and mice with CIDP, compared to age-matched controls. Moreover, our data suggest that peripheral nerve-infiltrating CD4+ T cells actively signal to adjacent PNS cell types, including Schwann cells, in a mouse model of CIDP. Thus, in this R21 proposal, we will test the hypothesis that senescence-associated CD4+ T cells predispose to PNS autoimmunity by inducing neighboring Schwann cells to acquire a senescent, dysfunctional state. In Aim 1, we will test how adoptive transfer of senescent T cells into an immunodeficient mouse recipients alters Schwann cell phenotype in the peripheral nerves of recipients. We will also assess whether conditioned media from senescent T cells of CIDP patients will induce senescence in a human Schwann cell line. In Aim 2, we will examine how disease protection is conferred by a senomorphic agent, ruxolitinib, in mice with CIDP and through the use of CIDP patient samples. Completion of these Aims are important steps toward a more comprehensive understanding of autoimmune mechanisms in CIDP and may point to the use of senomorphic therapies for the benefit of CIDP patients.