Elucidating the role of APCs in immune tolerance during direct lymph node immunotherapy

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Project Summary Multiple Sclerosis (MS) is a debilitating autoimmune disease that occurs when the immune system incorrectly recognizes myelin as foreign. Myelin is a protective matrix that insulates neurons in the central nervous system (CNS). Current therapies require continual treatment over the patient’s life, do not address the underlying cause of disease, and causes susceptibility to infection. While recent advances have improved therapeutic targeting, even the newest monoclonal antibodies are unable to differentiate between disease causing inflammatory cells and healthy immune cells. In MS, myelin reactive T cells are activated by antigen presenting cells (APCs) in lymph nodes (LNs) – sites that coordinate immune cell interactions. APCs (dendritic cells (DCs), macrophages, and B cells) present antigens, costimulatory molecules, and polarizing cytokines to T and B cells. The signals present during T cell-APC interactions polarize T cells to either regulatory (e.g. TREG) or inflammatory (e.g. TH1 and TH17) cell functions. During MS, myelin reactive immune cells migrate to the CNS where they secrete inflammatory cytokines promoting inflammatory cell recruitment. Our lab has shown a single intra LN (iLN) microparticle (MP) treatment permanently reverses paralysis in a mouse model of MS. These MPs encapsulate a myelin antigen (myelin oligodendrocyte glycoprotein, MOG), and immune regulatory molecule, rapa. These MPs are designed to be too large to drain from the LN, instead serving as depots that slowly release the cargo as the MPs degrade. Despite this potent and durable efficacy, the contribution of APCs to this therapeutic impact remain unknown. This system provides a unique opportunity to understand how APCs regulate antigen specific immune responses. APCs provide critical signals required for T cell activation, proliferation, and differentiation, thus it is important to understand the regulation of APC signals. During the award period, I will test the hypothesis that iLN delivery of MOG/rapa MPs drives tolerogenic APC phenotype and function. In addition, I will measure how the changes in APCs impact downstream T cell-APC interactions and promote regulatory functions among myelin-specific T cells. In support of this idea, my preliminary studies revealed mice treated with MOG/rapa MPs had DCs that displayed lower levels of activation than DCs from mice treated with empty MPs. Strikingly, DCs from mice treated with MOG/rapa MPs caused lower levels of myelin specific T cell proliferation as measured by flow cytometry. These results indicate that MOG/rapa MP treatment alters the function of DCs and the subsequent interactions of these cells with myelin-specific T cells. Motivated by these pilot studies, I will use a mouse model of MS to carry out two aims: 1) Assess alterations in APC phenotype as well as MP and APC tissue localization and 2) Determine functional changes MPs exert on APCs and the downstream impact on T cell development. These aims will provide understanding about the role APCs play in establishing antigen-specific tolerance. In addition to my proposed research, I designed a holistic training plan that will help me advance toward my goal of leading an independent research lab. The revised work planned for the F31 award period will be valuable in terms of both research and training opportunities.