Targeted in vivo perturbation for dissecting tissue immune responses

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PROJECT 3: PROJECT SUMMARY Successful vaccination represents the interplay of multiple, interacting innate, humoral, and cellular adaptive factors which have not yet been fully defined. The immune system as a whole is engaged, including both tissue resident and circulating populations. While we have elucidated important elements of the integrated response, many nuances in the role of selected cell subtypes remain to be determined both in isolation and in combination. One approach to dissect complex networks of immune responses that has been applied successfully in model systems - and in vitro for human immunology – involves molecularly specific, targeted perturbation of the baseline network of cellular interactions. Subsequent changes in immune responses can then begin to highlight the elements of the network involved in vaccine response related to the molecular entity that was targeted. Here, we deploy this strategy leveraging the fact that individuals with multiple sclerosis (MS) are treated with molecularly specific treatments and therefore present an opportunity to examine, in vivo, how targeted perturbation alters established responses to CMV and response to new vaccines in humans. We focus on two such treatments which are used as monotherapy: (1) B cell depletion with ocrelizumab and (2) sequestration of lymphocytes in the lymph node using fingolimod. We propose to longitudinally sample participants with MS treated with one of these two therapies - and healthy subjects to serve as a reference – through three vaccination cycles: two with SARS-CoV-2 vaccine and one with an influenza vaccine. At the pre-vaccination time point and up to 8 subsequent time points, we will assess humoral and T cell responses to CMV, influenza and SARS-CoV-2 using multiple different modalities, including high-dimensional cytometric, single cell CITEseq, and functional assessments in response to antigen-specific stimulation. We will therefore be in a rare position to model longitudinal responses to multiple different, antigen-specific stimulations over 3-4 years in the healthy and in vivo targeted perturbation context.