Immulogical Niches and Non-invasive Biosensors for Autoimmune Monitoring; Diversity Supplement

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Multiple sclerosis (MS) is a demyelinating autoimmune disease that is difficult to manage clinically, because it is characterized by unpredictable periods of remission and relapse. If the disease could be adequately monitored, it is possible drugs could intervene to prevent damage, reducing rates of relapse and overall progression. Ideally, it would be possible to repeatedly biopsy the CNS for monitoring, but this is too challenging/morbid to have utility. In the K99 phase of my work, we developed an approach that harnesses tissue engineering principles to develop an immunological niche (IN) in vivo to enable harvest of physiologically relevant immune populations. Furthermore, we developed synthetic biology-based biosensors that produce optically detectable signals in response to specific ligands. In the R00 phase, I propose to continue my work in this space, by testing the biosensors in vivo, engineering INs that specifically enrich pathogenic populations of adaptive immune cells, and leverage the combination biosensors and engineered IN to monitor expression of cytokines during antigen presentation in vivo. In Aim 2 (in progress) we developed three different engineered receptor systems that upon binding ligand dimerize and liberate an engineered transcription factor (TF). This TF traffics to the nucleus and induces expression of a transgene (bioluminescent protein). In the remaining work for Aim 2, we will load these cells into biomaterial niches and implant them in vivo to monitor for expression of specific cytokines involved in experimental autoimmune encephalomyelitis (EAE – mouse model of MS). In Aim 3 we will develop INs reflective of adaptive immune populations in the CNS, by incorporating antigens within the scaffolds. This section will create a non-invasive sensor and multivariate signature reflective of adaptive immune changes within the surrogates and harness both innate and adaptive INs to investigate mechanistic questions about innate-adaptive crosstalk in the development of MS. Taken together these studies will create engineered immunological niches and non-invasive sensors that enable the creation of enhanced diagnostics, prognostics, treatment monitors, and longitudinal immunology studies without euthanasia.