Exploiting the DNA damage response to selectively sculpt the T cellrepertoire

Cincinnati Childrens Hosp Med Ctr, Cincinnati OH

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Abstract

DESCRIPTION (provided by applicant): The inability to selectively target undesirable T cell responses driving a myriad of immunopathologic conditions including autoimmunity, allergy, inborn disorders of immune regulation, and allogeneic rejection, is a fundamental clinical problem. While progress has been made with newer immunosuppressive drugs, the underlying strategy remains one of global suppression in order to inhibit a few detrimental effector T cells. This broad inhibitory approach is the equivalent of declaring martial law on the immune system; curtailing the normal and beneficial actions of most adaptive immune cells in order to stop the rare rogue T cell. Current strategies have three major drawbacks: (i) they lack specificity; (ii) they increase the risks of opportunistic infections and cancers; and (iii) they are associated with substantial agent-specific organ damage and toxicity. Thus, it is clear that we need to find novel and non-toxic means of controlling infrequent, yet injurious T cells, while maintaining beneficial memory and na?ve T cells to combat pathogens. We believe we have a novel approach to the specific targeting of unwanted T cells in vivo. As T cells transition between their developmental states - na?ve, activated effector, quiescent memory, and activated memory - we have found that they exhibit unique attributes that can be exploited to render their demise. First, we have observed that acutely-activated T cells display a strong DNA damage response (DDR) in vivo. Second, we found that etoposide, a chemotherapeutic agent in wide clinical use, ablates activated T cells while sparing na?ve and quiescent memory T cells. Mechanistically, we hypothesize that antigenic activation of T cells renders them uniquely susceptible toDDR-mediated apoptosis, which may be therapeutically triggered with either DNA- damaging and/or DDR-modulating agents, while affording survival of na?ve and pre-existing memory T cells. This hypothesis will be tested by (i) defining the parameters of successful in vivo targeting of effecto T cells using modulators of the DDR; (ii) defining downstream mechanisms of DDR-driven apoptosis in activated T cells; and (iii) determining the selectivity/efficacy of DDR manipulation for targeting human disease-associated T cells. Our long-term goal is to spare beneficial immunity, while purging undesirable T cells with minimal toxicity in a broad array of clinical contexts.