Exploiting the DNA damage response to selectively sculpt the T cellrepertoire

描述（由申请人提供）：无法选择性地靶向不良T细胞反应，导致无数的免疫病理状况，包括自身免疫、过敏、先天免疫调节障碍和异体排斥，是一个基本的临床问题。虽然新的免疫抑制药物取得了进展，但潜在的策略仍然是全局抑制，以抑制少数有害的T细胞。这种广泛的抑制方法相当于对免疫系统宣布戒严令；减少大多数适应性免疫细胞正常和有益的行为，以阻止罕见的流氓T细胞。目前的战略有三个主要缺点：(i)缺乏特异性；（ii）增加机会性感染和癌症的风险；（iii）他们与

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.