Exploiting the DNA damage response to selectively sculpt the T cellrepertoire

描述(由申请人提供)：不能选择性地靶向不良的T细胞反应，导致无数的免疫病理情况，包括自身免疫、过敏、先天性免疫调节障碍和同种异体排斥，是一个基本的临床问题。虽然在新的免疫抑制药物方面取得了进展，但潜在的策略仍然是全局抑制，以抑制少数有害的效应性T细胞。这种广泛的抑制方法相当于对免疫系统宣布戒严；限制大多数适应性免疫细胞的正常和有益活动，以阻止罕见的无赖T细胞。目前的战略有三大缺陷：(1)缺乏针对性；(2)增加机会性感染和癌症的风险；(3)与 实质性的特定毒剂的器官损伤和毒性。因此，很明显，我们需要找到新的、无毒的方法来控制罕见但有害的T细胞，同时保持有益的记忆和NA�ve T细胞来对抗病原体。我们相信我们有了一种新的方法来在体内特异性地靶向不想要的T细胞。当T细胞在它们的发育状态-NA�ve、激活效应器、静止记忆和激活记忆-之间转换时，我们发现它们表现出独特的属性，可以用来呈现它们的死亡。首先，我们观察到急性激活的T细胞在体内表现出强烈的DNA损伤反应(DDR)。第二，我们发现，临床上广泛使用的化疗药物依托泊苷可以消融活化的T细胞，而保留NA�Ve和静止的记忆T细胞。从机制上说，我们假设T细胞的抗原性激活使它们对DDR介导的凋亡具有独特的敏感性，这可能是由DNA损伤和/或DDR调节剂在治疗上触发的，同时提供NA�Ve和先前存在的记忆T细胞的存活。这一假设将通过(I)确定使用DDR调节器在体内成功靶向T细胞效应的参数；(Ii)定义DDR驱动活化T细胞凋亡的下游机制；以及(Iii)确定DDR操纵靶向人类疾病相关T细胞的选择性/有效性。我们的长期目标是节省有益的免疫，同时在广泛的临床环境中以最小的毒性清除不受欢迎的T细胞。

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.