Designing induction therapies to target memory T cells in high risk recipients

 描述（由申请方提供）：抗体介导的耗竭广泛用作致敏移植受者的诱导治疗，以克服预先存在的供体反应性免疫的有害作用。然而，记忆性T细胞比幼稚T细胞更不容易耗尽，目前还没有努力提高诱导疗法的疗效。 靶向供者反应性T细胞记忆。我们先前在使用兔抗鼠胸腺球蛋白（mATG）的小鼠心脏移植模型中的研究表明，恢复记忆性CD 8 T细胞是mATG治疗的受体中介导同种异体移植排斥反应的主要效应机制。初步实验表明，在抗体介导的耗竭后，记忆性CD 8 T细胞的恢复需要来自耗竭抗性记忆性CD 4 T细胞的帮助，并且鉴定出B细胞是这种帮助的关键介质。限制性CD 4 T细胞帮助延迟记忆性CD 8 T细胞重建显著增强mATG诱导治疗在致敏受者中的功效，并且与具有调节表型的T和B细胞的增加相关。这项研究的目的是确定抗体介导的耗竭后记忆T细胞重建的机制，并利用这些信息制定改善高危受者同种异体移植结局的策略。我们假设，在抗体介导的淋巴消融后，残留的记忆性CD 4 T细胞通过TCR/MHC II类和CD 40/CD 154与B细胞相互作用，并诱导Beff细胞活化，产生炎性细胞因子，如TNFα。随后，同源B细胞/CD 8 T细胞相互作用和B细胞衍生的细胞因子促进稳态CD 8 T细胞扩增。干扰辅助信号将增加布雷格/Beff和Treg/Teff细胞比率，并有效抑制记忆性CD 8 T细胞恢复和致病性抗供体应答的发展。我们将在三个具体目标中检验这一假设：目标1。确定抗体介导的淋巴消融后B细胞介导记忆性CD 8 T细胞重建的机制。目标2.检测阻断CD 4 T细胞是否有助于提高致敏心脏移植受者中mATG诱导治疗的疗效。目标3.目的：检测调节性T细胞在清除淋巴细胞策略中对同种异体移植免疫应答的作用。我们预计，这些研究中开发的方法将专门针对预先存在的供体反应性记忆T细胞，并将提高致敏移植患者淋巴消融术的疗效。

 DESCRIPTION (provided by applicant): Antibody-mediated depletion is widely used as induction therapy in sensitized transplant recipients to overcome the deleterious effects of preexisting donor-reactive immunity. However, memory T cells are less susceptible to depletion than naïve T cells and there are no current efforts to improve the efficacy of induction therapies in targeting donor-reactive T cell memory. Our previous studies in a mouse model of cardiac transplantation using rabbit anti-murine thymoglobulin (mATG) showed that recovering memory CD8 T cells are the primary effector mechanism mediating allograft rejection in mATG treated recipients. Preliminary experiments showed that help from depletion-resistant memory CD4 T cells is required for memory CD8 T cell recovery following antibody-mediated depletion and identified B cells as critical mediators of this help. Limiting CD4 T cell help delays memory CD8 T cell reconstitution markedly enhances the efficacy of mATG induction therapy in sensitized recipients and is associated with the increase in T and B cells with regulatory phenotypes. The goal of the proposed study is to determine the mechanisms of memory T cell reconstitution following antibody mediated depletion and to use this information to develop strategies improving allograft outcome in high risk recipients. We hypothesize that following antibody-mediated lymphoablation, residual memory CD4 T cells interact with B cells through TCR/MHC class II and CD40/CD154 and induce Beff cell activation to produce inflammatory cytokines such as TNFα. Subsequently, cognate B cell/CD8 T cell interactions and B cell derived cytokines facilitate homeostatic CD8 T cell expansion. Interference with helper signals will increase Breg/Beff and Treg/Teff cell ratios and effectively inhibit memory CD8 T cell recovery and the development of pathogenic anti-donor responses. We will test this hypothesis in three Specific Aims: Aim 1. To determine the mechanisms through which B cells mediate memory CD8 T cell reconstitution following antibody-mediated lymphoablation. Aim 2. To test whether blocking CD4 T cell help increases the efficacy of mATG induction therapy in sensitized heart allograft recipients. Aim 3. To test the contribution of regulatory T cells to allograft prolongatin by lymphoablative strategies. We anticipate that the approaches developed in these studies will specifically target pre-existing donor-reactive memory T cells and will improve the efficacy of lymphoablation in sensitized transplant patients.