Antigen Specific T Cell tolerance by Anti CD3 Antibodies

描述(由申请人提供)：移植异基因供者的造血干细胞后可能会发生严重的移植物抗宿主病(GVHD)，尽管可用于免疫抑制的最佳方案。实验动物数据和临床试验结果表明，T细胞在移植物抗宿主病中起核心作用。最近对外周T细胞耐受机制的研究进展使得验证T细胞受体(TCR)部分激动剂配体通过选择性去除同种异体反应性T细胞来预防人类GVHD的假说成为可能。移植耐受是由特定的同种异体抗原引起的外周T细胞活化诱导细胞死亡(AICD)促进的，而TCR信号是诱导抗原特异性耐受所必需的。TCR参与可以诱导T细胞的增殖和分化，也可以诱导AICD。CD3是与TCR复合体相关的单态链，抗CD3的单抗模拟抗原并诱导TCR信号和T细胞活化。Fc受体(FCR)结合的抗CD3单抗可以募集抗原提呈细胞(APC)，并传递完整的激动剂信号，促进T细胞的增殖和效应功能，而不依赖于抗原。相反，非FCR结合的抗CD3单抗诱导部分激动型TCR信号模式，在初始T细胞中引起无能，在抗原激活的循环T细胞中引起AICD。在小鼠中，我们发现非FCR结合的抗CD3单抗诱导识别受体同种异体抗原的供体T细胞选择性耗尽，从而防止跨越MHC差异的移植物抗宿主病，并保留针对第三方抗原的T细胞。与J.Tso合作，我们设计了一种人源化的非FCR结合的抗CD3单抗，visilizumab，它向TCR传递部分激动剂信号。Visilizumab比其他抗CD3单抗更有效地诱导激活的、循环的人类T细胞发生AICD。我们在人体试验中的初步结果表明，visilizumab可以在一些严重的急性GVHD患者中诱导完全临床反应，这对传统的免疫抑制药物是无效的。我们建议研究visilizumab预防人类白细胞抗原相合供者造血细胞移植后移植物抗宿主病(GVHD)的疗效，并评估其免疫抑制作用是否对同种异体抗原具有选择性。我们将追求以下具体目标：目的1：确定人源化非FCR结合的抗CD3单抗visilizumab预防人类白细胞相合供者T全血细胞移植后严重GVHD的安全性和有效性。目的：研究visilizumab治疗是否耗尽同种异体反应性T细胞池，同时保留对第三方同种异体抗原、巨细胞病毒(CMV)和EB病毒(EBV)以及肿瘤相关抗原WT1的免疫。公共卫生相关性：开发预防移植物抗宿主病的有效方案将提高移植后患者的安全性和存活率，并将这一程序的使用推广到更多的患者。在预防移植物抗宿主病方面的进展有可能推进器官移植和自身免疫性疾病的治疗领域。抗CD3单抗代表了一类新型治疗剂的原型，这种治疗剂通过诱导流产的激活和T细胞死亡来抑制免疫系统。抗CD3单抗之所以独特，比其他药物更具吸引力，是因为它具有快速和不可逆转地实现免疫耐受的潜力。表明非FCR结合的抗CD3单抗备用针对病毒和肿瘤相关抗原的T细胞是预测患者安全性的关键。

DESCRIPTION (provided by applicant): Transplantation of hematopoietic stem cells from an allogeneic donor can be followed by serious graft-versus-host disease (GVHD) despite the best available regimen for immune suppression. Experimental animal data and results of clinical trials have demonstrated that T cells play a central role in GVHD. Recent advances in understanding the mechanisms of peripheral T cell tolerance have made it feasible to test the hypothesis that GVHD can be prevented in man by T cell receptor (TCR) partial agonist ligands through the selective depletion of alloreactive T cells. Transplantation tolerance is facilitated by activation-induced cell death (AICD) of peripheral T cells triggered by the specific alloantigens, and TCR signals are indispensable for induction of antigen-specific tolerance. TCR engagement can induce either T cell proliferation and differentiation or AICD. Monoclonal antibodies (mAb) to CD3, a monomorphic chain associated to the TCR complex, mimic antigen and induce TCR signaling and T cell activation. Fc receptor (FcR)-binding anti-CD3 mAbs recruit antigen-presenting cells (APC) and deliver full agonist signals that promote T cell proliferation and effector functions, independent of antigen. In contrast, non-FcR-binding anti-CD3 mAbs induce a partial agonist TCR signaling pattern causing anergy in naive T cells and AICD in antigen-activated, cycling T cells. In mice, we found that non-FcR-binding anti-CD3 mAbs induce selective depletion of donor T cells that recognize recipient alloantigens thereby preventing GVHD across MHC disparities, and spare T cell specific to third party antigens. In collaboration with J. Tso, we designed a `humanized' non-FcR-binding anti-CD3 mAb, visilizumab, which delivers a partial agonist signal to the TCR. Visilizumab is more effective than other anti-CD3 mAbs in inducing AICD of activated, cycling human T cells. Our preliminary results in human trials show that visilizumab can induce complete clinical responses in some patients with severe acute GVHD, refractory to conventional immune suppressive agents. We propose here to study efficacy of visilizumab in the prevention of GVHD after hematopoietic cell transplantation (HCT) from HLA incompatible donors, and assess whether its immune suppressive effects are selective for alloantigens. We will pursue the following specific aims: Aim 1: Determine the safety and efficacy of humanized non-FcR-binding anti-CD3 mAb visilizumab in preventing severe GVHD after transplantation of T-replete hematopoietic cell grafts from HLA-incompatible donors. Aim 2: Investigate whether visilizumab therapy depletes the alloreactive T cell pool, while sparing immunity to third party alloantigens, cytomegalovirus (CMV) and Epstein-Barr virus (EBV), and tumor- associated antigen WT1. PUBLIC HEALTH RELEVANCE: The development of effective regimens for the prevention of GVHD will improve patient safety and survival after transplantation, and extend the use of this procedure to a larger number of patients. Progress in the prevention of GVHD has the potential for advancing the fields of organ transplantation and therapy for autoimmune disorders. Anti-CD3 mAbs represent the prototype of a new class of therapeutic agents that suppress the immune system by inducing an abortive activation and T cell death. What makes anti-CD3 mAbs unique and more attractive than other agents is the potential for achieving immunological tolerance rapidly and irreversibly. Showing that non-FcR-binding anti-CD3 mAbs spare T cells specific for viral and tumor-associated antigens is key to predict patient safety.