CELLULAR CORRECTION OF CONGENITAL HEMATOPOIETIC DISORDERS

当组织相容性供体可用时，同种异体造血干细胞移植（HSCT）提供了一种非常成功的方式来纠正先天性造血障碍。阻碍更广泛使用这一方法的主要障碍是能否找到匹配的供体，特别是对于服务不足的少数群体和疾病迅速进展的患者。在过去的五年中，我们和其他人在克服这一障碍方面取得了重大进展，试图开发促进单倍体造血干细胞移植的策略。我们假设，通过操纵供体t细胞诱导对受体同种异体抗原的长期无反应性，可以增加供体库，同时改善与同种异体反应性相关的HSCT毒性。在我们体外诱导供体t细胞能量到受体同种异体抗原的I期试验中，我们证明了这种方法的可行性，并成功地对2名先天性造血疾病儿童进行了单倍体同种供体造血干细胞移植。为了使更多的先天性造血障碍患者能够更早地接受这种方式，我们必须提高造血干细胞移植的治疗指标。为了实现这一目标，我们必须权衡来自同种异体匹配和单倍体相同供体的造血干细胞移植的短期和长期毒性与慢性疾病患者的预期寿命和生活质量。对这些患者来说，无论是从根本上增加急性发病率或死亡率，还是用一种慢性病代替另一种慢性病，都不是可接受的结果。如果：1)可以特异性消除每个供体和受体对特有的同种异体反应性，治疗指数将显著提高；2)放化疗清髓治疗的短期和长期副作用可以减少或预防；3)造血干细胞移植后免疫能力迅速恢复。只要这些目标没有实现，风险：收益比率将继续倾向于更良性的姑息治疗形式，而不是有风险但有疗效的HSCT方法。为实现这些目标，提出了三个具体目标。首先，我们将修改我们的方法，这样我们将能够诱导和评估供体T细胞中的同种抗原特异性T细胞能量，为先天性造血疾病患者进行造血干细胞移植。其次，我们将把这种改进的方法应用于临床转化试验，目标是为所有合适的患者提供供体，降低临床显著急性和/或慢性GVHD的发生率，提高免疫重建的比率和程度。第三，我们将尝试通过探索产生针对造血干细胞和祖细胞抗原的T细胞或单克隆抗体的可行性来减少或改善对高剂量放化疗的需求，这些抗体可能能够消融造血。虽然这些目标雄心勃勃，但我们期望在这一供资期间取得相当大的进展。实现这些目标可能使使用几乎普遍的供体穷人通过HSCT纠正先天性造血疾病成为可能，而不会产生伴随同种异体、免疫能力和方案相关的终末器官损伤的急性和慢性毒性。

When a histocompatible donor is available, allogeneic hematopoietic stem cell transplantation (HSCT) provides a highly successful modality with which to correct congenital disorders of hematopoiesis. The major barrier preventing more widespread use of this approach is the availability of a matched donor, especially for underserved minorities and patients with rapidly progressive disease. During the past five years, we and others have made significant progress in overcoming this barrier by attempting to develop strategies that will facilitate haploidentical HSCT. We hypothesized that manipulation of donor T-cells to induce long lasting unresponsiveness to recipient alloantigens would increase the donor pool while ameliorating HSCT toxicities associated with alloreactivity. In our phase I trial of ex vivo induction of donor T-cell anergy to recipient alloantigens, we demonstrated the feasibility of this approach and have successfully performed haploidentical donor HSCT in 2 children with congenital disorders of hematopoiesis. In order for greater numbers of patients with congenital disorders of hematopoiesis to be offered this modality earlier, their disease course, we must improve the therapeutic index of HSCT. To achieve this goal, we must weight the we-established and considerable short-term and long-term toxicities of HSCT from allogeneic matched and haploidentical donors against the immediate life- expectancy and quality of life of the patient with a chronic disease. For these patients, neither radically increasing acute morbidity or mortality nor substituting one chronic disease for another would be acceptable outcomes. The therapeutic index would be significantly improved if: 1) alloreactivity unique to each donor: recipient pair could be specifically eliminated; 2) short and long term side-effects of chemoradiotherapeutic myeloablative therapy could be reduced or prevented; and 3) immunocompetence could be rapidly restored after HSCT. As long as these goals are not met, the risk: benefit ratio will continue to favor the more benign forms of palliative care rather than the risky but curative approach of HSCT. To achieve these ends, three specific aims are proposed. First, we will modify our methodology such that we will be able to induce and assess alloantigen specific T-cell anergy in donor T- cells to perform HSCT for patients with congenital disorders of hematopoiesis. Second, we will apply this improved methodology in clinical translational trials with the goals of making donors available for all suitable patients, reducing the rate of clinically significant acute and/or chronic GVHD and improving the rate and degree of immunologic reconstitution. Third, we will attempt to reduce or ameliorate the need for high dose chemoradiotherapy by exploring the feasibility of generating T- cells or monoclonal antibodies directed against hematopoietic stem and progenitor cell antigens which might be able to ablate hematopoiesis. Although these aims are ambitious, we expect to make considerable progress during this funding period. Realization of these goals may make it possible to use a near universal donor poor to correct congenital diseases of hematopoiesis by HSCT without the debilitating acute and chronic toxicities which accompany allogenicity, immunocompetence, and regimen related end-organ damage.