Strategies to Enhance Lymphoid Recovery After Radiation-Induced Injury

描述(由申请人提供)：淋巴样细胞对辐射损伤的影响特别敏感，使辐射损伤的受害者面临更高的感染和恶性肿瘤风险。我们对白介素7(IL-7)和角质形成细胞生长因子(KGF)的临床前和临床研究表明，这些药物通过保护和促进胸腺基质(KGF)的增殖、促进胸腺生成(IL-7和KGF)以及外周T细胞的凋亡和增殖(IL-7)来促进T细胞的恢复。“现成”同种异体淋巴前体的过继治疗导致胸腺和胸腺外部位的T和NK细胞重建的早期“波”，从而增强T细胞免疫。基于这些数据，我们建议在小鼠辐射损伤模型中进行研究，以分析KGF和IL-7的应用效果，以及体外产生的同种异体淋巴前体的过继免疫治疗。我们假设，给予IL-7、KGF或受托淋巴前体细胞可以促进辐射损伤后淋巴系统的恢复。我们的具体目标是：研究(目标1)KGF、(目标2)IL-7和(目标3)同种异体淋巴前体在辐射诱导的淋巴系统损伤中的作用。我们将分析IL-7、KGF和/或淋巴前体在急性暴露于不同剂量的辐射后对淋巴恢复(特别是T细胞)和功能的影响。我们将研究辐射损伤的以下几个方面：(A)辐射剂量(B)局部照射与全身照射，以及(C)接受者的年龄。对于所有策略，我们将评估对胸腺和胸腺外(胃肠道)重建和外周T细胞功能的影响。在我们对IL-7和KGF的研究中，我们将分析(D)IL-7和KGF受体的表达水平，(E)KGF或IL-7的剂量水平，(F)剂量间隔，(G)治疗持续时间，(H)开始治疗的时间对IL-7或KGF疗效的影响，以及(I)细胞群体对KGF或IL-7的反应的细胞内信号特征。此外，在我们对同种异体淋巴前体细胞的研究中，我们将使用生物发光成像对转移的前体细胞进行体内时空分析。最后，我们将评估淋系前体与KGF和/或IL-7的组合策略。在这一应用中，我们建议开展研究，以开发治疗辐射损伤后淋巴系统缺陷的策略。我们之前已经在异基因骨髓移植和放射治疗的临床前和临床模型中表明，角质细胞生长因子、白介素7和体外产生的淋巴前体细胞过继治疗都可以促进淋巴重建(特别是T细胞重建)。我们现在将测试这些策略作为治疗辐射损伤受害者的应用。

DESCRIPTION (provided by applicant): Lymphoid cells are particularly sensitive to the effects of radiation injury and subject victims of radiation injury to increased risk of infections and malignancy. Our pre- clinical and clinical studies with Interleukin 7 (IL-7) and Keratinocyte Growth Factor (KGF) suggests that these agents can enhance T cell recovery through effects on: protection and proliferation of thymic stroma (KGF), enhanced thymopoiesis (IL-7 and KGF), and peripheral T cell apoptosis and proliferation (IL-7). Adoptive therapy with "off- the-shelf" allogeneic lymphoid precursors resulted in an early 'wave' of T and NK cell reconstitution from thymic and extrathymic sites, resulting in enhanced T cell immunity. Based upon these data, we propose studies in mouse models of radiation-induced injury to analyze the effects of KGF and IL-7 administration, as well as adoptive immunotherapy with ex vivo generated allogeneic lymphoid precursors. We hypothesize that administration of IL-7, KGF, or committed lymphoid precursor cells can improve lymphoid recovery after radiation injury. Our specific aims are: to study the effects of (Aim 1) KGF, (Aim 2) IL-7, and (Aim 3) allogeneic lymphoid precursors on radiation-induced damage to the lymphoid system. We will analyze the effects of IL-7, KGF and/or lymphoid precursors on lymphoid recovery (especially T cells) and function after acute exposure to varying doses of radiation. We will study the following aspects of radiation injury: (a) dose of radiation (b) partial vs. total body irradiation, and (c) age of recipient. For all strategies we will assess the effects on thymic and extra-thymic (gastrointestinal) reconstitution and peripheral T cell function. In our studies with IL-7 and KGF, we will analyze (d) the expression levels of the IL-7 and KGF receptors, (e) the dose level of KGF or IL-7, (f) dose interval, (g) duration of treatment, (h) timing of the initiation of treatment on the efficacy of IL-7 or KGF, and (i) the intracellular signaling profiles of cell populations in response to KGF or IL-7. In addition, in our studies with allogeneic lymphoid precursors, we will use bioluminescent imaging to perform an in vivo spatial-temporal analysis of the transferred precursor cells. Finally, we will assess combination strategies of lymphoid precursors with KGF and/or IL-7. In this application we propose studies to develop therapeutic strategies for the lymphoid deficiency after radiation injury. We have previously shown in preclinical and clinical models for allogeneic bone marrow transplantation and irradiation that Keratinocyte Growth Factor, Interleukin 7, and Adoptive Therapy with ex vivo generated lymphoid precursor cells can all enhance lymphoid reconstitution (particularly T cell reconstitution). We will now test the application of these strategies as treatment for victims of radiation injury.