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.
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