Neuroendocrine Hormones to Promote Immune Reconstitution

描述（由申请人提供）： 骨髓移植后或艾滋病中的免疫缺陷使患者极易受到威胁生命的机会性感染。免疫系统的恢复，特别是T细胞功能，通常会延迟长达数年，特别是在老年人中。到目前为止，虽然临床上已经给予细胞因子以加速骨髓恢复，但很少有药物被证明促进多谱系免疫细胞恢复，更少的是促进胸腺生成和T细胞恢复。神经内分泌激素如生长激素（GH）和催乳素（PRL）已被证明对免疫系统发挥多效性作用。我们以前已经证明，生长激素和催乳素促进T细胞功能和恢复胸腺细胞在神经内分泌激素缺乏侏儒小鼠。本研究将在几种BMT模型中评价GH和PRL对免疫恢复的影响，比较年轻（小于10周）和老年（大于18个月）小鼠的影响。使用这些小鼠将允许评估年龄对BMT后结果的作用。为了实现这一目标，我们制定了5个具体目标：具体目标1将评估GH和PRL对年轻和老年小鼠同基因BMT后免疫恢复的影响。将特别强调对胸腺和T细胞恢复的影响。具体目标2将使用胸腺器官培养模型来确定激素对胸腺影响的潜在机制。具体目标3将使用T细胞耗竭的BMC评价GH和PRL在同种异体BMT模型中的作用，以确定对宿主排斥机制和后续植入的作用。具体目标4将检查GH和PRL对发生移植物抗宿主病（GVHD）的同种异体BMT模型的影响，以确定激素治疗后GVHD是否恶化。最后，特定目标5将使用非清髓性BMT模型来确定GH和PRL预处理对胸腺恢复和供体来源细胞植入的影响。所有特定目标将使用年轻和老年小鼠来确定年龄是否会显著影响激素反应性。到目前为止，尽管老年人的免疫重建仍然是一个重要的和日益增长的问题，很少有临床前研究已经解决了年龄的作用和潜在的使用神经内分泌激素，以规避与年龄相关的免疫恢复受阻。因此，该提案将解决基础科学（激素在免疫发育中的作用）和临床有用（年龄在BMT程序中的作用和使用激素促进恢复）问题。

DESCRIPTION (provided by applicant): Immune deficiency following bone marrow transplantation or in AIDS leaves a patient highly susceptible to life threatening opportunistic infections. Recovery of the immune system, particularly T cell function, is often delayed for up to several years, especially in aged individuals. Thus far, while cytokines have been given clinically to accelerate myeloid recovery, very few agents have been demonstrated to promote multi-lineage immune cell recovery and fewer yet promote thymopoiesis and T cell recovery. Neuroendocrine hormones such as growth hormone (GH) and prolactin (PRL) have been demonstrated to exert pleiotropic effects on the immune system. We have previously demonstrated that GH and PRL promote T cell function and restore thymopoiesis in neuroendocrine hormone-deficient dwarf mice. This proposal will now evaluate the effects of GH and PRL on immune recovery in several BMT models, comparing the effects in both young (less than 10 weeks) and aged (greater than18 months) mice. Use of these mice will allow for the assessment on the role of age on the outcome following BMT. Toward this goal, we have developed 5 specific aims: Specific Aim 1 will assess the effects of GH and PRL on immune recovery after syngeneic BMT in young and aged mice. Particular emphasis will be given to effects on the thymus and T cell recovery. Specific Aim 2 will use a thymic organ culture model to determine the mechanism underlying the effects of hormones on the thymus. Specific Aim 3 will evaluate the effects of GH and PRL in allogeneic BMT models using T cell depleted BMC to ascertain effects on host rejection mechanisms and subsequent engraftment. Specific Aim 4 will examine the effects of GH and PRL on allogeneic BMT models in which graft-versus-host disease (GVHD) occurs to determine whether GVHD is worsened after hormone treatment. Finally, Specific Aim 5 will use nonmyeloablative BMT models to determine the effects of GH and PRL conditioning on thymic recovery and engraftment of donor-derived cells. All of the Specific Aims will use young and aged mice to ascertain if age significantly impacts hormone responsiveness. Thus far, even though immune reconstitution in the aged remains a significant and growing concern, very few preclinical studies have addressed the role of age and potential use of neuroendocrine hormones to circumvent the hampered immune recovery associated with age. This proposal will thus address both basic science (role of hormones in immune development) and clinically useful (role of age in BMT procedures and use of hormones to promote recovery) issues.