Immunoregulatory and Adjuvant effects of Hormones on the

人和动物的免疫功能与年龄相关的变化不仅对老年人的一般健康而且对免疫系统本身的一般特征都是相当重要的。研究表明，老年人更容易受到病毒和细菌的感染，也被认为更容易患癌症。一系列临床研究表明，与年轻受试者相比，老年受试者对疫苗的细胞和体液免疫反应较差，即使在标准佐剂存在的情况下也是如此。目前，许多实验室都在集中研究开发更有效的佐剂，用于老年人群。我们还通过在老化的啮齿动物模型中使用GM-CSF和各种趋化因子作为疫苗佐剂来解决这个问题，从而增加了疫苗特异性免疫反应。此外，我们的实验室与国家癌症研究所的各种研究人员合作，在体外和体内都证明了催乳素和人类生长激素都能增强人和啮齿动物淋巴细胞的激活和增殖，以响应各种抗原和刺激。这些激素还被证明可以调节多种白细胞功能，包括增强中性粒细胞对细菌和酵母的杀伤力，淋巴细胞对特定抗原和免疫刺激的激活，调节细胞因子的产生，增强自然杀伤细胞的活性，胸腺的植入和再生，肥大细胞和粒细胞的脱颗粒，以及增加抗体的产生。正在继续努力，在年轻人和老年人中启动激素输注研究，以检查它们作为免疫佐剂的作用和对胸腺再生的影响。我们还开始了使用年轻和老年小鼠的研究，以检查这些脑下垂体激素对胸腺结构和再生的影响。鉴于最近的报道显示，生长激素治疗后12-16月龄小鼠的胸腺部分退缩和胸腺细胞数增加，我们重点研究了胸腺内和全身应用生长激素、催乳素和生长激素分泌物对不同年龄段小鼠胸腺细胞数、结构和活性的影响。这样的研究可能会导致可能的临床策略，通过这些策略，我们可以促进胸腺再生，从而改善老年人的免疫反应。 最近，我们还开始研究促食欲激素Ghrelin和厌食激素Leptin在免疫系统中的作用和拮抗关系。Grehlin是最近被发现的生长激素促分泌素受体(GHS-R)的内源性配体，由胃产生，是一种有效的循环Orexigen，控制能量消耗、肥胖和GH分泌。GHS-R在包括淋巴系统在内的多种组织中表达，但这些受体在免疫系统中的功能相关性仍有待确定。我们最近发现GHS-R和Ghrelin在人T细胞、单核细胞和PBMC中都有表达，并且特异性地定位于GM1筏。Grehlin的表达和产量通过细胞激活而增加。此外，Ghrelin通过对人外周血单个核细胞和T淋巴细胞表达GHS-R，对炎性细胞因子IL-1b、IL-6和TNF-a具有特异性的抑制作用，但对转化生长因子-b的表达无明显影响。相比之下，瘦素已知可以抑制进食，并似乎在啮齿动物中发挥促炎作用。鉴于瘦素和Ghrelin的相互拮抗作用，我们接下来证明了这两种激素对促炎细胞因子的产生有不同的调节作用。Ghrelin以剂量依赖的方式抑制瘦素诱导的这些细胞因子的增加。此外，我们最近证实，瘦素直接调节人T细胞和PBMCs上GHS-R的表达。我们的结果为之前未知的Ghrelin的免疫调节功能提供了证据，并表明Ghrelin可能是管理与慢性炎症、癌症和年龄相关的消耗的新靶点。

Age-associated changes in immune function in humans and animals are quite important with regard not only to the general health of aged persons but also to the general features of the immune system itself. Elderly subjects have been shown to be more susceptible to viral and bacterial infections and are believed to be more susceptible to cancer. A series of clinical studies have revealed that elderly subject, in contrast to their younger counterparts, exhibit poor cellular and humoral immune responses to vaccines even in the presence of standard adjuvants. Currently, many laboratories are focusing their research efforts into developing more effective adjuvants for use in elderly populations. We have also approached this problem by utilizing GM-CSF and various chemokines as vaccine adjuvants in aging rodent models resulting in increased vaccine-specific immune responses. Moreover, our laboratory in collaboration with various investigators at the National Cancer Institute has demonstrated that both prolactin and human growth hormone potentiate human and rodent lymphocyte activation and proliferation in response to various antigens and stimuli both in vitro and in vivo. These hormones have also been shown to modulate a variety of leukocyte functions including potentiating neutrophil killing of bacteria and yeast, lymphocyte activation to specific antigens and immune stimuli, modulating cytokine production, enhancing natural killer cell activity, thymic engraftment and regeneration, mast cell and granulocyte degranulation, and augmenting antibody production. Continuing efforts are underway to initiate hormone infusion studies in young and older subjects to examine their role as immunoadjuvants and effects on thymic regeneration. We have also initiated studies using young and aged mice to examine the effects of these pituitary hormones on thymic structure and regeneration. Given recent reports demonstrating a partial reversal of thymic involution and an increase in thymic cellularity in 12-16-month old mice post growth hormone treatment, we have focused our efforts on the effects of intrathymic and systemic growth hormone, prolactin and growth hormone secretagogues administration on thymic cellularity, structure, and activity within mice of varying ages. Such studies may lead to possible clinical strategies by which we can facilitate thymic regeneration and thus improve immune responses in the elderly. Recently, we have also initiated studies examining the function and antagonistic relationship between the orexigenic hormone, ghrelin and the anorexigenic hormone, leptin within the immune system. Grehlin, a recently described endogenous ligand for growth hormone secretagogue receptors (GHS-R), is produced from stomach serving as a potent circulating orexigen controlling energy expenditure, adiposity and GH secretion. The GHS-R are expressed in variety of tissues including lymphoid system; however, functional relevance of these receptors in immune system remains to be established. We have recently found that both GHS-R and ghrelin are expressed in human T cells, monocytes and PBMCs and specifically localize in GM1 rafts. Grehlin expression and production is increased by cellular activation. Moreover, ghrelin exerts specific potent inhibitory effects on inflammatory cytokines, IL-1 b, IL-6 and TNF-a but not TGF-b expression through functional GHS-R on human peripheral blood mononuclear cells and T lymphocytes. In contrast, leptin is known to inhibit feeding and appears to exert a proinflammatory effects in rodents. Given the believed mutually antagonistic effects of leptin and ghrelin, we next demonstrated that these hormones differentially regulate proinflammatory cytokine production. Ghrelin inhibits leptin-induced increments in these cytokines in a dose-dependent manner. Also, we have recently demonstrated that leptin directly modulates the expression of GHS-R expression on human T cells and PBMCs. Our results provide evidence for previously unknown immunoregulatory function of ghrelin and suggest that ghrelin might be a novel target for management of wasting associated with chronic inflammation, cancers and age.