Immunoregulatory and Adjuvant effects of Hormones on the

人类和动物免疫功能中与糖尿病相关的变化不仅对老年人的总体健康非常重要，而且对免疫系统本身的一般特征也非常重要。老年受试者已被证明更容易受到病毒和细菌感染，并被认为更容易患癌症。一系列临床研究表明，与年轻人相比，老年人对疫苗的细胞和体液免疫应答较差，即使在标准佐剂的存在下也是如此。目前，许多实验室正在集中精力开发更有效的佐剂用于老年人群。我们还通过利用GM-CSF和各种趋化因子作为老化啮齿动物模型中的疫苗佐剂来解决这个问题，导致疫苗特异性免疫应答增加。此外，我们的实验室与美国国家癌症研究所的各种研究人员合作，证明催乳素和人生长激素在体外和体内都能增强人类和啮齿动物淋巴细胞对各种抗原和刺激的活化和增殖。这些激素还显示调节多种白细胞功能，包括增强嗜中性粒细胞对细菌和酵母的杀伤、淋巴细胞对特异性抗原和免疫刺激的活化、调节细胞因子产生、增强自然杀伤细胞活性、胸腺植入和再生、肥大细胞和粒细胞脱粒以及增加抗体产生。正在继续努力，在年轻和老年受试者中开展激素输注研究，以检查其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，以检查这些垂体激素对胸腺结构和再生的影响。鉴于最近的报告表明，部分逆转胸腺退化和胸腺细胞在12-16个月大的小鼠生长激素治疗后的增加，我们集中我们的努力胸腺和全身生长激素，催乳素和生长激素促分泌素管理的影响胸腺细胞，结构和活动在不同年龄的小鼠。这些研究可能会导致可能的临床策略，我们可以促进胸腺再生，从而提高老年人的免疫反应。 最近，我们也开始研究食欲素，生长激素释放肽和食欲素，瘦素在免疫系统中的功能和拮抗关系。Grehlin是近年来发现的一种生长激素促分泌素受体（GHS-R）的内源性配体，由胃产生，作为一种强有力的循环增食欲素，控制能量消耗、肥胖和生长激素分泌。GHS-R在包括淋巴系统在内的多种组织中表达，然而，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中表达，并且特异性地定位于GM 1筏。Grehlin的表达和产生通过细胞活化而增加。此外，ghrelin通过人外周血单个核细胞和T淋巴细胞上的功能性GHS-R对炎性细胞因子IL-1 B、IL-6和TNF-α的表达发挥特异性的有效抑制作用，但对TGF-B的表达不起作用。相反，已知瘦素抑制摄食，并且似乎在啮齿动物中发挥促炎作用。鉴于瘦素和生长素释放肽的相互拮抗作用，我们接下来证明了这些激素差异调节促炎细胞因子的产生。Ghrelin以剂量依赖性方式抑制瘦素诱导的这些细胞因子的增加。此外，我们最近已经证明，瘦素直接调节人T细胞和PBMC上GHS-R表达的表达。我们的研究结果为以前未知的ghrelin的免疫调节功能提供了证据，并表明ghrelin可能是一个新的目标，用于管理与慢性炎症，癌症和年龄相关的消耗。

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.