ENHANCING AGED CD4 COGNATE FUNCTION WITH CYTOKINES

用细胞因子增强老年人CD 4同源功能。老年人的免疫接种至关重要，因为它可以减少老年人感染传染病的发病率。问题是，疫苗的效力在老年人中可能会降低60%至70%。这一点极为重要，因为与年轻人相比，老年人因流感等传染病住院和死亡的风险要高得多。我们已经使用了T细胞受体转基因（TCR Tg）模型来研究年龄如何影响CD 4功能。TCR Tg模型的优点是它们允许我们直接比较TCR Tg的体外和体内功能。 来自年轻和老年小鼠的抗原特异性CD 4细胞的同质群体。通过使用这些模型，我们可以消除年轻和老年人群中的一些差异，例如记忆细胞与幼稚细胞的比例随着年龄的增长而增加。在初步研究中，我们已经表明，与年轻细胞相比，来自老年小鼠的幼稚Tg CD 4细胞在体外TCR刺激后产生较少的IL-2。这对幼稚老化细胞的初始扩增和效应子的后续分化具有深远影响。此外，我们已经表明，这些老化的缺陷，在扩大和细胞因子的生产也发生在体内过继转移 模型在体内，由于衰老导致的CD 4功能下降可能会影响B细胞和CTL应答。事实上，我们的研究表明，老年CD 4细胞的同源辅助功能存在严重缺陷。这项拨款提案的目标是确定外源性细胞因子或佐剂是否可以改善衰老的CD 4 T细胞的功能。我们已经确定，通过用诱导炎性细胞因子的佐剂免疫或通过细胞因子本身免疫，克服了扩增和IL-2产生中的老化CD 4缺陷。在这项研究中，我们将研究这些细胞因子对老年人CD 4+细胞的体外和体内功能的影响。 细胞我们将研究细胞因子如何在体外增强老年CD 4细胞产生IL-2。我们还将确定细胞因子或佐剂是否可以改善同源辅助功能-包括对抗原特异性抗体产生和诱导保护性抗体的影响，以及对CD 8应答的同源帮助。这些研究将为如何改善老年人体内抗原特异性CD 4细胞的功能提供有价值的信息。

Enhancing aged CD4 cognate function with cytokines. Immunization of the elderly is critically important since it can reduce the morbidity associated with infectious disease seen in the aged. The problem is that vaccine efficacy can be decreased 60 to 70% in the aged. This is extremely important since elderly persons exhibit a much increased risk of hospitalization and death from infectious diseases, such as influenza, compared to younger persons. We have used a T cell receptor transgenic (TCR Tg) model to examine how age affects CD4 function. The advantage of TCR Tg models is that they allow us to directly compare the in vitro and in vivo function of homogenous populations of antigen-specific CD4 cells from young and aged mice. By using these models, we can eliminate some of the differences in young and aged populations, such as the proportion of memory to naive cells that increases with age. In preliminary studies, we have shown that naive Tg CD4 cells from aged mice produce less IL-2 upon in vitro TCR stimulation compared to young cells. This has a profound impact on the initial expansion of naive aged cells and on subsequent differentiation of effectors. Furthermore, we have shown that these aged defects in expansion and cytokine production also occur in vivo in an adoptive transfer model. In vivo, decreased CD4 function due to aging could potentially impact both B cell and CTL responses. In fact, our studies show that there is a profound defect in the cognate helper function of aged CD4 cells. The goal of this grant proposal is to determine if exogenous cytokines or adjuvants can improve the function of aged CD4 T cells. We have determined that the aged CD4 defect in expansion and IL-2 production is overcome by immunization with adjuvants that induce inflammatory cytokines or by the cytokines themselves. In this grant, we will examine the effects of these cytokines on the in vitro and in vivo function of aged CD4 cells. We will examine how cytokines can act to enhance IL-2 production by aged CD4 cells in vitro. We will l also determine if cytokines or adjuvants can improve cognate helper function--including the impact on antigen-specific antibody production and induction of protective antibodies, as well as cognate help for CD8 responses. These studies will provide us with valuable information on how to improve the in vivo function of antigen-specific CD4 cells in the aged.