AGING AND APOPTOTIC MODULATION OF IMMUNE RESPONSIVENESS

描述（由申请人提供）：免疫衰老的特征是适应性和先天性免疫应答的矛盾变化。随着年龄的增长，许多个体的炎症状态显著增加-即使在没有明显感染的情况下-以及调节这些反应的能力减弱，这与各种衰老相关疾病的发病机制有因果关系，并且可能主要涉及衰老相关免疫功能障碍的所有方面。在这种情况下，凋亡细胞的抗炎作用随年龄的潜在变化以前没有被考虑过。我们最近的研究已经证明了凋亡细胞调节与它们相互作用的巨噬细胞的促炎反应的深刻能力。凋亡尸体的调节活性，代表在生理性细胞死亡过程中获得的功能获得，表现为吞噬巨噬细胞内促炎细胞因子基因转录的立即早期抑制，并在与巨噬细胞结合时发挥作用，与随后的吞噬无关。识别和炎症调节代表先天免疫应答的关键要素，独立于Toll样受体信号传导，其区分活细胞和衰竭细胞。 我们推测，凋亡细胞所施加的免疫调节的程度可能会改变衰老相关的方式，这些变化的基础和加剧的矛盾和病理变化的免疫衰老。本申请中提出的探索性实验将通过采用严格的定量方法，检查作为动物年龄的函数的巨噬细胞与凋亡细胞的体内相互作用，以及这些相互作用相对于各种先天巨噬细胞免疫应答的后果，来测试这种新的假设。我们将直接评估巨噬细胞与凋亡细胞相互作用和吞噬凋亡细胞的能力，从而调节其炎症和其他免疫反应的能力是否以衰老相关的方式改变。我们还将测试外源性凋亡调节剂在体内减弱炎症反应的能力作为动物年龄的函数。 对凋亡细胞生理性免疫调节过程的更全面了解，对于干预导致和加剧免疫衰老的有害和病理性炎症反应的病例具有巨大意义。

DESCRIPTION (provided by applicant): Immunosenescence is characterized by paradoxical alterations in adaptive and innate immune responsiveness. Striking increases in the inflammatory status of many individuals with age - even in the absence of overt infection - and the diminished ability to modulate those responses have been implicated causally in the pathogenesis of a variety of aging-associated disorders, and may be involved centrally in all aspects of aging-associated immune dysfunction. In this context, potential changes with age in the anti-inflammatory effects of apoptotic cells have not been considered previously. Our recent studies have demonstrated the profound ability of apoptotic cells to modulate the pro-inflammatory responses of macrophages with which they interact. The modulatory activity of the apoptotic corpse, representing a gain-of-function acquired during the physiological cell death process, is manifest as an immediate-early inhibition of pro-inflammatory cytokine gene transcription within the engulfing macrophage, and is exerted upon binding to the macrophage, independent of subsequent engulfment. Recognition and inflammatory modulation represent key elements of an innate immune response, independent of Toll-like receptor signaling, that discriminates live from effete cells. We hypothesize that the extent of immune modulation exerted by apoptotic cells may be altered in an aging-associated manner, and that these changes underlie and exacerbate the paradoxical and pathological alterations of immunosenescence. The exploratory experiments proposed in this application will test this novel hypothesis by examining, as a function of animal age, the interactions in vivo of macrophages with apoptotic cells, as well as the consequences of those interactions with respect to a variety of innate macrophage immune responses, employing rigorous quantitative approaches. We will evaluate directly whether the abilities of macrophages to interact with and engulf apoptotic cells and consequently to modulate their inflammatory and other immune responses are altered in an aging-associated manner. We will test as well the ability of exogenous apoptotic modulators to attenuate inflammatory responses in vivo as a function of animal age. A fuller understanding of the process of immune modulation exerted physiologically by apoptotic cells has enormous significance for efforts to intervene in cases of deleterious and pathological inflammatory responses that underlie and exacerbate immunosenescence.