Potentiating DC Function through B7-DC

描述（由申请人提供）：抗体与活细胞结合时可以成为重要生物学变化的介质。我们试图通过参与调节免疫系统的细胞受体来调节免疫。这些研究解决了一种新型抗体sHIgM12增强免疫反应的机制，该抗体结合B7-DC， B7家族成员在树突状细胞（DC）上表达。在体内或体外施用该抗体可增强T细胞的抗原特异性反应。在接受抗体的动物中发现对B16黑色素瘤有很强的抗肿瘤反应。该抗体不结合肿瘤细胞或淋巴细胞，提示免疫反应的增强是由结合DC引起的生理变化介导的。我们积累的证据表明，DC上的B7-DC交联可以传导激活NF-kappaB的信号，并上调免疫调节细胞因子IL-12的表达。B7-DC被认为是T细胞上受体的配体，而不是介导细胞内信号的受体。我们的发现很简单，这种分子提供了DC和它们的环境之间的双向通信。需要解决的机制问题包括识别DC表达的介导信号转导到细胞中的分子，抗体诱导DC细胞内信号的性质，以及抗体对基因表达的影响，特别强调趋化因子受体和细胞因子。DC与体内和培养中激活的T细胞的细胞间相互作用也将被探索，并关注B7-DC在上调抗体处理DC激活nave T细胞能力中的作用。这些功能包括通过I类途径交叉呈递外源抗原。对细胞间接触和细胞因子释放的要求也将进行研究。我们的目的是了解这种抗体如何作为免疫增强剂发挥作用，并从这些研究中收集增强体内免疫的方法，同时深入了解天然B7-DC功能。

DESCRIPTION (provided by applicant): Antibodies can be mediators of important biological changes when bound to living cells. We seek to modulate immunity by engaging receptors on cells that regulate the immune system. These studies address the mechanisms underlying the potentiation of the immune response by a novel antibody, sHIgM12, which binds to B7-DC, a B7 family member expressed on dendritic cells (DC). Administration of the antibody in vivo or in vitro potentiates antigen specific responses by T cells. A strong anti-tumor response to B16 melanoma is seen in animals receiving antibody. The antibody does not bind tumor cells or lymphocytes, suggesting that potentiation of the immune response is mediated by physiological changes induced in the bound DC. We have accumulated lines of evidence demonstrating that cross-linking B7-DC on DC transduces a signal activating NF-kappaB and up-regulating expression of immune modulating cytokine IL-12. B7-DC is known as a ligand for receptors on T cells and not as a receptor mediating intracellular signals. Our finding simply that this molecule provides for two-way communication between DC and their environment. Mechanistic issues to be addressed include identification of the molecules expressed by DC that mediate the transduction of signals into the cells, the nature of intracellular signals in DC induced by the antibody, and the influence of the antibody on gene expression, with particular emphasis on chemokine receptors and cytokines. The intercellular interaction of DC with T cells that become activated in vivo and in culture will also be explored with attention to the role of B7-DC in upregulating the ability of antibody treated DC to activate nave T cells. Among these functions are those associated with cross-presentation of exogenous antigen by the class I pathway. The requirements for intercellular contact and cytokine release will also be investigated. Our intention is to discern how this antibody functions as an immune potentiator and to glean from these studies approaches to enhance immunity in vivo, while obtaining insight into natural B7-DC functions.