(provided bny applicant): Dendritic cells (DCs) have a remarkable ability to interpret environmental information and then "decide" the most appropriate response. They have known roles in promoting innate and adaptive immunity, and accumulating evidence supports their role in immune tolerance during steady state conditions. While DC responses to exogenous stimuli are well studied, less is known about endogenous signals that activate and regulate DCs. Galectin-1 is an endogenous galactoside-binding lectin that has a broad range of immunomodulatory abilities on various innate and adaptive immune cells. Galectin-1 can also have different effects on the same cell depending on the concentration of the lectin and the activation state of the cell. Notably, our laboratory recently made a novel observation that galectin-1 uniquely activates human monocyte-derived DCs to mature while enhancing their migration through extracellular matrix. Because DCs are a dynamic population consisting of functionally distinct subsets in varying stages of differentiation and activation, I posit that galectin-1 will have different effects at various stages of DC differentiation and maturation. The immunomodulatory function of galectin-1 on DCs will be characterized in the following specific aims:
Aim 1 : To identify the signaling mediators of galectin-1 induced maturation. I will use biological inhibitors and knock-out mouse models to identify the key signaling molecules and receptors utilized by galectin-1.
Aim 2 : To determine the immunomodulatory functions of galectin-1 on DCs at different stages of differentiation and maturation. I will use in vitro and in vivo models to assess the ability of galectin-1 treated DCs to regulate immune responses. Ultimately, these studies on the role and mechanism of galectin-1 on the immunomodulatory functions of DCs will lead to novel therapeutic approaches to immune-based diseases. Galectin-1 has well-documented effects on ameliorating autoimmune diseases. These studies will establish whether regulation of DC function by galectin-1 contributes to the promotion of immune tolerance and avoidance of autoimmunity. Immune-based diseases are devastating in their effects and challenging to treat, with complex symptoms involving major and multiple organ systems. Recently, there has been some success with patient-specific therapeutic vaccines based upon dendritic cells. Improved understanding of the biology of dendritic cells and their roles in immune pathogenesis will form the rationale for novel targeted therapies for immune-based diseases.
|Fulcher, Jennifer A; Chang, Margaret H; Wang, Shuo et al. (2009) Galectin-1 co-clusters CD43/CD45 on dendritic cells and induces cell activation and migration through Syk and protein kinase C signaling. J Biol Chem 284:26860-70|