Alpha-galactosylceramides (a-GalCer) isolated form marine sponges can prevent liver metastases of cancer cells. This remarkable anti tumor effect of a-GalCer is mediated by NKT cells, a specialized set of T cells restricted by CD1d, a member of the lipid antigen-presenting CD1 family. Upon in vivo injection, a-GalCer stimulates NKT cells which rapidly induce a complex cascade of cellular activation involving NK cells, dendritic cells, B cells and T cells. Thus, through the NKT cells, its primary target, a-GalCer exhibits the properties of a glycolipid adjuvant with the potential to enhance or modify a brad range of immune responses. The long term goal is to understand the protective value of the CD1 system of antigen presentation. This application focuses on determining the cellular and molecular consequences of activation of the CD1/NKT pathway with a-GalCer, the ligand of NKT cells, and their potential applications in host defense against infections and tumors, and in autoimmunity. The specific aims are 1- to characterize the cascade of activation events that follows NKT cell activation in vivo, by defining the respective contributions of the cell types, the surface receptors and the soluble mediators (cytokines and chemokines) that are sequentially induced; 2-to determine the consequences of of NKT cell activation on adaptive, antigen specific T and B cell responses, and dissect the adjuvant effects of a-GalCer on the individual components of these responses; 3- to determine the consequences of NKT cell activation during the course of autoimmune, infectious and tumoral conditions such as NOD mouse autoimmune diabetes, MCMV infection and liver metastases of melanoma. These studies offer an opportunity to dissect the molecular and cellular events involved in the adjuvant effect of a glycolipid molecule an may lead to clinical applications in the prevention and treatment of infectious, autoimmune and tumor conditions.

R01CA087060

2000-05-01

2005-04-30