Adequate immune responses to various pathogens and antigens depend on the effective function of professional antigen presenting cells dendritic cells (DC). Defects in DCs play critical role in immunological abnormalities or failure of immune responses described at various pathological conditions. This is especially important for autoimmune diseases, some viral and parasite infections, and cancer. Despite intensive studies the mechanisms of DC defects remain largely unclear. Understanding of these mechanisms could be very important for the development of new therapeutic approaches. Most of the studies of DC function including those from our laboratory are focused on signal transduction pathways, expression of surface receptors and cytokine production. These studies are very important and provide valuable insight into the biology of DCs. However, they struggle to explain the mechanisms of the observed abnormalities. Here, we propose to test an entirely different novel concept of DC dysfunction. We suggest that the well-documented abnormalities in DC differentiation and function observed at different pathological conditions may be caused in part by abnormal metabolism of lipids culminating in accumulation of lipids in cytoplasm of the cells. This accumulation prevents normal DC differentiation and impairs antigen-presenting function of already matured DCs. This hypothesis is based on a number of preliminary observations made in vitro and in vivo in different experimental systems. To test this hypothesis we will focus on one pathological condition - cancer. Specifically, we will investigate biological significance of accumulation of lipids during DC differentiation in cancer.
Specific aim 1 will investigate lipid accumulation in DCs from tumor-bearing hosts and the role of tumor-derived factors in that process.
Specific aim 2 will study the immunological consequences of lipid accumulation in DCs. If our hypothesis is correct it would suggest not only a new model describing defects in antigen presenting cells in cancer and potentially other pathological conditions associated with lipid accumulation but also open a new avenue in treatment opportunities. In this case more detailed further studies will be warranted. Specifically, it will be important to understand the nature of the lipids accumulated in cytoplasm, up-stream molecular mechanisms responsible for lipid accumulation, the mechanisms of DC defects induced by accumulating lipids, the source of lipid accumulation, clinical significance of these findings and most importantly therapeutic approaches to correct this situation. However, all these studies will be irrelevant if we do not establish first the very basic fact: accumulation of lipids in DCs is immunologically relevant and biologically significant. This proposal is seeking limited support to test this """"""""high risk but possibly high gain"""""""" hypothesis. Proposed research will investigate novel mechanism responsible for the defects in immune system at different pathological conditions associated with abnormal lipid metabolism. We will test novel hypothesis that accumulation of lipids in professional antigen presenting cells prevents these cells from adequate stimulation of immune responses. This new mechanism may suggest an entirely new approach to the treatment of immune defects associated with such disease as cancer by inhibiting accumulation of lipids. ? ? ?
| Herber, Donna L; Cao, Wei; Nefedova, Yulia et al. (2010) Lipid accumulation and dendritic cell dysfunction in cancer. Nat Med 16:880-6 |
