IMPAIRED DENDRITIC CELLS IN IMMUNITY IN FRAIL ELDERLY

University Of California Los Angeles, Los Angeles CA

Investigators

Linked publications & trials

Abstract

Excess morbidity & mortality from infections in the elderly is attributed to age-related decline of the immune system & vaccine response to improve resistance is sub-optimal, particularly in frail elderly. Research focus has been to identity specific T cell impairments that contribute to this decline. Because 1) growing evidence shows antigen presenting cell (APC) defects may also be involved, 2) increased levels of the immunosuppressive interleukin-I0 (IL-10) are produced by APC from elderly, & 3) our data on APC & dendritic cells (DC) in frail elderly nursing home patients; we now propose a shift in the focus of our research efforts to identify fundamental changes in APC which can be exploited to enhance vaccination response in the frail elderly. Despite increased levels of IL-10, APC from healthy elderly produce more pro-inflammatory cytokine IL-12 & have enhanced antigen presentation vs. young controls. In contrast, APC function declines in frail nursing home residents, IL-12 levels are NOT increased, while IL-10 remains elevated & there is abnormal presentation & co-stimulatory molecule expression in the DC. This pilot proposal supports a shift of our research to a different cell lineage (DC & macrophages), & provides the foundation for a shift to mechanistic studies to enhance vaccine response in frail elderly subjects. This one-year proposal is centered on a hypothesis that age + chronic illness-related impaired immunity is due to altered APC function from impaired maturation of DC, attributable to excessive production of immunosuppressive factors by monocyte/macrophages. We postulate that the age-related increase in IL-10 +/- impaired DC response to pro-inflammatory factors alters maturation or enhances apoptosis of DC, diminishing vaccine efficacy in the frail elderly population. These specific aims are proposed: 1. To investigate inhibitory effects of IL-10 and macrophages on DC maturation & function (APC capacity, cytokine production & apopotosis) in frail elderly vs. healthy elderly and young controls (i.e., make young/reactive elderly DC function like frail, anergic elderly). 2. To enhance in vitro DC function of frail elderly subjects using specific modulators of cyclooxygenase, prostaglandins, and IL-10 (i.e., make frail DC function like young/reactive elderly and identify changes in function with respect to changes in COX-2/PGE2/IL-10 pathway from various immunomodulators).