This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Multicellular organisms have devised a variety of mechanisms that provide defenses against invading micro-organisms. These defenses include the presence of physical barriers such as keratinized surfaces and tight epihtelial junctions, the development of non-specific secretory products such as gastric and bile acid and lysozymes, and the evolution of immunologic defenses designed to identify and eliminate infection. The immunologic process is achieved through two systems, the specific and adaptive system comprised of T and B lymphocytes and the innate system comprised of polymorphonuclear leukocytes (PMNs), tissue macrophages, dendritic cells (DCs), mast cells, and natural killer cells. The cells that comprise the innate defense system respond rapidly to infection or breach of normal tisuue architecture through a variety of mechanisms that can include the exocytosis of neutrophil granular contents, phagolysosomal fusion, and the prodution of reactive oxygen species and nitrogen intermediates. Additionaly, these cells serve as a bridge to the adaptible immune response by presenting the products of mciro-organisms to T-lymphocytes in the context of the major histocompatibility antigens (MHC). Recently, a group of molecules named Toll-like receptors (TLRs), have been identified and described. TLRs are one subset of a diverse group of molecules referred to as pattern recognition receptors (PRRs). These PRRs include C-rective protein, serum amyloid protein and mannan-binding protein, the mannose receptor, the scavanger receptor, and the intracellular double -stranded RNA-activated protein kinase PKR. These molecules remove infecting organisms through a variety of different methods that include opsonization of foreign antigens, and induction of host complement, coagulation, phagocytic and pro-inflammatory signaling cascades. The PRRs recognize microbes by responding to invariant molecular structures named pathogen-associated molecular patterns (PAMPs) that are unique to micro-organisms. The recently identified members of the mammalian TLR family have been shown to recognize these microbial structures and are now recognized to play an essential role in the immune process. While bacterial infections have diminished as a cause of death in the general population, they constitute the second most common cause of death in the dialysis population. This is thought to be largely due to the impaired host immune response in uremia. However, the hemodialysis procedure has been shown to profoundly affect the numbers and functional properties of granulocytes and monocytes. Thus, the immune defects previously attributed to uremia may be in part related to the treatment itself. The immunologic abnormalities reported in this population include impaired T cell immunity, depressed antibody generation in response to vaccinations, abnormal helper-suppressor lymphocyte ratio and impaired granulocyte function. The precise mechanisms which result in abnormal function of granulocytes and monocytes are not clear. TLRs have emerged as an important mediators of granulocyte, monocyte and macrophage activation. We hypothesize that impaired neutrophil and monocyte function and the resultant susceptibility to bacterial infections in the hemodialysis population may be due in part to defective or deficient TLR expression by these cells. Moreover, we hypothesize that the dialysis procedure may further modify TLR expression. The proposed pilot study is intended to test these hypothesis by meeting the following specific aims: 1) to determine the abundance of TLRs in circulating neutrophils and monocytes of hemodialysis patients 2) to determine the effect of hemodialysis on TLR expression in patients dialysed with different dialysis membranes.
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