Neutrophils modulate immune function in two important ways: (1) by seeking out bacterial and fungal infectious agents and destroying the infectious agent by phagocytosis and (2) by generating cytokines when activated and can stimulate other immune responses. Neutrophil recovery after blood or marrow transplantation is essential for survival of the patient. Following blood and marrow transplantation, a significant number of patients will demonstrate an increased susceptibility to infectious agents, which can be related to the decreased neutrophil function. In this proposal we will examine the molecular signals that direct neutrophil function. We have demonstrated that FcyRIIa cross-linking will stimulate cellular tyrosine phosphorylation, actin filament polymerization and IL-6 cytokine production, which could direct neutrophil motility, phagocytosis and inflammation. However, co-cross-linking CD45 with FcyRIIa concomitantly will abrogate tyrosine phosphorylation and actin filament polymerization. Interestingly, co-cross-linking CD45 with FcyRIIa results in a synergistic increase in IL-6 production. We hypothesize that CD45 and FcyRIIa receptors direct competing and synergistic signals that control neutrophil function. Here, we will identify the cellular substrates that demonstrate an increase in tyrosine phosphorylation in response to Fc7RIIa cross-linking and relate this to neutrophil function. In addition, we will also address the mechanism by which both CD45 and FcyRIIa receptor crosslinking can synergistically stimulate IL-6 production.
The specific aims will determine: 1) the identity of proteins phosphorylated on tyrosine in response to FcyRIIa but not phosphorylated when CD45 receptor is cross-linked; 2) the mechanism by which these signal modulate changes in actin filament integrity and neutrophil function such as motility and phagocytosis and 3) the cellular signals that are synergistically stimulation upon CD45 and FcyRIIa activation that direct IL-6 production. Results from these investigations may enable us to identify molecular markers that will assist in identifying treatment or management strategies for patients recovering from blood and marrow transplantation.
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