Bone-marrow derived fibrocytes are unique, fibroblast-like cells with diverse functions and plasticity akin to adult stem/progenitor cells. Their potential immune functions and practical attributes prompted our preliminary investigations of the previously unexplored role of fibrocytes in sepsis. Our preliminary data suggest that an innovative cell therapy, adoptive transfer of fibrocytes, conserves T cell numbers and significantly improves survival in sepsis. Initial studies also show that contact with LPS-stimulated fibrocytes incites a Th1 cytokine response from naive T cells and that fibrocytes derived from the septic abdomen increase the proliferation of CD4+ T cells. Therefore, we hypothesize: Therapeutic administration of fibrocytes improves outcome in sepsis by increasing the proliferation of T cells with the Th1 phenotype. Using the murine cecal ligation and puncture (CLP) model, Specific Aim I seeks to determine the role of T cell subtypes in the mechanisms behind fibrocyte enhanced sepsis survival. To compare survival parameters, plasma IL-6 levels will be used as a predictive biomarker of CLP-induced mortality. By performing adoptive transfer at various intervals after the induction of sepsis, the window of efficacy and parameters associated with survival will be confirmed.
Specific Aim II will determine the basic mechanisms responsible for the fibrocyte-associated increases in T cell proliferation and activation. The co-stimulatory molecules responsible for interactions between T cells and fibrocytes will be identified. In addition, the impact of cytokine production by fibrocytes will be determined and the role of specific cytokines of interest will be validated. Finally, the findings from mechanistic studies will be used to examine the effects of bacterial products on the programming of fibrocytes for beneficial interactions with T cells. While these studies are designed to be of independent value, they will also supply important background for further investigation of this unique cell type in the immunopathology of sepsis.
Sepsis is a complex systemic inflammatory response to infection that can produce serious consequences. It promotes several immune defects that result in a high mortality rate. Our studies indicate that bone marrow-derived fibrocytes have immune functions, including phagocytosis, pro-inflammatory cytokine production, and the ability to activate naive T cells, that could be beneficial in cases of sepsis. The purpose of this proposal is to find the mechanisms behind the advantageous effects of fibrocytes in order to exploit them as a treatment for sepsis.