The life-threatening consequences of sepsis have been attributed to immune imbalance or dysfunction. Our laboratories have discovered major immunomodulatory effects from a novel cell transfer therapy that can counteract many of the well-described immune dysfunctions found in sepsis. Specifically, the adoptive transfer of tissue-derived fibrocytes significantly enhances bacterial clearance and increases splenic T cell populations. Based on our preliminary data, the beneficial effects of the cell transfer appear to be direct influences of the fibrocytes. However, the mechansims behind these effects are not clearly understood. Therefore, we hypothesize: Fibrocytes improve sepsis outcomes through direct mechanisms that improve bacterial clearance and cause proliferation of T cells. Our studies will seek functional differences between resident and transferred fibrocytes to help define the benefits of adoptive transfer. These studies will also consider the influences of fibrocyte transfer on other immune cell populations.
Specific Aim I will identify the mechanisms for increased bacterial clearance after adoptive transfer of fibrocytes in the CLP model of sepsis, particularly phagocytosis and bacterial killing.
Specific Aim II will explore the role of gamma c cytokines in the innate, antigen- independent proliferation and activation of CD4+ and CD8+ T cells in response to fibrocyte transfer during sepsis.
Specific Aim III will mark the first investigation of human fibrocytes in sepsis.
This aim will characterize the kinetics and functions of human fibrocytes during sepsis as well as determine the effects of sepsis on cultured fibrocytes that could one day be used in cell therapy. Overall, this proposal will further define te mechanisms driving two distinct, beneficial effects of fibrocyte transfer in sepsis. Ultimately, th results would be used to maximize those effects and optimize the application of the adoptive transfer of fibrocytes in sepsis and other diseases.
Sepsis is a frequent complication in intensive care units and can lead to devastating consequences including death. Immunosuppression is a major contributor to sepsis-associated deaths. The goal of this proposal is to investigate the immunomodulatory functions of fibrocytes and their potential as a cell therapy to combat sepsis.
| Collins, Dalis; Fry, Christopher; Moore, Bethany B et al. (2018) Phagocytosis by Fibrocytes as a Mechanism to Decrease Bacterial Burden and Increase Survival in Sepsis. Shock : |
