Sepsis is associated with aberrations in adaptive immunity that place the host at increased risk of secondary opportunistic infections. The overall goal of this proposal is to determine whether myeloid-derived suppressor cell populations (MDSC) contribute to outcome and the adaptive immune suppression seen in severe sepsis. MDSCs are a heterogeneous population of immature myeloid cells with suppressor cell activities. Understanding how these regulatory cells act during sepsis may permit the development of potential novel therapeutic avenues to ameliorate the immune suppression observed in severe sepsis. Therefore, three specific aims are proposed: 1. To determine which MDSC cell subpopulations possess these immunosuppressive properties, and through what mechanism(s) (NO, reactive oxygen species) are these immunosuppressive properties obtained. 2. To confirm and identify the MyD88 dependent cell processes that are required for the expansion of the MDSC populations in microbial sepsis, and whether these MyD88 dependent processes involve endogenous production of members of the CSF superfamily, and 3. To determine whether alterations in the MDSC population in response to sepsis modulates the acquired immune response, and can alter outcome to a secondary infectious challenge. Both MDSC numbers and function will be quantitated in septic mice, as will the degree of adaptive immunosuppression and susceptibility to a secondary bacterial challenge. MdSC numbers (CD31+CD11b+GR-1+) will be determined by flow cytometry, while suppressor cell activity will be evaluated functionally by co-culture with CD4+ and CD8+ splenocytes in response to antigen specific and nonspecific proliferative signals. Under in vivo conditions, the effect of these MDSC populations on T helper cell polarization (Th1 vs Th2) will also be determined. Finally, mice at the above time points post-CLP will be subjected to a secondary bacterial infection (Pseudomonas aeruginosa pneumonia, or Listeriosis) to determine their susceptibility. Thus, the proposed studies represent an innovative examination of a novel suppressor cell population as a potential mechanism for immune suppression during sepsis.
Sepsis is a life-threatening disease associated with significant immune suppression. Understanding the role that immature myeloid derived suppressor cells play in sepsis could lead to new therapeutic interventions. This program will explore the mechanisms responsible for the massive expansion of this cell population in the bone marrow, spleen and lymph nodes in sepsis, and the mechanisms behind its contribution to sepsis induced immune suppression.
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