Sepsis remains the leading cause of mortality in our intensive care units, and is the most common cause of late organ injury after trauma and surgical intervention. The only FDA-approved drug for severe sepsis (Xigris"""""""") was voluntarily withdrawn from the market this past year when post-marketing trials showed no significant improvements in outcome. So, the obvious question is 'why have all of these clinical trials failed?'Clearly the answers are multifactoral, but we believe that an over-reliance on a reductionist approach to the treatment of severe sepsis has led to many of these failures. Rather, we argue that an improved understanding of how innate immune systems communicate bidirectionally with adaptive immune cell populations can lead to improvements in protective immunity, and new therapeutic approaches. During the previous funding period, we made the startling observation that B cells regulate the early innate immune responses to polymicrobial sepsis in an antibody-independent manner. This B cell dependent effect on outcome and innate immunity required type I interferon and CXCL10. These findings have been recently confirmed by others in Science and Immunity and were highlighted in the News and Views section of Nature-Medicine and Nature-Immunology Reviews this year. In this renewal application, we intend to extend and refine these initial observations and to identify their underlying mechanisms.
Our specific aims are: (1) To identify the specific B cell populations that are responsible for the bidirectional communication between adaptive and innate immunity that promotes protective immunity in sublethal models of polymicrobial sepsis. and, (2) To identify the specific mediators and pathways by which cells of the innate immune system bidirectionally communicate with B cell subpopulations during polymicrobial sepsis. Using mice deficient in T and B cell populations, GM-CSF and type I IFN signaling, a series of murine studies are proposed to dissect the individual B cell populations that confer protective immunity, and whether this is accomplished through an autocrine/juxtacrine signaling loop involving type I IFNs, or through GM-CSF production. This program will further develop and promulgate an integrative view that the immunological dyscrasia associated with polymicrobial sepsis results from a complex interaction between cell populations of both the innate and adaptive immune response. Moving forward, biological treatments will not only have to consider their direct target, but how those cells communicate bidirectionally with other immune cell populations.
Bidirectional communication between B cell subpopulations and the innate immune system contribute to the regulation of protective immunity in polymicrobial sepsis. Autocrine and juxtacrine signaling loops involving type I interferons and GM-CSF appear to be crucial to this process.
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