The treatment of the hospitalized patient with sepsis remains a clinical conundrum, due in large part to the complexity of the host response to infection and tissue injury. Pro- and antiinflammatory cytokines play critical roles in the development of sepsis syndromes, but their production is often localized to individual tissues, rather than the systemic circulation. Current therapeutic approaches for the treatment of sepsis syndromes involve the systemic administration of biological response modifiers, such as cytokine antagonists or antiinflammatory agents. To date, none of these agents has proven effective, and one explanation may be that their systemic administration is an inefficient or even inappropriate means to treat a more localized inflammatory or immunosuppressive response. We have proposed that he targeted delivery of protein-based therapies using a recombinant adenoviral vector can directly modulate the inflammatory or apoptotic processes occurring in the target tissue, without systemic immune suppression or activation. Therefore, the overall objective of these studies is to determine the feasibility of adenovirus gene transfer as a herapeutic modality. More specifically, the goals of this proposal are to determine whether the forced overexpression of initially IL-10, but also in later years, a dominant negative I-KB super-repressor, will blunt the sepsis responses in arget organs without producing systemic immune suppression. The two specific aims of the current application are: 1) To determine whether targeted expression of IL- 10 in the lungs of mice with an adenoviral vector can prevent the development of respiratory distress syndrome in a zymosan-induced model of multisystem organ failure, without increased expression in other organs or the induction of T-cell hyporesponsiveness and immune suppression, and 2) To determine the mechanisms by which targeted expression of IL- 10 in the thymus of mice can reduce caspase-3 iependent thymocyte apoptosis and improve outcome in a cecal ligation and puncture model of a compensatory mtiinflammatory response syndrome. The studies proposed in this application will ultimately determine the utility and safety ofadenovirus based gene therapy as a means of targeting protein-based therapies to individual tissues and organs in sepsis syndromes.
Showing the most recent 10 out of 13 publications
