Asthma is an inflammatory disease of the lower airways that is mediated by allergen-specific CD4+ T helper (TH) cells. In a mouse model of asthma, it was found that lung CD5+ B cells expressed the death-inducing molecule Fas ligand. These FasL+ 'killer'B cells were reduced in Xid mice which led to an increase in lung T cell cytokine production, and airway inflammation in response to chronic allergen challenge. These data suggested an important role for killer B cells in the regulation of asthma, and led to the current hypothesis that increasing killer B cell activity in the lung will suppress allergen-specifc TH cells and decrease airway inflammation and asthma. The following aims are proposed:
Aim 1 : Measure effects of adoptive transfer of killer/regulatory B cells on TH cell death and asthma pathogenesis.
Aim 2 : Investigate IL-5R signaling pathways involved in modulating FasL and IL-10 expression by B cells. The ability of a relatively small number of killer B cells in the lung to suppress asthma, makes it reasonable to suspect that increasing their numbers or potency even by a few fold will have a therapeutic effect. The regulatory functions of B cells are activated by IL-5, but the use of IL-5 as therapy for asthma is not advisable due to its proinflammatory effects on eosinophils. The long range goal of this research is to identify drug targets that selectively activate IL-5-dependent responses in B cells or other methods of inducing regulatory and/or killer B cell activity in asthmatic patients.
Poor immune suppression is thought to be a major contributor to the development and severity of allergic asthma. One subset of cells that suppresses immune responses has not received enough attention. These 'killer B cells'have the ability to induce death of specific subsets of target cells. One of the known target cell populations of killer B cels is the T helper lymphocyte, which plays a central role in causing and maintaining asthma. Mice with a genetic mutation that caused a deficiency of killer B cells in the lung showed decreased death of lung T helper lymphocytes and increased severity of many disease parameters in a model of allergic asthma. The goals of the current proposal are to find ways of enhancing the number and activity of killer B cells in the lungs to study their ability to protect mice from the induction and maintenance of asthma. Ultimately, we hope to develop drugs or other methods of controlling killer B cell functions in humans as a means of preventing and treating human asthma.
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