Enhancing Killer B Lymphocyte Function as a Treatment for Allergic Asthma

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): 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.