Induction of Respiratory Tolerance By Mucosal CpG ODN

University Of Iowa, Iowa City IA

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Abstract

DESCRIPTION (provided by applicant): Asthma is characterized by Th2-cytokine-mediated airway-centered inflammation. Tolerance to inhaled antigens (Ag), as is seen in non-atopic individuals or following specific immunotherapy in atopic asthmatics, may be promoted by a variety of mechanisms. We have induced inhalation tolerance by mucosal immunotherapy with CpG-ODN (oligonucleotides containing unmethylated CpG dinucleotides) and Ag; neither stimulus alone was successful in suppressing the Th2-cytokine-mediated inflammation. Although stimulation with CpG-ODN induces strong Th1 responses, suppression of Th2 responses is only moderately reduced in the absence of Th1 cytokines such as IFN-gamma and IL-12; therefore, alteration of the balance between Th1 and Th2 responses does not explain the mechanisms through which CpG-ODN promote tolerance. We have found that mucosal immunotherapy promotes suppression of Ag-specific, to a much greater extent than Ag-non-specific, responses, and that cell-to-cell contact is necessary for maximal effect. Protection against airway eosinophilia can be adoptively transferred by antigen presenting cells (APC) treated with OVA+CpG-ODN. IL-10, and possibly TGF-beta, are involved in the tolerogenic effects of CpG-ODN. Based on these findings, we hypothesize: CpG-ODN-induced respiratory tolerance is mediated through interactions between dendritic cells and regulatory T-lymphocytes in the lung. In order to identify these interactions ultimately, we will first focus on the effects of CpG-ODN on each of these cell populations separately. We will explore this hypothesis in the context of these complementary Specific Aims: Aim 1: To evaluate whether anti-inflammatory effects of airway mucosal exposure to CpG-ODN are mediated through lung dendritic cells. Aim 2: To evaluate whether anti-inflammatory effects of airway mucosal exposure to CpG-ODN are mediated through regulatory T-lymphocytes.