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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059324-09
Application #
7058354
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Noel, Patricia
Project Start
1997-12-10
Project End
2009-04-30
Budget Start
2006-05-01
Budget End
2009-04-30
Support Year
9
Fiscal Year
2006
Total Cost
$324,077
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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Racila, Doina M; Kline, Joel N (2005) Perspectives in asthma: molecular use of microbial products in asthma prevention and treatment. J Allergy Clin Immunol 116:1202-5