Vitamin D Regulation Of Th2 Immune Responses In Mice And Humans: Role Of Ox40l

N. L. Nguyen , J. Pilewski , J. L. Kreindler , C. Steele , J. F. Alcorn , J. K. Kolls , A. Ray , S. ZIEGLER , E. Hartigan , M. Kurs-Lasky , H. Rockette

Author address: 

LSUHSC-New Orleans, New Orleans, LA, Children's Hospital of Philadelphia, Philadelphia, PA, University of Alabama, Birmingham / School of Medicine, Birmingham, AL, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, LSUHSC, New Orleans, LA


Rationale:4-15% of cystic fibrosis (CF) patients develop Allergic Bronchopulmonary Aspergillosis (ABPA) characterized by Th2 responses to Aspergillus. Aspergillus in CF can approach 40-50% suggesting immune tolerance may prevent ABPA. We have previously shown that CD11c dendritic cells (DCs), OX40 Ligand, Vitamin D play a role in sensitization versus tolerance to Aspergillus. We have set up an animal model to further explore the roles of CD11c DCs, OX40L, and Vitamin D response to Aspergillus. Methods:Genes from CF patients in the Vitamin D pathway have been sequenced to identify SNPs in sensitized versus tolerant CF patients. Vitamin D deficient mice (by nutritional diet) and Vitamin D normal mice where sensitized and challenged with Aspergillus. Lung, lymph nodes (LN), and bronchoalveolar lavage (BAL) fluid where analyzed for Th2 cytokine production. Mouse CD11cDCs from Vitamin D deficient and normal mice where cultured with naive CD4+ T cells and pulsed with Aspergillus extract. Outcome measures included IL-4, IL-5, IL-13, IL-10, and FACS analysis for CD4, CD25, FoxP3, IL-10 and TGFB. Results:Several mutations have been identified in the ABPA and nonABPA in genes in the Vitamin D pathway. Vitamin D deficient mice have increased Th2 and OX40L response to Aspergillus in lung, BAL, and LN. CD11cDCs from Vitamin D deficient mice elicit significantly greater Th2 responses compared to Vitamin D normal mice. Addition of 1,25OH Vitamin D3 to culture significantly inhibits Th2 production from Vitamin D deficient mice. Treating Vitamin D deficient cells with soluble OX40L reverses inhibition of Th2 production from exogenous Vitamin D suggesting a critical role of OX40L in Vitamin D mediated Th2 suppression. Conclusion:These results support therapeutic trial of Vitamin D to treat ABPA in CF and suggest Vitamin D plays a role in immune tolerance to Af.

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Full conference title: 

American Thoracic Society
    • ATS 2011