Signaling Mechanism of Tolerance following Repetitive Stimulation with a Single Allergen and its Reversal by Stimulation with Multiple Allergens

Z. Karim, N. Goplen, M. Gorska, R. Alam

Author address: 

National Jewish Health, Denver, CO

Abstract: 

RATIONALE: We reported the induction of tolerance and chronic asthma following repetitive exposure of mice to single and triple allergens, respectively. The objective of this study was to delineate the signaling mechanism. METHODS: Mouse myeloid dendritic cells (mDC) were generated by culturing bone marrow cells in a GM-CSF containing culture. CD4 T cells were isolated by negative selection. Signaling molecules were analyzed by flow cytometry. RESULTS: DC studies: Both a single and triple allergen (dust mite, ragweed and Aspergillus extract) stimulation of mDC activated p38 MAPK & ERK1/2. Triple allergens induced a synergistic effect on p38. Repetitive stimulation (daily for 3 days) with a single allergen caused desensitization of pERK1/2 but not p-p38. Repetitive stimulation with triple allergens abrogated the desensitization effect of a single allergen on pERK1/2. This was associated with an ex vivo tolerizing and stimulatory effect of mDC obtained from single and triple allergens-treated mice. T-cell studies: A single stimulation with allergen loaded (single or triple) mDC induced pERK1/2 and p-p38 in CD4 T cells, which resolved in 3 days. Restimulation on day 3 and 6 caused further increase in pERK1/2 but not p-p38. Unlike that after the first stimulation, pERK1/2 failed to return to baseline in 3 days upon subsequent stimulations. Sustained pERK1/2 (feature of bistability) was associated with a significant reduction in TCR threshold on day 9. CONCLUSIONS: Repetitive stimulation with single and triple allergens induces a dichotomous effect on ERK1/2 in mDC and T cells. The combined effect explains the induction of tolerance or chronic asthma in vivo.
2011

abstract No: 

AB64

Full conference title: 

American Academy of Allergy Asthma & Immunology
    • AAAAI 2011 (67th)