Combination blockade of OX40L and CD30L inhibits allergen-driven memory TH2 cell reactivity and lung inflammation
| Autor: | Amit Mehta, Donald T. Gracias, Rinkesh K. Gupta, Gurupreet S. Sethi, Hideo Yagita, Haruka Miki, Michael Croft |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Thymic stromal lymphopoietin Immunology Inflammation medicine.disease_cause 03 medical and health sciences 0302 clinical medicine Allergen medicine Immunology and Allergy House dust mite biology medicine.diagnostic_test business.industry Effector respiratory system biology.organism_classification respiratory tract diseases Blockade 030104 developmental biology Bronchoalveolar lavage Tumor necrosis factor alpha medicine.symptom business 030215 immunology |
| Zdroj: | Journal of Allergy and Clinical Immunology. 147:2316-2329 |
| ISSN: | 0091-6749 |
| Popis: | Background The selective reduction of memory TH2 cell responses could be key to affording tolerance and protection from the recurrence of damaging allergic pathology. Objective We asked whether TNF family costimulatory molecules cooperated to promote accumulation and reactivity of effector memory CD4 T cells to inhaled complex allergen, and whether their neutralization could promote airway tolerance to subsequent reexposure to allergen. Methods Mice were sensitized intraperitoneally or intranasally with house dust mite and challenged with intranasal allergen after memory had developed. We assessed whether single or combined blockade of OX40L/CD252 and CD30L/CD153 inhibited memory T cells from driving acute asthmatic lung inflammation and protected mice following exposure to allergen at a later time. Results OX40- or CD30-deficient animals showed strong or partial protection against allergic airway inflammation; however, neutralizing either molecule alone during the secondary response to allergen had little effect on the frequency of effector memory CD4 T cells formed and acute lung inflammation. In contrast, a significant reduction in eosinophilic inflammation was observed when OX40L and CD30L were simultaneously neutralized, with dual blockade inhibiting effector memory TH2 cell expansion in the lungs, whereas formation of peripherally induced regulatory T cells remained intact. Moreover, dual blockade during the secondary response resulted in a tolerogenic state such that mice did not develop a normal tertiary memory TH2 cell and lung inflammatory response when challenged weeks later with allergen. Conclusion Memory T-cell responses to complex allergens are controlled by several TNF costimulatory interactions, and their combination targeting might represent a strategy to reduce the severity of inflammatory reactions following reexposure to allergen. |
| Databáze: | OpenAIRE |
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