Searching for Mechanistic Targets to Treat Severe, Drug-Resistant Asthma

Research Assistant Professor Michelle Manni, PhD, from the UPMC Children’s Hospital of Pittsburgh Division of Pediatric Pulmonary Medicine, studies the immunological mechanisms of severe, steroid insensitive asthma. She also investigates the immune mechanisms that underlie the pathogenesis of acute asthma exacerbations and obesity-associated asthma.

In March, Dr. Manni received her first National Institutes of Health (NIH) R01 grant to continue her studies of the IL-22 signaling pathway in the context of severe and treatment-resistant asthma. This translational work utilizes a preclinical animal model and human samples, aiming to uncover new therapeutic targets for severe asthma treatment.

Severe and Refractory Asthma — Prevalence and Morbidity

Allergic asthma is a heterogenous respiratory disease that affects approximately 300 million people worldwide. Although the majority of patients have mild to moderate, well-managed disease, approximately 5% to 10% of asthmatics have severe refractory disease, which accounts for more than half of the disease-related health care costs. As the incidence of asthma continues to rise, studies linking immune and pathophysiologic mechanisms to asthma endotypes are crucial to establishing more targeted and effective therapies.

IL-22 and Interferon Functions

In severe refractory asthma, allergen-specific steroid-insensitive T helper (Th) 17 and/or Th2 cells are thought to critically orchestrate asthma pathogenesis, resulting in pulmonary inflammation, mucus hypersecretion, and airway hyperresponsiveness. The Th17 immune cytokine interleukin-22 (IL-22) plays a vital role in maintaining epithelial integrity and promoting repair. IL-22 receptor alpha-2 (IL-22Ra2), an endogenous soluble receptor for IL-22, inhibits its activity.

The significance of IL-22 and endogenous IL-22Ra2, as well as the pathways that regulate them in severe asthma, are unknown. Aside from IL-22Ra2, type I IFNs also are immunomodulators that can alter IL-10 and IL-22 signaling in certain inflammatory disease contexts. Based on preliminary and published findings from Dr. Manni and her colleagues, they hypothesize that IL-22Ra2 and type I IFNs perpetuate severe allergic airway disease (AAD) by blocking IL-22 signaling, which is necessary to alleviate AAD and maintain epithelial integrity in the lung.

Study Aims

Dr. Manni’s team will investigate whether IL-22Ra2 modulates severe AAD by altering IL-22 bioavailability in the lung. Her research also seeks to determine if type I IFNs influences severe AAD through IL-22 signaling. Finally, Dr. Manni’s investigation will examine if IL-22 is protective by signaling through the pulmonary epithelium during severe asthma.

Clinical Significance

Severe, drug-resistant asthma is a growing public health issue in the United States and worldwide that causes thousands of deaths every year and creates a large burden on the health care system. Despite advancements in treatments, a significant portion of asthmatics fail to achieve asthma control, and nearly half of all asthmatics do not exhibit a type 2, eosinophil-dominant phenotype, especially those with severe refractory disease. As much less is known about pathogenic mechanisms in non-type 2 asthma, an unmet clinical need exists to better understand these subsets of disease. The goal of Dr. Manni’s work is to model these clinical subsets in mice to investigate the molecular mechanisms underlying the disease. This work will contribute to the understanding of asthma pathogenesis and aid in the development of more targeted therapeutic approaches. 

Reference

Immune Mediators of Il-22 Signaling Alter Allergic Airway Disease. 1R01HL146445-01A1. Principal investigator: Michelle Manni, PhD.

Further Reading

Manni ML, Mandalapu S, Salmeron A, Lora JM, Kolls JK, Alcorn JF. Bromodomain and Extra-Terminal Protein Inhibition Attenuates Neutrophil-dominant Allergic Airway Disease. Sci Rep. 2017 Feb 24; 7: 43139.

Manni ML, Alcorn JF. The Enigmatic Role of IL-22 in Asthma. Expert Rev Respir Med. 2016 Jun; 10(6): 619-623.

Manni ML, Mandalapu S, McHugh KJ, Elloso MM, Dudas PL, Alcorn JF. Molecular Mechanisms of Airway Hyperresponsiveness in a Murine Model of Steroid-Resistant Airway Inflammation. J Immunol. 2016 Feb 1; 196(3): 963-977.

Manni ML, Trudeau JB, Scheller EV, Mandalapu S, Kolls JK, Wenzel SE, Alcorn JF. The Complex Relationship Between Inflammation and Lung Function in Severe Asthma. Mucosal Immunology. 2014; 7: 1186-1198.

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