Distinct molecular endotypes in CD8+ T cells contribute to the pathogenesis of patients with the combination of COPD and asthma.

• Applicant: Professorin Michaela Schedel-Bockholt, Ph.D.
• Subject Area: Pneumology, Thoracic Surgery
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 425340650

Chronic obstructive pulmonary disease (COPD), most often tobacco smoke-related, is characterized by a progressive loss of lung function, significant disability, and mortality. However, given the heterogeneity among patients, additional risk and genetic factors contribute to the decline in pulmonary function. A significant subset of patients have features of both COPD and asthma. Outcomes, including health-related quality of life impairment, are worse for patients with concomitant COPD and asthma compared to individuals with COPD alone. Presently, little information is available defining mechanisms accounting for more severe disease and treatment refractoriness in patients with COPD and asthma. Central to our hypothesis is that a subset of T lymphocytes, CD8+ T cells, are major contributors to more severe disease. In severe steroid-resistant asthmatics as well as in mouse models, we characterized an important role for CD8+ T cells capable of IL-13 production in an atopic (IL-4) environment with distinct cellular and molecular signatures. CD8+ T cells, unlike CD4+ T cells, are steroid-insensitive. Moreover, CD8+ T cells have been implicated in COPD because of their predominance in lung tissue. Similar to steroid-resistant asthmatics, CD8+ T cell numbers in the lung parenchyma and small airways inversely correlated with lung function and asthma-associated inflammatory pathways (type 2, IL-13) have been shown to contribute to the disease pathogenesis.Substantial interest exists to explore cellular and molecular mechanisms (endoytpes) that can be associated with different COPD phenotypes including COPD patients with co-existing asthma. The current proposal addresses this significant but unmet need to understand the consequences of COPD and asthma in the same patient using a candidate approach coupled with an untargeted approach. Analyzing the cellular and molecular programming of peripheral blood CD8+ T cells from COPD patients with or without asthma will elucidate, for the first time, distinct disease-causing pathways between subsets of COPD patients. COPD is not a uniform disease but with this approach novel identifiers to distinguish and classify different subsets of COPD patients will be developed. We will further elucidate how smoke exposure in COPD patients with or without asthma shifts networks and pathways leading to pathogenic CD8+ T cells. An important corollary to this work is the potential to identify a subset of patients who may benefit from Vitamin D treatment and the novel IL-4/IL-13 dual receptor antagonist, dupilumab. As an extension, we will be able to discover new target genes specific to patients with a concomitant diagnosis of COPD and asthma. Achieving these milestones will allow us to progress towards personalized medicine and to improve clinical practice in patients with chronic respiratory diseases.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Christian Taube