T cell depletion protects against alveolar destruction due to chronic cigarette smoke exposure in mice

Abstract

The role of T cells in chronic obstructive pulmonary disease (COPD) is not well understood. We have previously demonstrated that chronic cigarette smoke exposure can lead to the accumulation of CD4(+) and CD8(+) T cells in the alveolar airspaces in a mouse model of COPD, implicating these cells in disease pathogenesis. However, whether specific inhibition of T cell responses represents a therapeutic strategy has not been fully investigated. In this study inhibition of T cell responses through specific depleting antibodies, or the T cell immunosuppressant drug cyclosporin A, prevented airspace enlargement and neutrophil infiltration in a mouse model of chronic cigarette smoke exposure. Furthermore, individual inhibition of either CD4(+) T helper or CD8(+) T cytotoxic cells prevented airspace enlargement to a similar degree, implicating both T cell subsets as critical mediators of the adaptive immune response induced by cigarette smoke exposure. Importantly, T cell depletion resulted in significantly decreased levels of the Th17-associated cytokine IL-17A, and of caspase 3 and caspase 7 gene expression and activity, induced by cigarette smoke exposure. Finally, inhibition of T cell responses in a therapeutic manner also inhibited cigarette smoke-induced airspace enlargement, IL-17A expression, and neutrophil influx in mice. Together these data demonstrate for the first time that therapeutic inhibition of T cell responses may be efficacious in the treatment of COPD. Given that broad immunosuppression may be undesirable in COPD patients, this study provides proof-of-concept for more targeted approaches to inhibiting the role of T cells in emphysema development.

T-Regulatory Cells and Programmed Death 1+ T Cells Contribute to Effector T-Cell Dysfunction in Patients with Chronic Obstructive Pulmonary Disease

“…Antiinflammatory drugs salmeterol and fluticasone or increased indoleamine 2,3-dioxigenase activity have been reported to reduce severity of COPD symptoms by enhancing Treg activity (27,28). A recent study in a mouse model of chronic cigarette smoke exposure has shown that therapeutic inhibition of effector T cells protected mice from alveolar destruction and the development of emphysema; a similar approach may be efficacious for COPD (29). Our studies suggest the dual nature of Tregs in COPD.…”

Liver growth factor treatment reverses emphysema previously established in a cigarette smoke exposure mouse model

“…Our data suggest that animals with chronic airflow limitation had significantly raised levels of various systemic inflammatory markers like circulating leukocytes (specifically T-cells and neutrophils) and serum TNF-␣ level, indicating that persistent systemic inflammation is present in AKR/J. LGF treatment decreases T-lymphocyte population in peripheral blood, what seems to be in agreement with a recently published article that shows that T-cell depletion protects against alveolar destruction attributable to chronic CSE in mice (37). It is possible in some cases that the inflammatory process may "spill" over into the systemic circulation, promoting a generalized inflammatory reaction.…”

“…It is possible in some cases that the inflammatory process may "spill" over into the systemic circulation, promoting a generalized inflammatory reaction. Our findings are consistent with systemic inflammation present in some patients with COPD (1) associated with an increased influx of T-cells into the airway (6,28,31,37). This finding may explain, at least in part, the high prevalence of systemic complications, such as cachexia, osteoporosis, and cardiovascular diseases among patients with COPD.…”

Cigarette smoke and CFTR: implications in the pathogenesis of COPD

“…Furthermore, T cell responses have been shown to be important in COPD. Podolin et al (113) found that T cell depletion in a mouse model of COPD inhibited alveolar destruction caused by chronic cigarette smoke exposure. Cigarette smoke has been shown to induce reversible changes in energy metabolism and the cellular redox status that are not related to the inflammatory responses in mouse lung (6).…”