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

PL Podolin, JP Foley, DC Carpenter… - … of Physiology-Lung …, 2013 - journals.physiology.org
PL Podolin, JP Foley, DC Carpenter, BJ Bolognese, GA Logan, E Long III, OJ Harrison
American Journal of Physiology-Lung Cellular and Molecular …, 2013journals.physiology.org
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 …
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.
American Physiological Society