title: 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.
authors.affiliation: Respiratory Therapeutic Area, GlaxoSmithKline, King Of Prussia, PA, USA.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Podolin
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Foley
authors.forename: Donald C
authors.initials: DC
authors.lastname: Carpenter
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bolognese
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Logan
authors.forename: Edward
authors.initials: E
authors.lastname: Long
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Harrison
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Walsh
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D053148:Caspase 3 / Q000097:blood; D053179:Caspase 7 / Q000096:biosynthesis / Q000235:genetics; D016572:Cyclosporine; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D007165:Immunosuppression Therapy; D020381:Interleukin-17 / Q000097:blood; D008176:Lung Volume Measurements; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000276:immunology; D011650:Pulmonary Alveoli / Q000276:immunology / Q000473:pathology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology* / Q000473:pathology; D012907:Smoking; D014028:Tobacco Smoke Pollution
chemical_list: D020381:Interleukin-17; D014028:Tobacco Smoke Pollution; D016572:Cyclosporine; D053148:Caspase 3; D053179:Caspase 7