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Citation Information: J Clin Invest. 1998;102(9):1653-1661. https://doi.org/10.1172/JCI4174.
Abstract
CD8(+) T cells infiltrate the lung in many clinical conditions, particularly in interstitial lung disease. The role(s) that CD8(+) T cells might be playing in the pathogenesis of inflammatory lung disease is unclear at present, as is the direct contribution of CD8(+) T cell effector activities to lung injury. This report describes a transgenic model used to evaluate the impact, on respiratory structure and function, of CD8(+) T lymphocyte recognition of a target antigen expressed endogenously in alveolar epithelial cells. We found that adoptive transfer of cloned CD8(+) cytotoxic T lymphocytes (CTLs) specific for an alveolar neo-antigen (influenza hemagglutinin) leads to progressive lethal injury in transgenic mice, which dramatically affects lung structure and function. Transgenic recipients of CD8(+) CTLs exhibited tachypnea and progressive weight loss, becoming moribund over a period of several days. Concomitantly, the animals developed a progressive interstitial pneumonitis characterized initially by lymphocytic infiltration of alveolar walls and spaces, followed by an exuberant mononuclear cell infiltration that correlated with restrictive pulmonary mechanics and a progressive diffusion impairment. These results indicate that antigen-specific CD8(+) T cell recognition of an alveolar epithelial "autoantigen" is, in and of itself, sufficient to trigger an inflammatory cascade that results in the histological and physiological manifestations of interstitial pneumonia.
Authors
R I Enelow, A Z Mohammed, M H Stoler, A N Liu, J S Young, Y H Lou, T J Braciale
Consequences of alveolar inflammation
Submitter: Robert Paine, M.D. | rpaine@umich.edu
University of Michigan School of Medicine
Published November 16, 1998
To the Editor: I read with interest the description by Enelow et al. ( J. Clin. Invest. 1998. 102:1653-1661) of their elegant model of experimental lung disease induced by type II alveolar epithelial cell recognition by CD8+ T cells. Transgenic expression of a neo-antigen under control of the surfactant protein C promoter, followed by transfer of specific cytotoxic T lymphocytes, resulted in progressive respiratory dysfunction, with diminished lung compliance, impaired gas exchange and death due to respiratory failure. The authors describe a progressive interstitial pneumonitis with mononuclear cell infiltration of the alveolar wall. They propose that the abnormalities in gas exchange are a consequence of this interstitial pneumonitis, and argue that activation of the inflammatory cascade is the cause of the physiological abnormalities. This is a reasonable explanation. However, it must be recognized that the transfer of cytotoxic T cells specifically recognizing type II cells would be expected to result in severe abnormalities in surfactant expression in the lungs. Progressive loss of pulmonary surfactant due to selective type II cell injury would cause precisely the sort of changes in diffusing capacity and lung compliance described by the authors. In assessing the lessons to be derived from this model it is important to consider the relative contributions of surfactant abnormalities vs. alveolar septal infiltration. Measurements of surfactant phospholipids in the experimental animals would be of great help in this regard. A very different result might be obtained if the inflammatory cascade were initiated by expression of the neo-antigen on a different alveolar cell. The authors are to be commended for their carefully designed study, but should recognize the possibility that these studies may be most relevant to newborn respiratory distress syndrome rather than to interstitial lung disease.
Robert Paine, M.D. University of Michigan School of Medicine
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