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Alloreactive Th1 Cells Localize in Lung and Induce Acute Lung Injury^*

^* From the Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA.

Correspondence to: Joan G. Clark, MD, Pulmonary and Critical Care Program, Fred Hutchinson Cancer Research Center, D3 190, 1100 Fairview Ave, Seattle, WA 98109-1024

Acute lung injury is a common complication of bone marrow transplantation. Acute graft-vs-host disease (GVHD) is a major risk factor for this acute, noninfectious lung injury. Studies in murine models of GVHD and humans undergoing allogeneic marrow transplantation have implicated Th1-type responses in the generation of severe GVHD. We have previously described a murine model of acute lung injury induced by cloned alloreactive Th1 cells that recognize a polymorphic cell surface glycoprotein, Ly5 (CD45), expressed on hematopoietic cells.^{1 2} Two Ly5 alleles (Ly5a and Ly5b) have been described in mice. IV administered alloreactive cloned T cells specific for host Ly5 antigen cause a mononuclear cell pulmonary vasculitis and interstitial pneumonitis. In vitro activation of anti-Ly5a T cells causes similar injury in Ly5b animals, indicating that a lung-specific antigen is not required. However, T cells labeled in vitro with bromodeoxyuridine were visualized by immunohistochemistry in lung inflammatory foci 24 h after injection.

We hypothesized that the selective lung injury observed in this model was dependent on selective homing of T cells to lung, mediated by interaction of T-cell integrins and their counter adhesion molecules in lung. To investigate this hypothesis, we studied the in vivo distribution of radiolabeled T-cell clones after injection into mice. Resting anti-Ly5a T cells, labeled with ⁵¹Cr, were administered by tail vein injection into Ly5a and Ly5b mice. The mice were killed at 1, 3, 6, and 24 h, and radioactivity was measured in lung, spleen, liver, kidney, thymus, blood, and heart. After 1 h, > 85% of injected radioactivity was detected in lung, and the level of radioactivity was approximately 18-fold higher in lung than in any other organ. At 24 h, 40% of radioactivity was still localized in lung. The results were similar in both Ly5a and Ly5b mice, but only Ly5a mice showed histologic evidence of lung inflammation. We then sought to determine if localization of the cloned T cells in lung depends on integrin and vascular adhesion molecule interactions. ⁵¹Cr-labeled resting T cells (anti-Ly5a) were preincubated with antibody to CD11a (mAbM17/4), thereby neutralizing the lymphocyte function-associated antigen-1 (LFA-1) integrin. At 1 h and 3 h after administration to Ly5a mice, localization of the radiolabeled T cells in lung was unaffected by antibody pretreatment. However, radioactivity in lung was reduced by approximately 50% at 24 h. In a similar experiment, antibody neutralization of LFA-1 on in vitro activated T cells reduced localization of radiolabeled T cells in lung at 1 h. Localization of activated T cells in lung was also reduced in intercellular adhesion molecule-1 deficient mice.³

These findings indicate that localization of these Th1 cell clones is predominantly in the lung and is initially independent of antigenic specificity and LFA-1. However, activated T cells utilize LFA-1 and intercellular adhesion molecule-1 in adherence to lung. This model of Th1 cell-mediated lung injury provides an opportunity for further studies to delineate the mechanisms of T-cell localization in lung and its relationship to the development of immune-mediated lung injury.

References

1. Chen, W, Chatta, GS, Rubin, WD, et al (1998) T cells specific for polymorphic segment of CD45 induce graft-versus-host disease with predominant pulmonary vasculitis. J Immunol 161,909-918[Abstract/Free Full Text]
2. Clark, JG, Hackman, RC, Madtes, DK, et al (1998) Lung injury induced by alloreactive Th1 cells is characterized by host derived mononuclear cell inflammation and activation of alveolar macrophages. J Immunol 161,1913-1920[Abstract/Free Full Text]
3. Sligh, JE, Ballantyne, CM, Rich, SS, et al (1993) Inflammatory and immune responses are impaired in mice deficient in intercellular adhesion molecule 1. Proc Natl Acad Sci USA 30,8529-8533

This article has been cited by other articles:

				A. E. Dixon, J. B. Mandac, D. K. Madtes, P. J. Martin, and J. G. Clark Chemokine expression in Th1 cell-induced lung injury: prominence of IFN-gamma -inducible chemokines Am J Physiol Lung Cell Mol Physiol, September 1, 2000; 279(3): L592 - L599. [Abstract] [Full Text] [PDF]

This Article Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dixon, A. E. Articles by Clark, J. G. Search for Related Content PubMed PubMed Citation Articles by Dixon, A. E. Articles by Clark, J. G.