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Activation Pathways Implicate Anti-HLA-DP and Anti-LFA-1 Antibodies as Lead Candidates for Intervention in Chronic Berylliosis¹

Yuan K. Chou^2,*,, David M. Edwards^2,*, Andrew D. Weinberg^¶, Arthur A. Vandenbark^*,,, Brian L. Kotzin^||, Andrew P. Fontenot^|| and Gregory G. Burrows^3,*,

Departments of ^* Neurology, Biochemistry and Molecular Biology, and Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR 97239; Neuroimmunology Research, Veterans Affairs Medical Center, Portland, OR 97207; ^¶ Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, Portland, OR 97213; and ^|| Department of Medicine and Immunology, University of Colorado Health Sciences Center, Denver, CO 80206

CD4⁺ T cells play a key role in granulomatous inflammation in the lung of patients with chronic beryllium disease. The goal of this study was to characterize activation pathways of beryllium-responsive bronchoalveolar lavage (BAL) CD4⁺ T cells from chronic beryllium disease patients to identify possible therapeutic interventional strategies. Our results demonstrate that in the presence of APCs, beryllium induced strong proliferation responses of BAL CD4⁺ T cells, production of superoptimal concentrations of secreted proinflammatory cytokines, IFN-, TNF-,and IL-2, and up-regulation of numerous T cell surface markers that would promote T-T Ag presentation. Ab blocking experiments revealed that anti-HLA-DP or anti-LFA-1 Ab strongly reduced proliferation responses and cytokine secretion by BAL CD4⁺ T cells. In contrast, anti-HLA-DR or anti-OX40 ligand Ab mainly affected beryllium-induced proliferation responses with little impact on cytokines other than IL-2, thus implying that nonproliferating BAL CD4⁺ T cells may still contribute to inflammation. Blockade with CTLA4-Ig had a minimal effect on proliferation and cytokine responses, confirming that activation was independent of B7/CD28 costimulation. These results indicate a prominent role for HLA-DP and LFA-1 in BAL CD4⁺ T cell activation and further suggest that specific Abs to these molecules could serve as a possible therapy for chronic beryllium disease.

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				A. P. Fontenot, T. S. Keizer, M. McCleskey, D. G. Mack, R. Meza-Romero, J. Huan, D. M. Edwards, Y. K. Chou, A. A. Vandenbark, B. Scott, et al. Recombinant HLA-DP2 Binds Beryllium and Tolerizes Beryllium-Specific Pathogenic CD4+ T Cells J. Immunol., September 15, 2006; 177(6): 3874 - 3883. [Abstract] [Full Text] [PDF]