Activation pathways implicate anti-HLA-DP and anti-LFA-1 antibodies as lead candidates for intervention in chronic berylliosis.
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-gamma, TNF-alpha,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.
Chou
Yuan K
YK
Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA.
Edwards
David M
DM
Weinberg
Andrew D
AD
Vandenbark
Arthur A
AA
Kotzin
Brian L
BL
Fontenot
Andrew P
AP
Burrows
Gregory G
GG
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001607:Berylliosis / Q000188:drug therapy*; D001608:Beryllium / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002908:Chronic Disease; D006682:HLA-DP Antigens / Q000235:genetics / Q000276:immunology*; D059868:HLA-DP beta-Chains; D006579:Heterozygote; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology*; D015398:Signal Transduction
D000911:Antibodies, Monoclonal; D006682:HLA-DP Antigens; D059868:HLA-DP beta-Chains; C083176:HLA-DPw2 antigen; D016169:Lymphocyte Function-Associated Antigen-1; D001608:Beryllium