Activation pathways implicate anti-HLA-DP and anti-LFA-1 antibodies as lead candidates for intervention in chronic berylliosis.

Abstract

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.

• Authors: Yuan K Chou, David M Edwards, Andrew D Weinberg, Arthur A Vandenbark, Brian L Kotzin, Andrew P Fontenot, Gregory G Burrows
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 174 Issue 7 Pg. 4316-24 (Apr 01 2005) ISSN: 0022-1767 [Print] United States
• PMID: 15778396 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• HLA-DP Antigens
• HLA-DP beta-Chains
• HLA-DPw2 antigen
• Lymphocyte Function-Associated Antigen-1
• Beryllium

Topics

• Antibodies, Monoclonal (therapeutic use)
• Berylliosis (drug therapy)
• Beryllium (immunology)
• CD4-Positive T-Lymphocytes (immunology)
• Chronic Disease
• HLA-DP Antigens (genetics, immunology)
• HLA-DP beta-Chains
• Heterozygote
• Humans
• Immunotherapy (methods)
• Lymphocyte Activation
• Lymphocyte Function-Associated Antigen-1 (immunology)
• Signal Transduction