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HLA-DP-unrestricted TNF- release in beryllium-stimulated peripheral blood mononuclear cells

¹ Laboratory of Clinical Pathology, and ² Division of Respiratory Diseases of the University of "Tor Vergata", National Institute for Infectious Diseases (L. Spallanzani, IRCCS), Rome, ³ Division of Occupational Medicine, Policlinico, Modena, and ⁴ Division of Pulmonary Medicine, Policlinico, Modena, Italy. ⁵ Pulmonary and Intensive Care Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA

CORRESPONDENCE: M. Amicosante, Laboratory of Clinical Pathology, INMI L. Spallanzani-IRCCS, Via Portuense 292, I-00149, Rome, Italy. Fax: 39 065582237. E-mail: amicosante@inmi.it

Keywords: berylliosis, cytokines, human leukocyte antigen-DPGlu69, interferon-, T-cell proliferation, tumour necrosis factor-

Received: November 16, 2001
Accepted June 12, 2002

This study was supported by grants from US Dept of Energy (DoE) grant DE-FG02-93ER61714 and grant 99060855594 from MIUR, Italy.

Berylliosis is a granulomatous disorder of the lung caused by inhalation of beryllium (Be) and dominated by the accumulation of CD4+ T-helper (Th)1 memory T-cells proliferating in response to Be in the lower respiratory tract. Two gene markers have been associated with susceptibility to berylliosis: 1) the human leucocyte antigen (HLA)-DP gene whose allelic variants, carrying glutamate in position 69 of the ß-chain (HLA-DPGlu69), can bind Be directly and present it to interferon (IFN)- releasing Th1 T-cell clones from patients with berylliosis; and 2) the cytokine gene tumour necrosis factor (TNF)- which has been shown to increase berylliosis risk independent of HLA-DPGlu69.

In order to determine whether TNF- release was triggered by Th1 T-cell activation by Be stimulation in the context of HLA-DPGlu69 molecules, the proliferation of BeSO₄-stimulated blood mononuclear cells and the release of IFN-, TNF-, RANTES (regulated on activation normal T-cell expressed and secreted), granulocyte-macrophage colony-stimulating factor, interleukin (IL)-4, IL-6, IL-8, IL-10 and IL-12 by BeSO₄-stimulated blood mononuclear cells was quantified in 11 individuals with berylliosis using an anti-HLA-DP antibody as a probe for HLA-DP restricted T-cell activation.

While proliferation and IFN- release were completely abrogated by HLA-DP inhibition (inhibition with anti-HLA-DP monoclonal antibody (mAb): 88±16 and 77±16%, respectively; anti-HLA-DR: 29±38 and 14±10%, respectively), the release of TNF- was not (inhibition with anti-HLA-DP mAb: 8.9±7.8%). No other cytokine was detected at significant levels. Moreover, Be was able to induce TNF- production in healthy control subjects not exposed to Be in the absence of T-cell proliferation and IFN- production.

In conclusion, these data suggest that the tumour necrosis factor- response of mononuclear cells is independent of the activation of beryllium-specific human leucocyte anitgen-DP restricted T-cells, which is consistent with the finding that the tumour necrosis factorA2 and the human leucocyte anitgen-DPGlu69 genetic markers are independently interacting in increasing berylliosis risk.

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