Project Details Immunochemistry of metal sensitization

Project No.:
1999-047-1-700
Start Date:
01 April 2000
End Date:
25 October 2006
Division Name:
Chemistry and Human Health Division
Division No.:
700

Objective

New immunological methods are developing for clinical evaluation of immune sensitization by a number of occupationally and iatrogenically important metals. Our goals are to evaluate and systematize the application of these methods, and to produce a critical examination of the molecular structural foundations of the sensitizing response.

Description

A number of metals are immunological sensitizers in humans. Examples include occupational exposures to Ni, Co, and Cr, inhalation of Pt compounds and the possibility of sensitization to chloroplatinic catalysts in silicone implants, beryllium-related lung disease, and components of alloys used in joint replacements and skeletal stabilization. In general, activation of the immune system occurs when the metal ion (hapten) binds to an endogenous protein carrier, altering its structure and causing it to become antigenic. T-cells may recognize metal-modified peptides or the T-cell’s MHC class II-peptide complex may itself be modified by a metal ion. The nature of the metal hapten-carrier complex has not been systematically reviewed for metals that are important occupational or iatrogenic immunosensitizers.

While immunochallenges such as patch testing are widely used in assessing sensitivity to a given metal, they are of variable specificity and involve potentially exacerbating exposure for the subject. A number of newer in vitro immunological tests are developing as useful clinical correlates and biomarkers of metal sensitization, such as the Be-lymphocyte proliferation test and Ni-, Co-, Cr-lymphocyte proliferation test. Cytokine (IL-4, IL-5) production after specific Ni stimulation of the lymphocytes seems to be a very sensitive marker of Ni sensitization. These tests are not yet applied systematically or in a standardized manner.

We propose to review the structural aspects of metal-protein interactions that lead to sensitization, and present recommendations for state-of-the-art immunological tests for sensitization to specific metals.

Progress

> project initial announcement published in Chem. Int. 23(3) 2001

The development of methodology in clinical immunology is movingat a rapid pace. The Task Group initially planned a paper to surveyand recommend methods that would include cytokine profiling, thelymphocyte proliferation test, lymphocyte subtyping, etc. It becameclear that each topic warranted a paper in itself:

– ‘Diagnostic relevance of the lymphocyte transformation test forsensitization to beryllium and other metals’, PureAppl. Chem. 76(6), 1269-1281, 2004

– ‘Cytokine profiles in human exposure to metals’, PureAppl. Chem.78(11), 2155-2168, 2006

– ‘Lymphocyte subpopulations in human exposure to metals’, Pure Appl. Chem. 80(6), 1349-1364, 2008

Another aspect of the original project was to survey mechanismsby which metals cause immune reactions. This has published: ‘Mechanismsof immunosensitization to metals’, PureAppl. Chem.76(6), 1255-1268, 2004. However, developments in Hg sensitization(and issues surrounding dental amalgams and Hg chelation) demandthat this be given a very careful appraisal that should be donein a separate manuscript; a draft is being completed.

Jan 2009 publication: ‘Immunological effects of mercury’, PureAppl. Chem. 81(1), 153-167, 2009.

Project completed