Tolerance to Nickel: Oral Nickel Administration Induces a High Frequency of Anergic T Cells with Persistent Suppressor Activity

• Published in: The Journal of immunology (1950) Vol. 167; no. 12; pp. 6794 - 6803
• Main Authors: Artik, Suzan, Haarhuis, Karin, Wu, Xianzhu, Begerow, Jutta, Gleichmann, Ernst
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15-12-2001
• Subjects: Adjuvants, Immunologic - pharmacology; Administration, Oral; Adoptive Transfer; Animals; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - transplantation; Cells, Cultured; Clonal Anergy; Dermatitis, Allergic Contact - drug therapy; Dermatitis, Allergic Contact - immunology; Dermatitis, Allergic Contact - metabolism; Female; Hydrogen Peroxide - pharmacology; Injections, Intraperitoneal; Interleukin-2 - biosynthesis; Kinetics; Lymph Nodes - immunology; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Nickel - administration & dosage; Nickel - pharmacokinetics; Nickel - pharmacology; Spleen - immunology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - transplantation
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.167.12.6794

We adapted our mouse model of allergic contact hypersensitivity to nickel for the study of tolerance. Sensitization in this model is achieved by the administration of nickel ions with H(2)O(2); nickel ions alone are unable to prime naive T cells, but can restimulate primed ones. A 4-wk course of oral or i.p. administration of 10 mM NiCl(2) to naive mice induced tolerance, preventing the induction of hypersensitivity for at least 20 wk; long term desensitization of nickel-sensitized mice, however, required continuous NiCl(2) administration. When splenic T cells of orally tolerized donors, even after a treatment-free interval of 20 wk, were transferred to naive recipients, as with lymph node cells (LNC), they specifically prevented sensitization of the recipients. The LNC of such donors were anergic, because upon in vivo sensitization with NiCl(2) in H(2)O(2) and in vitro restimulation with NiCl(2), they failed to show the enhanced proliferation and IL-2 production as seen with LNC of mice not tolerized before sensitization. As few as 10(2) bulk T cells, consisting of both CD4(+) and CD8(+) cells, were able to specifically transfer tolerance to nickel. A hypothesis is provided to account for this extraordinarily high frequency of nickel-reactive, suppressive T cells; it takes into account that nickel ions fail to act as classical haptens, but form versatile, unstable metal-protein and metal-peptide complexes. Furthermore, a powerful amplification mechanism, such as infectious tolerance, must operate which allows but a few donor T cells to tolerize the recipient.