Short- and long-term effects of T-cell modulating agents in experimental autoimmunity.

Abstract

Due to the easy and reliable induction of a disease condition with many of the features present in human autoimmunity, mercury-induced autoimmunity (mHgAI) in rodents is a favourable autoimmune model. Genetically susceptible (H-2(s)) mice develop in response to mercury (Hg) a systemic autoimmune condition with antinucleolar antibodies (ANoA) targeting the protein fibrillarin, transient polyclonal B-cell activation, hyperimmunoglobulinemia, and systemic immune-complex (IC) deposits. In order to study the short- and long-term effects of treatment with immunomodulating agents on the disease parameters in HgAI, groups of B10.S (H-2(s)) mice were given 6 mg HgCl(2)/l drinking water for 22 weeks. Three weeks initial treatment with cyclosporin A (CyA), a high dose of tacrolimus (HD tacrolimus), or anti-CD4 monoclonal antibody (a-CD4) inhibited induction of ANoA and IC deposit by Hg. This effect persisted for the subsequent 19 weeks when the mice were only treated with Hg. Initial treatment with anti-IL-4 monoclonal antibody (a-IL-4) for 3 weeks inhibited induction of IgE and IC deposits by Hg, but not ANoA. However, subsequent treatment with Hg without a-IL-4 for 19 weeks induced IC deposits. The T-cell modulating agents aggravated some of the HgAI disease parameters: a-CD4 stimulated the polyclonal B-cell activation, a-IL-4 increased the IgG antichromatin antibody response, and a low dose of tacrolimus (LD tacrolimus) enhanced the ANoA, the polyclonal B-cell activation, and the IC deposits. We conclude that a short initial treatment with a-CD4 or CyA efficiently protects against induction of systemic autoimmunity for an extended period of time. However, some of the T-cell modulating agents, especially a low dose of tacrolimus, aggravate autoimmune manifestations not only during ongoing treatment, but also after treatment with these agents has ceased.

• Authors: Johan Mellergård, Said Havarinasab, Per Hultman
• Journal: Toxicology (Toxicology) Vol. 196 Issue 3 Pg. 197-209 (Mar 15 2004) ISSN: 0300-483X [Print] Ireland
• PMID: 15036746 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adjuvants, Immunologic
• Antibodies, Monoclonal
• Antigen-Antibody Complex
• Autoantibodies
• Chromatin
• Chromosomal Proteins, Non-Histone
• Immunoglobulin M
• Immunosuppressive Agents
• fibrillarin
• Immunoglobulin E
• Mercuric Chloride

Topics

• Adjuvants, Immunologic (pharmacology)
• Animals
• Antibodies, Monoclonal (pharmacology)
• Antigen-Antibody Complex (drug effects, immunology)
• Autoantibodies (immunology)
• Autoimmunity (drug effects)
• B-Lymphocytes (drug effects, immunology)
• Cell Nucleolus (immunology)
• Chromatin (immunology)
• Chromosomal Proteins, Non-Histone (immunology)
• Enzyme-Linked Immunosorbent Assay
• Female
• Immunoglobulin E (biosynthesis)
• Immunoglobulin M (biosynthesis)
• Immunosuppressive Agents (pharmacology)
• Mercuric Chloride (toxicity)
• Mice
• Mice, Inbred Strains
• T-Lymphocytes (drug effects)
• Time Factors