Short- and long-term effects of T-cell modulating agents in experimental autoimmunity.
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.
Mellergård
Johan
J
Division of Molecular and Immunological Pathology, Department of Molecular and Clinical Medicine, Linköping University, SE-581 85 Linköping, Sweden.
Havarinasab
Said
S
Hultman
Per
P
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000936:Antigen-Antibody Complex / Q000187:drug effects / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002466:Cell Nucleolus / Q000276:immunology; D002843:Chromatin / Q000276:immunology; D002868:Chromosomal Proteins, Non-Histone / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007073:Immunoglobulin E / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000096:biosynthesis; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008627:Mercuric Chloride / Q000633:toxicity; D051379:Mice; D008815:Mice, Inbred Strains; D013601:T-Lymphocytes / Q000187:drug effects*; D013997:Time Factors
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D001323:Autoantibodies; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; C047458:fibrillarin; D007073:Immunoglobulin E; D008627:Mercuric Chloride