aurotioprol and Autoimmune-Diseases

Immunological tolerance can be achieved in animals by exposure of newborn to a foreign antigen. Depending on the dose and timing of the antigenic challenge, tolerance has been reported to result in clonal deletion, anergy or active suppression. In this latter case, regulatory T cells prevent autoimmunity by suppressing the reactivity of pathogenic self-reactive T cells. We have previously reported the generation of a neonatal, mercury-specific, and dominant tolerance to autoimmunity induced by mercury salts in rats. Chronic exposure to mercury salts can lead to SLE-like autoimmune responses, mediated by autoreactive CD4+ Th2 cells, that regulate and are followed by a resistant state mediated by protective CD8+ T cells. The aim of the study was to compare the resistance to the neonatal tolerance to mercury disease, and to further characterize the CD8+ T cells endowed with regulatory capacity in the neonatal tolerance model. We report here that resistance to mercury disease is long lasting and not mercury-specific, suggesting that different CD8+ T cells are involved in resistance and neonatal tolerance, and that regulatory CD8+ Tc1 cells generated in tolerance are required to control the CD8- cell population from developing Th2-mediated autoimmunity. Upon mercury recall, CD8+ CD45RC(high) T cells, that represent the Tc1 subset in the rat, expanded and were polarized towards IFNgamma production. Interestingly, identical results were obtained with the CD8+ CD25+T cell population. Substantial amounts of FasL gene expression were detected in CD8+ T lymphocytes upon recall with the tolerogen. AICD may be one of the regulatory mechanisms used by these regulatory CD8+ Tc1 cells that control neonatal tolerance to a Th2-mediated autoimmune disorder.

Topics: Adoptive Transfer; Animals; Animals, Newborn; Apoptosis; Autoimmune Diseases; CD4 Antigens; CD4-Positive T-Lymphocytes; CD8 Antigens; CD8-Positive T-Lymphocytes; Dimercaprol; Fas Ligand Protein; Gene Expression; Immune Tolerance; Immunoglobulin E; Interferon-gamma; Interleukin-2; Leukocyte Common Antigens; Lymphocyte Transfusion; Male; Membrane Glycoproteins; Mercuric Chloride; Organogold Compounds; Organometallic Compounds; Propanols; Rats; Receptors, Interleukin-2; Spleen; Sulfhydryl Compounds; T-Lymphocyte Subsets; T-Lymphocytes, Cytotoxic; Th2 Cells

Brown Norway rats injected with aurothiopropanolsulfonate sodium salt develop systemic autoimmunity. The aim of this study was to assess the influence of the sulfur-containing group in this experimental model of gold-induced autoimmunity. It was shown that the sulfur-containing group does not induce autoimmunity of itself, but potentiates the immunotoxic effects of gold.

Topics: Animals; Antirheumatic Agents; Autoimmune Diseases; Autoimmunity; Dimercaprol; Disease Models, Animal; Female; Organogold Compounds; Organometallic Compounds; Propanols; Rats; Rats, Inbred BN; Sulfhydryl Compounds

The pathogenesis of gold-induced autoimmunity and membranous glomerulopathy is not well understood. HgCl2 and D-penicillamine, other chemicals known to trigger membranous glomerulopathy in humans, induce autoimmune manifestations in Brown-Norway (BN) rats but not in Lewis (LEW) rats. These chemicals trigger T-cell clones which are specific for self class II molecules from the major histocompatibility complex and are probably responsible for the polyclonal B-cell activation observed. The aim of this work was to test the effects of aurothiopropanolsulphonate (ATPS) in BN and LEW rats. In BN rats, ATPS induced a polyclonal B-cell activation marked by lymphoproliferation, hyperimmunoglobulinaemia affecting mainly IgE, and by the production of numerous autoantibodies. A glomerulonephritis occurred, initially due to anti-glomerular basement membrane antibody deposition, and later to the formation of granular deposits, occasionally resulting in a typical membranous glomerulopathy. Self class-II-specific T-cells were found that might be responsible for the polyclonal B-cell activation. Lewis rats were free of glomerulopathy but, like BN rats, exhibited an interstitial nephritis and some degree of polyclonal B-cell activation. These findings demonstrate that, depending on the strain, ATPS triggers different B-cell clones inducing different degrees of autoimmunity.

Topics: Animals; Autoantibodies; Autoimmune Diseases; Autoimmunity; Dimercaprol; Female; Glomerulonephritis, Membranous; Gold; Immunoglobulin E; Lymphocyte Activation; Male; Organogold Compounds; Organometallic Compounds; Propanols; Rats; Rats, Inbred BN; Rats, Inbred Lew; Sulfhydryl Compounds

Cross-reactive idiotypes (CRId) borne on autoanti-glomerular basement membrane antibodies of Brown-Norway (BN) rats with mercury-induced glomerulonephritis have been described in the preceding study (Guéry, J.-C. et al., Eur. J. Immunol. 1990. 20:93). BN rats treated with sodium aurothiopropanol sulfonate or D-penicillamine, as well as (LEW X BN)F1 hybrids transferred with BN rat spleen cells, developed quite similar autoimmune abnormalities. In the present study, it is shown that immunoglobulins bearing such "public" idiotypes are also produced and deposited in the kidney in these three models. The CRId here described may, therefore, be considered as a marker of sets of recurrently expressed V region genes during the course of these autoimmune disorders. Anti-self class II T cells are present in the three models of toxin-induced autoimmunity and anti-allo class II T cells are responsible for the chronic graft-vs.-host reaction. The same B cell clones are probably triggered during these processes as a consequence of a polyclonal B cell activation mediated by anti-class II T cells.

Topics: Animals; Autoantibodies; Autoimmune Diseases; Basement Membrane; Cross Reactions; Dimercaprol; Fluorescent Antibody Technique; Graft vs Host Reaction; Immunoglobulin Idiotypes; Kidney Glomerulus; Laminin; Mercuric Chloride; Metalloproteins; Organogold Compounds; Organometallic Compounds; Propanols; Rats; Rats, Inbred BN; Rats, Inbred Lew; Sulfhydryl Compounds