oxazolone and Lupus-Erythematosus--Systemic

Short-term combination therapy with the costimulatory antagonists CTLA4Ig and anti-CD40 ligand induces prolonged suppression of disease onset in New Zealand Black/New Zealand White F(1) systemic lupus erythematosus-prone mice. To determine the mechanism for this effect, 20- to 22-wk-old New Zealand Black/New Zealand White F(1) mice were treated with six doses each of CTLA4Ig and anti-CD40 ligand Ab over 2 wk. Combination-treated mice, but not mice treated with either agent alone, had prolonged survival and the production of pathogenic IgG anti-dsDNA Ab was suppressed. Twenty weeks after completion of treatment the frequency of activated B cells producing anti-dsDNA Ab was decreased, and the abnormal transition of T cells from the naive to the memory compartment was blocked. Combination treatment partially suppressed class switching and decreased the frequency of somatic mutations in the V(H)BW-16 gene, which is expressed by pathogenic anti-DNA Abs. Treated mice were still able to respond to the hapten oxazolone when it was given 8 wk after treatment initiation, and they mounted a somatically mutated IgG anti-oxazolone response that was noncross-reactive with dsDNA. Fifty to 60% of previously treated mice, but only 14% of previously untreated mice, responded within 2-3 wk to a second course of therapy given at the onset of fixed proteinuria and remained well for a further 3-4 mo. Although this treatment had no immediate effect on serum anti-dsDNA Abs or on the abnormal T cell activation observed in sick mice, 25% of treated mice lived for >18 mo compared with 5% of untreated controls. These results suggest that the effect of costimulatory blockade in remission induction must be mediated by a different mechanism than is demonstrated in the disease prevention studies.

Topics: Abatacept; Amino Acid Sequence; Animals; Antibodies; Antibodies, Antinuclear; Antigens, CD; Antigens, Differentiation; B-Lymphocytes; CD40 Ligand; CTLA-4 Antigen; DNA; Hybridomas; Immunoconjugates; Immunoglobulin Class Switching; Immunosuppressive Agents; Kinetics; Lupus Erythematosus, Systemic; Mice; Mice, Inbred NZB; Molecular Sequence Data; Mutation; Oxazolone; Recombinant Fusion Proteins; Spleen; Treatment Outcome

Oestrogen is known to accelerate glomerulonephritis and autoantibody production in human and murine systemic lupus erythematosus (SLE). In this study we demonstrate that treatment of castrated autoimmune MRL +/+ mice with physiological doses of oestrogen results in enhanced immunoglobulin and autoantibody production as well as increased deposition of IgG in renal glomeruli. Accelerated development of glomerulonephritis was also evident from the increase of albuminuria. Interestingly, in contrast to these deteriorative effects of oestrogen on immune complex-mediated disease we now show that the lymphocytic infiltrations in the submandibular glands and perivascular lesions in the kidneys were significantly diminished after exposure to oestrogen. This remarkable impact of physiological oestrogen levels on the outcome of SLE in MRL +/+ mice is postulated to be the result of a differential effect on T and B cell-mediated immune responses.

Topics: Animals; Antibodies, Antinuclear; Autoimmunity; Castration; Concanavalin A; Estradiol; Glomerulonephritis; Hemoglobinuria; Immunoglobulins; Kidney; Lupus Erythematosus, Systemic; Male; Mice; Oxazolone; Rheumatoid Factor; Salivary Glands; Sialadenitis; Spleen; Vasculitis

Oestrogen (E2) has been suggested to be responsible for the female preponderance for systemic lupus erythematosus (SLE) and for exacerbations of disease during pregnancy. In lupus-prone (NZB x NZW) F1 (NZB/W) mice, sex hormones also influence disease progression, thus long-term treatment of NZB/W mice with high doses of oestradiol increases the mortality in immune-complex mediated disease. We have previously demonstrated that E2 suppression of delayed-type hypersensitivity (DTH) to oxazolone (OXA) in NZB/W mice is inherited from the healthy NZW (H-2z) and not from the autoimmune NZB (H-2d) parental strain. In this paper we have analysed the influence of E2 on DTH and antibody responses to OXA in backcrosses of NZB/W mice and the NZB and NZW parental strains. Suppressed DTH was found in 15/16 (94%) of female (NZB/W x NZW) F1 (NZB/W/W) mice treated with E2. In contrast, only 32/36 (51%) of (NZB/W x NZB)F1 (NZB/W/B) mice treated with E2 displayed suppressed DTH reactivity. These two findings are compatible with a single, rather than multiple, dominant gene inherited from the NZW strain encoding for E2-mediated suppression of DTH in NZB/W mice. FACS analysis, using a monoclonal antibody recognizing the H-2z but not the H-2d locus, identified the H-2 expression (H-2dd and H-2dz) of the NZB/W/B backcrosses and revealed that E2 suppression of DTH is not linked to the H-2 haplotype of the backcrosses. Furthermore, E2 treatment of NZB/W/W mice, but not of NZB/W/B mice, significantly enhanced the serum levels of anti-OXA antibodies of both IgG and IgM classes. Based on our results it is tempting to speculate whether similar genetic factors for E2 sensitivity of the immune system may be of importance for the female predominance of human SLE.

Topics: Animals; Estradiol; Female; Genes, Dominant; H-2 Antigens; Haplotypes; Hypersensitivity, Delayed; Immune Tolerance; Immunoglobulin G; Immunoglobulin M; Lupus Erythematosus, Systemic; Mice; Mice, Inbred NZB; Oxazolone

A number of phenotypic and functional T-cell abnormalities have been reported in autoimmune MRL lpr/lpr (MRL/l) mice. We examined hapten-specific delayed-type hypersensitivity (DTH) responses in male and female MRL/l mice and compared them to age- and sex-matched congeneic MRL +/+ (MRL/n) mice and outbred Swiss controls. Profound defects in DTH reactivity were demonstrated in female MRL/l mice at all ages tested. In contrast MRL/l males displayed only partly impaired and selective DTH defect toward one of the two haptens used. Congeneic MRL/n females expressed lower DTH reactivity than their male littermates. We conclude that DTH responses in autoimmune MRL/l mice are defective and sex hormone related.

Topics: Age Factors; Animals; Autoimmune Diseases; Female; Hypersensitivity, Delayed; Lupus Erythematosus, Systemic; Male; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Oxazolone; Picryl Chloride; Skin; T-Lymphocytes