Systemic lupus erythematosus (SLE) is considered to be the quintessential autoimmune disease. It has not been possible to induce SLE in animal models by DNA immunization or by challenge with anti-DNA antibodies. We herewith report a murine model of SLE-like disease induced by immunization of C3H.SW female mice with a common human monoclonal anti-DNA idiotype (16/6 idiotype). Following a booster injection with the 16/6 idiotype, high levels of murine anti-16/6 and anti-anti-16/6 antibodies (associated with anti-

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A peptide based on the sequence of the complementarity determining region (CDR) 1 of a human monoclonal anti-DNA autoantibody that bears the 16/6 idiotype (16/6Id) was synthesized as a potential candidate for the treatment of SLE patients. The peptide, designated hCDR1, did not induce experimental SLE upon active immunization of mice. The ability of the peptide to treat an already established lupus that was either induced in BALB/c mice or developed spontaneously in (NZB x NZW)F1 mice was tested. Ten weekly injections of hCDR1 (200, 50 microg/mouse) given subcutaneously mitigated disease manifestations (e.g., leukopenia, proteinuria and kidney damage) and resulted in a prominent reduction in the dsDNA specific antibody titers. Furthermore, treatment with hCDR1 resulted in reduced secretion and expression of the "pathogenic" cytokines [i.e., INFgamma, IL-1beta, TNFalpha (in the induced model) and IL-10], whereas the immunosuppressive cytokine TGFbeta was up-regulated. Thus, the significant ameliorating effects of hCDR1 are manifested at least partially via the immunomodulation of the cytokine profile. These results suggest that hCDR1 is a potential candidate for a novel treatment of SLE patients.

To investigate which parts of the acetylcholine receptor are involved in the initiation and development of myasthenia gravis (MG), peptides representing different sequences of the human acetylcholine receptor a-subunit were synthesized. These peptides were tested for their ability to stimulate T cells of myasthenic patients and healthy control patients in proliferation assays and to bind to sera antibodies. Three of eight peptides discriminated significantly between the two groups in the proliferation assay, as well as in their ability to bind to serum antibodies. HLA-DR3 and DR5 were associated with proliferative responses to specific AChR peptides in the group of myasthenics. Acetylcholine receptor epitopes that might play a specific role in myasthenia gravis thus were demonstrated.

Background: Sex hormones have been shown to influence the immune system and to modify the course of autoimmune disorders. Objective: To examine the effects of the oestrogen antagonist tamoxifen on the course of systemic lupus erythematosus (SLE) in (NZB×NZW)F1 mice. Methods: Groups of 8 week old (NZB×NZW)F1 female mice were treated with tamoxifen (800 µg/mouse; twice a week) or with double distilled water for four months. Mice were evaluated monthly for the presence of autoantibodies directed against DNA and nuclear extract (NE) by enzyme linked immunosorbent assay (ELISA). White blood cells and thrombocytes were quantified by a cell counter and proteinuria by combistix kit. At 6 months of age, all mice that did not die spontaneously were killed and evaluated for the presence of glomerular immune deposits by indirect immunofluorescence assay. IgG isotypes of autoantibodies in the mouse sera and glomeruli were determined by γ chain specific antibodies. Results: Tamoxifen treatment significantly reduced autoantibody production directed against either NE or DNA. The latter reduction was mainly in autoantibodies of the IgG3 isotype. Furthermore, tamoxifen had significant beneficial effects on the course of SLE in (NZB×NZW)F1 mice. At 6 months of age, 40% of the untreated mice died spontaneously, whereas all the tamoxifen treated mice were still alive. All untreated mice showed severe thrombocytopenia and persistent proteinuria, with diffuse glomerular immune deposits of IgG2a and IgG3 isotypes in their kidneys. In contrast, the tamoxifen treated mice had a normal number of thrombocytes and only minimal proteinuria. Moreover, glomerular immune deposits were detected in <40% of the tamoxifen treated mice. The latter were mainly of the IgG2a but not of the IgG3 isotype. Conclusion:The results clearly show the remarkable therapeutic effects of tamoxifen on SLE of (NZB×NZW)F1 female mice and suggest that these beneficial effects are related to the specific reduction of IgG3 autoantibodies.

A peptide based on complementarity-determining region (CDR)-1 of a monoclonal murine anti-DNA Ab that bears the common idiotype, 16͞6Id, was synthesized and characterized. The peptide, designated pCDR1, was found to be an immunodominant T-cell epitope in BALB͞c mice. The CDR1-based peptide was shown to be capable of inhibiting the in vivo priming of BALB͞c mice immunized with the peptide or with the whole anti-DNA 16͞6Id ؉ mAbs of either mouse or human origin. We show here that administration of pCDR1 (weekly, i.v., 100 g͞mouse) in aqueous solution for 5 weeks starting at the time of disease induction with the human 16͞6Id prevented the development of clinical manifestations of experimental systemic lupus erythematosus (SLE). Further, 10 weekly injections of pCDR1 to BALB͞c mice with an established experimental SLE down-regulated clinical manifestations of SLE (e.g., anti-DNA auto-Abs, leukopenia, proteinuria, immune complex deposits in the kidneys) in the treated mice. Prevention of SLE induction was shown to be associated mainly with a decrease in the levels of IL-2, INF␥, and the proinflammatory cytokine TNF␣. On the other hand, the secretion of the immunosuppressive cytokine TGF␤ was elevated. Amelioration of the clinical manifestations of an already established experimental SLE correlated with a dramatic decrease in TNF␣ secretion, elevated levels of TGF␤, and immunomodulation of the Th1 and Th2 type cytokines to levels close to those observed in healthy mice. T he induction of experimental systemic lupus erythematosus (SLE) has been previously reported in our laboratory and was achieved by using the human monoclonal anti-DNA Ab that bears the common idiotype, designated 16͞6Id (1). This Ab could induce SLE in naive mice of different susceptible strains (2). The 16͞6Id-induced disease resembles SLE in human and is manifested by high levels of auto-Abs, which include anti-DNA and antinuclear protein Abs as well as 16͞6Id and anti-16͞6Id specific Abs (1). The 16͞6Id-immunized mice also develop lupus-associated clinical symptoms (e.g., leukopenia, proteinuria, and kidney damage). Experimental SLE can also be induced in mice after their immunization with either a murine anti-16͞6Id mAb (3) or a murine anti-DNA 16͞6Idϩ mAb, 5G12 (4), suggesting the importance of the 16͞6Id network in the disease. Furthermore, T-cell lines specific to the human anti-DNA 16͞6Id ϩ mAb were shown to be capable of inducing experimental SLE in syngeneic recipient mice indicating the role of T cells in the disease (5). Experimental SLE, although induced in mice that normally develop no symptoms of SLE, was found to share features with the SLE model of (NZBxNZW)F1 mice, which develop the disease spontaneously. Thus, sequencing of the variable regions coding for the heavy and light chains of anti-DNA mAb isolated from mice afflicted with experimental SLE show high homology with the variable regions of anti-DNA mAb isolated from (NZBxNZW)F1 mice (6).Two peptides based on the sequences of the complementaritydetermining regions (CDR) of the...

Experimental systemic lupus erythematosus (SLE) can be induced in mice by immunization with a human monoclonal antibody to DNA that bears a common idiotype (16/6Id). These mice generate antibodies to 16/6Id, antibodies to DNA, and antibodies directed against nuclear antigens. Subsequently, manifestations of SLE develop, including leukopenia, proteinuria, and immune complex deposits in the kidney. In contrast, after immunization with 16/6Id, mice lacking major histocompatibility complex (MHC) class I molecules generated antibodies to 16/6Id but did not generate antibodies to DNA or to nuclear antigen. Furthermore, they did not develop any of the above clinical manifestations. These results reveal an unexpected function of MHC class I in the induction of autoimmune SLE.

Within 6 months of infection with the Petaluma isolate of feline immunodeficiency virus, specific-pathogenfree domestic cats exhibited a decrease in the percentage and number of circulating CD4+ lymphocytes and in the CD4+/CD8+ T-cell ratio, along with a marginally significant depression of pokeweed mitogen-induced lymphocyte proliferation in vitro. There was no loss of responsiveness to concanavalin A during this stage, and the cats were capable of mounting a satisfactory antibody response to a T-dependent, synthetic polypeptide immunogen. The pokeweed mitogen response deficit became clearly demonstrable by 11 to 12 months postinfection. A decline in the lymphocyte proliferative response to concanavalin A and a diminished ability to mount an in vivo antibody response to the T-dependent immunogen evolved by 25 to 44 months postinfection. Virus infection did not affect the ability of cats to mount an antibody response to a T-independent synthetic polypeptide immunogen. These data indicate that feline immunodeficiency virus produces a slowly progressive deterioration of T-cell function but does not affect the ability of B cells to recognize and respond to a T-independent antigenic stimulus.