concanavalin-a and Vasculitis

Successful immunosuppressive therapy is critical for the treatment of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis and nephrosis. However, a considerable number of patients have shown clinical resistance to therapy. Bacterial infection might influence the clinical response of patients to immunosuppressive drugs, but few studies have been carried out to investigate the effect of bacterial superantigens on the efficacy of the drugs in these patients. We evaluated the suppressive efficacy of prednisolone, methylprednisolone, cyclosporine, and tacrolimus on the blastogenesis of PBMCs obtained from 12 ANCA-associated vasculitis patients (ANCA patients), eight patients with nephrotic syndrome, and eight healthy subjects. PBMC-stimulation index was calculated from the formula: [3H]thymidine incorporated in the presence of stimulant (dpm)/[3H]thymidine incorporated in the absence of stimulant (dpm). In vitro drug concentrations giving 50% inhibition (IC50s) of PBMC blastogenesis stimulated with concanavalin A (con A) or toxic shock syndrome toxin 1 (TSST-1) derived from Staphylococcus aureus (S. aureus) were calculated. The IC50 values for the four drugs evaluated in TSST-1-stimulated PBMCs were significantly higher than those evaluated in con A-stimulated PBMCs in both ANCA patients and nephrosis patients (p<0.012-0.044). Whereas, the IC50 values for these immunosuppressive drugs, except methylprednisolone, were not significantly different between con A- and TSST-1-stimulated PBMCs in healthy subjects. The stimulation index was not significantly different between the con A- and TSST-1-stimulated PBMCs in either of the subject groups. These observations raise the possibility that TSST-1 induced by S. aureus infection attenuates the clinical efficacy of glucocorticoids and calcineurin inhibitors in ANCA patients and nephrosis patients.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Bacterial Toxins; Calcineurin Inhibitors; Cell Proliferation; Concanavalin A; Cyclosporine; Enterotoxins; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Inhibitory Concentration 50; Leukocytes, Mononuclear; Lymphocyte Activation; Male; Methylprednisolone; Middle Aged; Nephrosis; Prednisolone; Superantigens; Tacrolimus; Vasculitis

Effects on T lymphocyte mediated pathology, phenotypes, and functions in MRLlpr/lpr mice given mycophenolate mofetil (MMF) (100 mg/kg/day) via drinking water or controls given ip cyclophosphamide (CYC) injections (1.8 mg/mouse/week) or water were described. Both MMF and CYC treatment diminished kidney and large salivary gland perivascular cell infiltrates, reduced profoundly double-negative (DN) T cell frequencies, decreased total lymphocyte number in spleen, and increased in vitro proliferative response to Con A. IFN-gamma and IL-10 in supernatants from Con A stimulated spleen cells were augmented after MMF but not CYC treatment. MMF treatment increased whereas CYC reduced IL-12 in serum. Kidney expressions of IFN-gamma, IL-10, and IL-12 mRNA were unaffected by MMF but decreased by CYC. Our results demonstrate that MMF and CYC suppress perivascular T lymphocyte inflammation by reducing the DN T cell population and by amelioration of T cell function. The varying cytokine patterns suggest different mechanisms of the two drugs.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; B-Lymphocytes; Cell Count; Cell Division; Concanavalin A; Cyclophosphamide; Cytokines; Disease Models, Animal; Female; Hypersensitivity, Delayed; Immunophenotyping; Immunosuppressive Agents; Kidney; Lupus Erythematosus, Systemic; Male; Mice; Mice, Inbred MRL lpr; Mycophenolic Acid; RNA, Messenger; Salivary Glands; Spleen; T-Lymphocytes; Vasculitis

Many pathogenic bacteria produce superantigenic exotoxins. To study their pathogenetic role, in particular to test whether these toxins are able to induce vasculitis, we developed a local-type experimental model in rabbits. Toxins were injected along the intermediate auricular artery of the ear. The histology of ear skin, including the artery, was examined after single or repeated injections. Repeated injections of streptococcal erythrogenic toxins produced chronic-type arteritis characteristic of lymphocytic infiltration, whereas single injection induced no acute-type vasculitis. Staphylococcal enterotoxin B and toxic shock syndrome toxin-1 also induced the same type of arteritis, although weaker in degree. In human patients these lesions are similar to those of Kawasaki disease, a systemic vasculitis with unknown etiology. The Arthus reaction to human serum albumin in immunized rabbits included acute-type vasculitis similar to polyarteritis nodosa when examined in this model. Microvasculitis lesions similar to leukoclastic vasculitis were combined in the Arthus reaction but not in the superantigen-induced lesions. Our experimental model described here is widely applicable to the study of the etiology and pathogenesis of human diseases involving vasculitis lesions.

Topics: Animals; Antigens, Bacterial; Arteritis; Arthus Reaction; Bacterial Toxins; Concanavalin A; Erythema; Exotoxins; Female; Rabbits; Skin; Staphylococcus; Streptococcus; Superantigens; Vasculitis

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

Concanavalin A (Con A)-induced suppressor T cell activity was determined in 10 rheumatoid arthritis (RA) patients with vasculitis, 34 RA patients without vasculitis, and 10 healthy individuals. The percent Con A-induced suppression in RA patients with vasculitis was 24.6. In contrast, it was 68.4% in those RA patients without vascular lesions. Further, the proportion of T cells reactive with OKT8 monoclonal antibody was also decreased in RA patients with vasculitis. Accordingly, the reduced Con A-induced suppressor T cell activity in these RA patients resulted, in part, from the reduction in the number of cells of the suppressor T cell subset. Those patients with vascular lesions also had a higher percentage of positive antilymphocytotoxic antibodies than RA patients without vasculitis. Since the differences in Con A-induced suppressor T cell activity and frequency of positive antilymphocytotoxic antibodies were so great, we believe RA patients with vasculitis could be recognized as a disease group distinct from RA patients without vasculitis.

Topics: Adult; Aged; Antibodies, Monoclonal; Antilymphocyte Serum; Arthritis, Rheumatoid; Concanavalin A; Female; Humans; Immunoglobulin G; Lymphocytes; Male; Middle Aged; Pokeweed Mitogens; Rheumatoid Factor; T-Lymphocytes; T-Lymphocytes, Regulatory; Vasculitis