[Show abstract][Hide abstract] ABSTRACT: Oestrogen is not only a sex hormone but also an important regulator of the immune system. Expression of the heavy chain of IgM (mu) is essential for B-cell differentiation. However, a small number of IgA-positive B cells can be found in mice lacking the mu chain (muMT-/-). The aim of this study was to investigate the effects of oestrogen on this alternative B-cell pathway in muMT-/- mice. Our results clearly demonstrate that oestrogen increases the frequency of IgA-producing B cells in muMT-/- mice in both bone marrow and spleen cells. We also show that mature IgM-producing B cells are not required for oestrogen-mediated suppression of granulocyte-mediated inflammation or thymic involution. In conclusion, we demonstrate that 17beta-estradiol benzoate increases the frequency of IgA-producing B cells in muMT-/- mice, suggesting that oestrogen can influence the alternative B-cell pathway found in muMT-/- mice.
[Show abstract][Hide abstract] ABSTRACT: Autoimmune, lupus-prone MRL lpr/lpr mice were treated orally with oxo-quinoline-3-carboxamide (ABR-25757), a newly developed immunomodulator. Treatment was initiated in one set of experiment at the age of 10 weeks, before the onset of clinically apparent disease, and in another set at 15 weeks, after the development of established lupus disease. Beneficial therapeutic effects were obtained even when ABR-25757 was administered at the lowest dose tested (7.5 microg/mouse/week) to 15 weeks old mice with established lupus disease. The effects of ABR-25757 on longevity, as well as on development of glomerulonephritis were pronounced and comparable with those of LS-2616, a potent immunomodulator. Administration of ABR-25757 did not significantly alter T cell responses in vivo nor in vitro. In addition, it only marginally suppressed B cell responses measured as frequencies of immunoglobulin secreting cells. By the same token this compound did not affect overall leukocyte content in primary (bone marrow) or secondary (spleen) lymphoid tissues. In contrast, treatment with ABR-25757 up regulated expression of pro-inflammatory transcription factors NF-kappaB and AP-1. These results suggest (a) a potential therapeutic role of ABR-25757 in the treatment of experimental lupus and (b) that the effect of the treatment is mediated by immunodeviation rather than by immunosuppression.
International Immunopharmacology 12/2004; 4(12):1515-23. DOI:10.1016/j.intimp.2004.07.009 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: IL-1R-deficient mice (IL-1R(-/-)) and their wild-type controls (IL-1R(+/+)) were i.v. inoculated with 1 x 10(7) or 10(6) Staphylococcus aureus per mouse to mimic bacterial sepsis and septic arthritis. The disease outcome was severely worsened in the IL-1R(-/-) mice as compared with IL-1R(+/+) mice. Indeed, 3 days after inoculation of 10(7) S. aureus per mouse 84% of IL-1R(-/-) mice displayed clinical signs of septicemia as compared with none of the IL-1R(+/+) mice. On day 9 after inoculation with 10(6) S. aureus per mouse 75% of the IL-1R(-/-) mice were dead as compared with none of the IL-1R(+/+) mice. Also, the number of staphylococci in circulation was 25- to 30-fold increased in IL-1R(-/-) mice as compared with IL-1R(+/+) mice, the most probable reason for the outcome. The frequency and severity of septic arthritis were significantly increased in IL-1R(-/-) mice, as compared with IL-1R(+/+) mice, following i.v. inoculation of staphylococci. This was probably due to an increased accumulation of bacteria in the joints of IL-1R(-/-) mice as compared with their wild-type controls. Interestingly, while serum levels of IL-18 in IL-1R(-/-) mice were significantly lower than in IL-1R(+/+) mice 24 h after inoculation of S. aureus, both IL-18 and IL-1beta were significantly increased in IL-1R(-/-) vs IL-1R(+/+) mice 4 days after the bacterial inoculation. In conclusion, IL-1R signaling plays a crucial role in host protection during systemic S. aureus infection as seen by the fatal outcome of S. aureus sepsis and arthritis in IL-1R-deficient mice.
The Journal of Immunology 06/2002; 168(10):5207-12. DOI:10.4049/jimmunol.168.10.5207 · 4.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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-γ 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-γ, 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.
[Show abstract][Hide abstract] ABSTRACT: The aim of the present study was to evaluate the therapeutic effect of mycophenolate mofetil (MMF) on the course of disease in SLE-prone MRLlpr/lpr mice. Three-months-old mice displaying clinical symptoms of glomerulonephritis were given MMF (100 mg/kg per day) orally via the drinking water. Control mice received i.p. injections of cyclophosphamide (CYC) (1.8 mg/mouse per week) or saline. Survival, albuminuria and haematuria, immunoglobulin levels and anti-dsDNA antibodies in serum, frequencies of immunoglobulin-producing B lymphocytes and glomerular deposits of immunoglobulin and C3 were analysed. The results showed that MMF treatment significantly prolonged survival and reduced the occurrence of albuminuria and haematuria in MRLlpr/lpr mice. In addition, the number of immunoglobulin-producing B cells and serum levels of IgG and IgG anti-dsDNA antibodies were reduced after MMF and CYC treatment. MMF treatment significantly reduced the extent of deposition of C3 in glomeruli. We conclude that the reduced severity of glomerulonephritis following treatment of lupus-prone mice with MMF was as efficacious as that of CYC. These results warrant clinical trials of MMF in SLE patients with glomerulonephritis.
[Show abstract][Hide abstract] ABSTRACT: Oestrogen has the capacity to suppress T cell-dependent DTH. To explore the mechanisms whereby oestrogen exerts its effects on the immune system we have used SCID mice which are largely devoid of functional T and B lymphocytes, hence being unable to raise DTH, but display intact antigen-presenting capacity. Transfer of lymphocytes to SCID mice restores the DTH capacity. In order to analyse if oestrogen down-regulates DTH by a direct action on T cells we reconstituted SCID mice with either splenocytes or thymocytes from congenic C.B-17 or allogeneic B6 donor mice. Either donor or recipient mice were exposed to estradiol before cell transfer. DTH response was registered in recipient SCID mice 1 and 3 weeks after challenge with oxazolone (OXA). SCID mice receiving estradiol-exposed spleen cells from congenic or allogeneic donor mice displayed lower DTH responses compared with control mice. In contrast, SCID mice receiving estradiol-exposed thymocytes from congenic donor mice showed no significant difference in DTH response compared with control mice. Estradiol-treated SCID mice, transferred with either spleen cells or thymocytes from congenic, hormonally non-treated donors, displayed a significantly lower DTH response compared with control mice. In contrast, estradiol-treated SCID mice receiving hormonally non-treated allogeneic spleen cells showed no difference in DTH response compared with control mice. The results show that T lymphocytes are not the target cell population for estradiol-mediated suppression of DTH in reconstituted female SCID mice.