| 1. |
- Carlsten, Hans, 1954, et al.
(författare)
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The impact of a new immunomodulator oxo-quinoline-3-carboxamide on the progression of experimental lupus
- 2004
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Ingår i: Int Immunopharmacol. - : Elsevier BV. - 1567-5769. ; 4:12, s. 1515-23
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Tidskriftsartikel (refereegranskat)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.
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| 2. |
- Jonsson, Charlotte A, 1971
(författare)
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Purine synthesis inhibition in experimental lupus
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Systemic lupus erythematosus (SLE) is an autoimmune disease that mainly affects women. The effect of the immune modulating drug mycophenolate mofetil (MMF) on experimental SLE was investigated. Mycophenolic acid (MPA), the active metabolite of MMF, inhibits inosine 5 -monophosphate dehydrogenase (IMPDH), an important enzyme in the de novo synthesis of the purine guanine. The clinical and histopathological outcome of MMF administration to SLE-prone MRLlpr/lpr mice in vivo was assessed. In addition, the immunomodulating properties of MPA in vitro on splenocytes from MRLlpr/lpr mice as well as on the macrophage cell line IC-21 were studied.Treatment of MRLlpr/lpr mice with MMF prolonged survival and diminished kidney damage as demonstrated by reduced albuminuria, hematuria and immune complex depositions in glomeruli. Perivascular cell infiltrates in kidneys and salivary glands were also reduced following MMF treatment. MMF reduced lymphoproliferation, the production of IgG anti-dsDNA antibodies and the populations of double-negative T cells as well as immunoglobulin-producing B cells. All the clinical effects of MMF were comparable with those achieved with cyclophosphamide treatment. In vitro, mitogen-stimulated splenocytes from MMF-treated mice displayed increased proliferative responses and augmented IFN-g and IL-10 production. In vitro treatment of MRLlpr/lpr spleen cells with MPA resulted in decreased mitogen-induced proliferative responses and the decreased production of IFN-g, IL-10, immunoglobulins and anti-DNA antibodies. Furthermore, exposure of the macrophage cell line IC-21 to MPA decreased mitogen-induced proliferation and the production of NO2-, IL-1b, and TNF-a. Addition of guanosine in vitro totally abrogated the action of the drug, proving that guanine-nucleotide depletion is the mechanism whereby MPA exerts its immunomodulating effects. It is concluded that the immunomodulating effects of MMF are to a large extent mediated by purine synthesis inhibition in lymphocytes and in macrophages. In addition, the results indicate that MMF can be considered as a potentially efficacious treatment for SLE patients with glomerulonephritis.
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| 3. |
- Nilsson, Anna-Malin, 1972, et al.
(författare)
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Inhibition of the sensitizing effect of carvone by the addition of non-allergenic compounds.
- 2004
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Ingår i: Acta dermato-venereologica. - : Medical Journals Sweden AB. - 0001-5555. ; 84:2, s. 99-105
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Tidskriftsartikel (refereegranskat)abstract
- We have previously reported a reduction of sensitization to carvone in guinea pigs when adding non-allergenic, structurally related compounds simultaneously at induction. This study investigates the criteria needed to obtain a reduction of sensitization in contact allergy. Linalool, a non-sensitizer structurally unrelated to carvone, significantly reduced the sensitizing capacity of carvone in guinea pigs. The effect of different concentrations of inhibitors in mixtures with carvone was investigated. No significant differences in response were obtained between the concentrations explored. A possible anti-inflammatory effect from the inhibitory chemicals was investigated in vitro. No suppression of the immune system was seen. This study shows that a non-allergenic compound with a structure not resembling the hapten can reduce the sensitizing effect of the hapten. It indicates that reduction of an allergenic effect might occur in consumer products that are mixtures of different chemicals. Further studies with chemically unrelated compounds with and without allergenic effect are needed.
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