RESUMO
Cyclosporine A (CsA) is a fungus-derived molecule with potent immunosuppressive activity that has been largely used to downregulate cell-mediated immune responses during transplantation. However, previous data have indicated that CsA shows immunomodulatory activity that relays on the antigen concentration and the dose of CsA used. To test the hypothesis that minimal doses of CsA may show different outcomes on grafts, we used an experimental model for skin transplants in mice. ICR outbred mice received skin allografts and were either treated daily with different doses of CsA or left untreated. Untreated mice showed allograft rejection within 14 days, with graft necrosis, infiltration of neutrophils and macrophages and displayed high percentages of CD8+ T cells in the spleens, which were associated with high serum levels of IL-12, IFN-g and TNF-α. As expected, mice treated with therapeutic doses of CsA (15 mg/kg) did not show allograft rejection within the follow-up period of 30 days and displayed the lowest levels of IL-12, IFN-g and TNF-α as well as a reduction in CD8+ lymphocytes. In contrast, mice treated with consecutive minimal doses of CsA (5×10(-55) mg/kg) displayed an acute graft rejection as early as one to five days after skin allograft; they also displayed necrosis and strong inflammatory infiltration that was associated with high levels of IL-12, IFN-g and TNF-α. Moreover, the CD4+ CD25hiFoxP3+ subpopulation of cells in the spleens of these mice was significantly inhibited compared with animals that received the therapeutic treatment of CsA and those treated with placebo. Our data suggest that consecutive, minimal doses of CsA may affect Treg cells and may stimulate innate immunity.
Assuntos
Ciclosporina/efeitos adversos , Citocinas/metabolismo , Rejeição de Enxerto/induzido quimicamente , Imunossupressores/efeitos adversos , Transplante de Pele/imunologia , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Ciclosporina/uso terapêutico , Feminino , Imunossupressores/uso terapêutico , Interleucina-12/metabolismo , Camundongos , Transplante Homólogo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
La artritis reumatoide (AR) es una enfermedad crónica ydegenerativa, caracterizada por una inflamación crónica delas articulaciones. En la actualidad no existe cura para la AR,ni medicamentos que puedan revertir las deformaciones articularesque produce. El desafío principal en su tratamientoes la búsqueda de fármacos específicos que inhiban el cursode la enfermedad, los signos clínicos y los daños histopatológicosen las articulaciones. En el presente trabajo, proponemosla Ciclosporina A como tratamiento alopático, y como tratamientohomeopático un medicamento isopático de suero ysarcodes de cartílago, cápsula articular, tejido conjuntivo y líquidosinovial, asimismo el Guayacum como medicamentoantiinflamatorio.
Assuntos
Artrite Reumatoide/diagnóstico , Artrite Reumatoide/imunologia , Ciclosporina , Isoterapia , Linfócitos TRESUMO
La artritis reumatoide (AR) es una enfermedad crónica ydegenerativa, caracterizada por una inflamación crónica delas articulaciones. En la actualidad no existe cura para la AR,ni medicamentos que puedan revertir las deformaciones articularesque produce. El desafío principal en su tratamientoes la búsqueda de fármacos específicos que inhiban el cursode la enfermedad, los signos clínicos y los daños histopatológicosen las articulaciones. En el presente trabajo, proponemosla Ciclosporina A como tratamiento alopático, y como tratamientohomeopático un medicamento isopático de suero ysarcodes de cartílago, cápsula articular, tejido conjuntivo y líquidosinovial, asimismo el Guayacum como medicamentoantiinflamatorio.
Assuntos
Artrite Reumatoide/diagnóstico , Artrite Reumatoide/imunologia , Linfócitos T , Ciclosporina , IsoterapiaRESUMO
Parasitic helminths have developed complex mechanisms to modulate host immunity. In the present study we found that previous infection of mice with the cestode Taenia crassiceps favours parasitemia and induces larger cutaneous lesions during both Leishmania major and Leishmania mexicana co-infections. Analysis of cytokine responses into draining lymph nodes indicated that co-infection of T. crassiceps-Leishmania did not inhibit IFN-gamma production in response to Leishmania antigens, but significantly increased IL-4 production. Additionally, anti-Leishmania-specific IgG1 antibodies and total IgE increased in co-infected mice, whereas, IgG2a titers remained similar. Macrophages from Taenia-infected mice displayed increased mRNA transcripts of arginase-1, Ym1, and Mannose Receptor, as well as greater production of urea (all markers for an alternate activation state) compared to macrophages from Leishmania-infected mice. In contrast, lower mRNA transcripts for IL-12p35, IL-12p40, IL-23p19, and iNOS were detected in macrophages obtained from cestode-infected mice compared to uninfected and Leishmania-infected mice after LPS stimulation. The presence of cestode also generated impaired macrophage anti-leishmanicidal activity in vitro, as evidenced by the inability of these macrophages to prevent Leishmania growth compared to macrophages from uninfected mice. This was observed despite the fact that both groups of cells were exposed to IFN-gamma. Flow cytometry showed high IFN-gammaR expression on Taenia-induced macrophages. Thus, lack of response to IFN-gamma is not associated with the absence of its receptor. Our data suggest that cestode infection may favour Leishmania installation by inducing alternatively activated macrophages rather than inhibiting Th1-type responses.