RESUMO
Graft-versus-host disease (GVHD) remains a major problem after allogeneic haematopoietic stem cell transplantation, a curative therapy for haematological malignancies. Previous studies have demonstrated a role for the adenosine triphosphate (ATP)-gated P2X7 receptor channel in allogeneic mouse models of GVHD. In this study, injection of human peripheral blood mononuclear cells (PBMCs) into immunodeficient non-obese diabetic-severe combined immunodeficiency-interleukin (NOD-SCID-IL)-2Rγnull (NSG) mice established a humanized mouse model of GVHD. This model was used to study the effect of P2X7 blockade in this disease. From five weeks post-PBMC injection, humanized mice exhibited clinical signs and histopathology characteristic of GVHD. The P2X7 antagonist, Brilliant Blue G (BBG), blocked ATP-induced cation uptake into both murine and human cells in vitro. Injection of BBG (50 mg/kg) into NSG mice did not affect engraftment of human leucocytes (predominantly T cells), or the clinical score and survival of mice. In contrast, BBG injection reduced circulating human interferon (IFN)-γ significantly, which was produced by human CD4+ and CD8+ T cells. BBG also reduced human T cell infiltration and apoptosis in target organs of GVHD. In conclusion, the P2X7 antagonist BBG reduced circulating IFN-γ in a humanized mouse model of GVHD supporting a potential role for P2X7 to alter the pathology of this disease in humans.
Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Interferon gama/sangue , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Corantes de Rosanilina/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Doença Enxerto-Hospedeiro/imunologia , Humanos , Subunidade gama Comum de Receptores de Interleucina/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Receptores Purinérgicos P2X7/metabolismo , Transplante HomólogoRESUMO
Ground-based in situ measurements of hydrofluorocarbons HFC-125, HFC-134a, and HFC-152a, which are regulated under the Kyoto Protocol, are carried out at four European sites within the SOGE (System of Observation of Halogenated Greenhouse Gases in Europe) program. Concentrations measured at the high mountain stations of Jungfraujoch (Switzerland) and Mte Cimone (Italy) together with back-trajectory statistical analysis are used in order to identify potential source regions on a European scale. Combining concentration data recorded at the two sites allows to reduce one of the problem which is inherent to the back-trajectory approach, i.e. the localisation of "ghost" sources in the wake of real sources. In this way, a more reliable picture of the location of European potential source regions is given.
