RESUMEN
To study peripheral tolerance of CD8 T cells to a classically MHC-restricted peptide Ag expressed in hepatocytes, ALB1 transgenic (tg) mice expressing the CTL epitope GP33 of the lymphocytic choriomeningitis virus glycoprotein under control of the mouse albumin promoter were generated. ALB1 mice exclusively expressed the GP33 transgene in the liver and, at a 100- to 1000-fold lower level, in the thymus. TCR-tg mice specific for the GP33 epitope were used to directly follow GP33-specific T cells in vivo. These experiments revealed that 1) thymic expression of the GP33 transgene led to incomplete central deletion of TCR-tg cells; and 2) peripheral TCR-tg cells in ALB1 mice ignored the GP33 transgene expressed in hepatocytes. Ignorance of adoptively transferred TCR-tg cells in ALB1 mice was broken by infection with lymphocytic choriomeningitis virus, leading to induction of hepatitis in ALB1, but not in control, mice. Taken together, we have established a novel model of virus-induced CD8 T cell-mediated autoimmune hepatitis in mice and demonstrate that naive CD8 T cells may ignore Ags expressed in the liver.
Asunto(s)
Antígenos Virales/inmunología , Hepatitis Viral Animal/etiología , Hepatitis Viral Animal/inmunología , Tolerancia Inmunológica , Hígado/inmunología , Hígado/virología , Linfocitos T/inmunología , Proteínas Virales , Traslado Adoptivo , Animales , Antígenos Virales/biosíntesis , Antígenos Virales/genética , Epítopos de Linfocito T/genética , Epítopos de Linfocito T/inmunología , Glicoproteínas/biosíntesis , Glicoproteínas/genética , Hepatitis Viral Animal/genética , Tolerancia Inmunológica/genética , Hígado/metabolismo , Depleción Linfocítica , Coriomeningitis Linfocítica/genética , Coriomeningitis Linfocítica/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Transgénicos , Fragmentos de Péptidos/biosíntesis , Fragmentos de Péptidos/genética , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T/metabolismo , Timo/inmunología , Timo/metabolismo , Transgenes/inmunologíaRESUMEN
OBJECTIVE: This experimental study was initiated to determine whether transmyocardial laser revascularization (TMLR) after acute myocardial ischemia may improve clinical chemistry and diminish the amount of necrosis. In addition, the influence of TMLR on healthy myocardium was analyzed. METHODS: The prolonged short-term effectiveness of TMLR was evaluated in 44 open-chest anesthetized pigs with (n = 21) or without (n = 23) the setting of acute myocardial ischemia (observation period 6 h): seven pigs served as controls (thoracotomy only). An additional seven pigs had left anterior descending artery (LAD) occlusion only (ischemia group). A subsequent 14 pigs were treated by TMLR (CO2) prior to LAD occlusion: Seven pigs received one laser channel/cm2 (group 1) and in seven pigs two channels/cm2 in the LAD territory (group 2) were performed. In addition, 16 pigs underwent TMLR without ischemia: Eight pigs received one channel/cm2 (group 3) and eight pigs two channels/cm2 (group 4). Clinical chemistry, histo-chemical assessment and histology were performed. RESULTS: TMLR limits the expansion of the myocardial infarction zone: laser group 2 indicated a significant smaller area of necrosis in the area at risk (ischemic group (31%) vs. laser group 1 (19%), P = ns; laser group 2 (7%) vs. ischemic group, P < 0.01; laser group 1 vs. 2, P < 0.01). The amount of the area of necrosis and ischemia of laser groups 3 and 4 compared with control did not differ significantly (P = ns). Preventive creation of microchannels before ischemia did not diminish ischemic parameters (P = ns). The myocardial water content-measurements (MWC) in the ischemia, laser 1 and 2 groups did not show any difference at the end of the experiment, except higher values of laser group 2 (P < 0.05). Laser groups 3 and 4 revealed significantly higher MWC values compared with control (P < 0.001). CONCLUSIONS: This prolonged acute study demonstrates that CO2-TMLR significantly reduces the amount of necrosis in the area at risk, but does not reduce cardiac ischemic markers. In healthy myocardium, TMLR significantly increases myocardial water content and ischemic parameters and induces small ischemic and very small necrotic areas surrounding open laser channels. Generally, the elevated cardiac enzymes and proteins are mainly attributed to the expected rise caused by vaporization of myocardial tissue in all laser groups.