RESUMEN
Endotoxin and other immunostimulants ubiquitous in ambient air are potent mucosal adjuvants, yet only a minority of individuals develop aeroallergen hypersensitivities, whereas the majority develop tolerance. These investigations were performed to reconcile this paradox. During initial experiments, mice received a primary series of weekly intranasal OVA immunizations (1(0) vaccination). Selected mice also received intranasal sterile house dust extract (HDE) with each OVA vaccination, at a dose previously found to exert adjuvant activity. A third group of OVA-vaccinated mice received intranasal HDE on a daily basis, but at one seventh the adjuvant dose, beginning 1 week before the first and ending with the last 1(0) OVA vaccination. Mice were then left untreated for 4 weeks, and then received a secondary series of weekly intranasal OVA immunizations with adjuvant doses of HDE (2(0) sensitization). Three weeks later, OVA-specific airway challenges and immune responses were assessed. Analogous experiments were conducted with LPS. Mice receiving daily intranasal HDE or LPS during 1(0) OVA vaccination were highly resistant to 2(0) sensitization, whereas the mice in other experimental groups readily developed Th2-biased airway hypersensitivity. Tolerance was associated with poor OVA-specific CD4 cell proliferation and with local natural T-regulatory cell (Treg) expansion. Finally, Treg depletion by delivery of the anti-CD25 monoclonal antibody during 1(0) vaccination attenuated the tolerogenic effects of daily airway HDE exposures. These studies suggest that regular airway immunostimulant exposures selectively increase local Treg numbers and activity in an antigen-independent manner, thereby promoting the development of aeroallergen tolerance.
Asunto(s)
Alérgenos/metabolismo , Tolerancia Inmunológica/inmunología , Hipersensibilidad Respiratoria/inmunología , Linfocitos T Reguladores/citología , Alérgenos/química , Animales , Anticuerpos Monoclonales/química , Polvo , Femenino , Factores de Transcripción Forkhead/biosíntesis , Inmunoglobulina E/metabolismo , Subunidad alfa del Receptor de Interleucina-2/biosíntesis , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , VacunasRESUMEN
BACKGROUND: The natural history of chronic hepatitis C (CHC) remains to be defined in patients with end-stage renal disease (ESRD). AIMS: To determine the clinical presentation of CHC and the factors associated with stage III-IV fibrosis in patients with CHC and ESRD. METHODS: The study included patients with CHC and ESRD (n = 91) or normal renal function (NRF, n = 159). Both groups were matched for mean age, gender, history of alcohol use, and estimated duration of hepatitis C virus (HCV) infection. RESULTS: Presentation of CHC and ESRD was independently associated with non-Caucasian ethnicity (OR = 3.24, p= 0.0003), a history of diabetes mellitus (DM, OR = 7.911, p < 0.0001), and lower frequencies of being obese (OR = 0.457, p= 0.035), of having hepatic steatosis (OR = 0.372, p= 0.003), and stage III-IV fibrosis (OR = 0.403, p= 0.016). After adjusting for serum levels of alpha-fetoprotein (AFP) and HCV RNA, CHC, and ESRD were independently associated with lower frequencies of elevated alanine aminotransferase (ALT, OR = 0.175, p= 0.02) and aspartate aminotransferase (AST, OR = 0.169, p= 0.04), but higher frequencies of AST/ALT ratio >1 (OR = 7.173, p= 0.002) and hypoalbuminemia (OR = 9.567, p= 0.0007). Compared to patients with NRF and stage III-IV fibrosis, those with ESRD and stage III-IV fibrosis had a significantly higher frequency of a history of DM (OR = 8.014, p= 0.0031) and lower frequency of elevated AST (OR = 0.054, p= 0.004), which were independent of the frequencies of lower levels of ALT and albumin, and AST/ALT ratio >1. In patients with CHC and ESRD, the presence of stage III-IV fibrosis was significantly associated with hepatic steatosis (OR = 4.523, p= 0.012) and thrombocytopenia (OR = 4.884, p= 0.044), which were independent of the frequencies of a history of DM, splenomegaly, and a higher level of AST. CONCLUSIONS: CHC and ESRD are independently associated with a higher frequency of a history of DM, but lower frequencies of being obese, and having hepatic steatosis, stage III-IV fibrosis, and elevated transaminases. In patients with CHC and ESRD, stage III-IV fibrosis is not associated with a history of DM, but is independently associated with hepatic steatosis and thrombocytopenia.