ABSTRACT
CD8 T cells protect the liver against viral infection, but can also cause severe liver damage that may even lead to organ failure. Given the lack of mechanistic insights and specific treatment options in patients with acute fulminant hepatitis, we develop a mouse model reflecting a severe acute virus-induced CD8 T cell-mediated hepatitis. Here we show that antigen-specific CD8 T cells induce liver damage in a perforin-dependent manner, yet liver failure is not caused by effector responses targeting virus-infected hepatocytes alone. Additionally, CD8 T cell mediated elimination of cross-presenting liver sinusoidal endothelial cells causes endothelial damage that leads to a dramatically impaired sinusoidal perfusion and indirectly to hepatocyte death. With the identification of perforin-mediated killing as a critical pathophysiologic mechanism of liver failure and the protective function of a new class of perforin inhibitor, our study opens new potential therapeutic angles for fulminant viral hepatitis.
Subject(s)
Endothelial Cells/drug effects , Hepatitis, Viral, Animal/drug therapy , Liver/drug effects , Pore Forming Cytotoxic Proteins/antagonists & inhibitors , Protective Agents/pharmacology , Sulfonamides/pharmacology , Adenoviridae/genetics , Adenoviridae/immunology , Adenoviridae/pathogenicity , Animals , Antibodies/administration & dosage , CD40 Antigens/antagonists & inhibitors , CD40 Antigens/genetics , CD40 Antigens/immunology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , Capillaries/drug effects , Capillaries/virology , Disease Models, Animal , Endothelial Cells/immunology , Endothelial Cells/virology , Gene Expression , Genes, Reporter , Green Fluorescent Proteins/genetics , Green Fluorescent Proteins/metabolism , Hepatitis, Viral, Animal/immunology , Hepatitis, Viral, Animal/virology , Hepatocytes/drug effects , Hepatocytes/immunology , Hepatocytes/virology , Humans , Liver/blood supply , Liver/pathology , Liver/virology , Luciferases/genetics , Luciferases/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Ovalbumin/administration & dosage , Poly I-C/administration & dosage , Pore Forming Cytotoxic Proteins/genetics , Pore Forming Cytotoxic Proteins/immunologyABSTRACT
Recruitment effort and costs in clinical trials are very often underestimated. As funding constraints increase, more precise estimates of costs as well as methods to monitor effectiveness are needed. However, few studies exist that report recruitment cost effectiveness and costs. The study reported here was developed in Portland, Oregon as an ancillary study to the Lung Health Study. The authors developed a monitoring and evaluation system to track response rates and costs associated with each of five recruitment methods. These methods include (1) media (TV, radio, newspapers), (2) neighborhood promotion, (3) direct mail, (4) worksite promotion, and (5) referral by other study participants. The analysis is limited to a 6-month period (April 1-September 30, 1987) or the middle phase of recruitment. During the study period, 46% were recruited from media, 30% from neighborhood promotion, 1.5% from direct mail, 11% from worksites, and 12% from referrals. Neighborhood promotion and direct mail were least cost-effective, media most cost-effective, with worksite and referral moderately cost-effective. The cost-effectiveness of media promotion is explained in part by the limited number of media sources in Portland, making it possible to reach a large audience with less effort, as well as the ability to provide rapid feedback to media sources. We conclude that the effectiveness of recruitment in a clinical trial is maximized by using multiple overlapping recruitment strategies coupled with a monitoring system that can provide rapid feedback regarding the effectiveness and costs of each strategy.
