DNA Immunization with Fusion of CTLA-4 to Hepatitis B Virus (HBV) Core Protein Enhanced Th2 Type Responses and Cleared HBV with an Accelerated Kinetic

BACKGROUND: Typically, DNA immunization via the intramuscular route induces specific, Th1-dominant immune responses. However, plasmids expressing viral proteins fused to cytotoxic T lymphocyte antigen 4 (CTLA-4) primed Th2-biased responses and were able to induced effective protection against viral challenge in the woodchuck model. Thus, we addressed the question in the mouse model how the Th1/Th2 bias of primed immune responses by a DNA vaccine influences hepatitis B virus (HBV) clearance. PRINCIPAL FINDINGS: Plasmids expressing HBV core protein (HBcAg) or HBV e antigen and HBcAg fused to the extracellular domain of CTLA-4 (pCTLA-4-HBc), CD27, and full length CD40L were constructed. Immunizations of these DNA plasmids induced HBcAg-specific antibody and cytotoxic T-cell responses in mice, but with different characteristics regarding the titers and subtypes of specific antibodies and intensity of T-cell responses. The plasmid pHBc expressing HBcAg induced an IgG2a-dominant response while immunizations of pCTLA-4-HBc induced a balanced IgG1/IgG2a response. To assess the protective values of the immune responses of different characteristics, mice were pre-immunized with pCTLA-4-HBc and pHBc, and challenged by hydrodynamic injection (HI) of pAAV/HBV1.2. HBV surface antigen (HBsAg) and DNA in peripheral blood and HBcAg in liver tissue were cleared with significantly accelerated kinetics in both groups. The clearance of HBsAg was completed within 16 days in immunized mice while more than 50% of the control mice are still positive for HBsAg on day 22. Stronger HBcAg-specific T-cell responses were primed by pHBc correlating with a more rapid decline of HBcAg expression in liver tissue, while anti-HBs antibody response developed rapidly in the mice immunized with pCTLA-4-HBc, indicating that the Th1/Th2 bias of vaccine-primed immune responses influences the mode of viral clearance. CONCLUSION: Viral clearance could be efficiently achieved by Th1/Th2-balanced immune response, with a small but significant shift in T-cell and B-cell immune responses

Time trends in socioeconomic differences in incidence rates of cancers of gastro-intestinal tract in Finland

BACKGROUND: The magnitude of socioeconomic differences in health varies between societies, and over time within a given society. We studied the association between social class and incidence of cancers of the gastro-intestinal tract over time in a large cohort in Finland. METHODS: We studied social class variation among 45–69 year-old Finns during 1971–95 in incidence of cancers of the gastro-intestinal tract by means of a computerized record linkage of the Finnish Cancer Registry and the 1970 Population Census, which included social class data. RESULTS: There were 2.3 million individuals in the cohort under follow-up, with 1622 cases of cancer of the esophagus, 8069 stomach (non-cardia), 1116 cardia, 408 small intestine, 6361 colon, 5274 rectum, 1616 liver, 1756 gallbladder, and 5084 pancreas during 1971–1995. Cancers of the esophagus, stomach, cardia, gallbladder and pancreas were most common among persons belonging to a low social class. Cancers of the small intestine in males only, colon in both genders, and rectum in females were most common in the higher social classes. Incidence of stomach cancer decreased and incidence of colon cancer increased over time in both genders in all social classes, and the large differences between social classes remained unchanged over time. Incidence rates of cardia cancer did not change substantially over time. CONCLUSION: There is a large variation in incidence of cancer of the gastrointestinal tract by social class in Finland. Although much of the observed social class differences probably could be explained by known etiological factors such as diet, physical exercise, alcohol consumption, smoking and exogenous hormone use, part of the variation is apparently attributable to largely unknown factors