Five different viruses have been identified as causes of viral hepatitis. These include hepatitis A, B, C, D and E viruses. Of these, the viruses which cause the most serious infections are hepatitis B virus (HBV) and hepatitis C virus (HCV).
Hepatitis A virus has a single serotype and causes a self-limited acute infection. A large percentage of the population, approaching 50%, has hepatitis A antibodies in serum and is probably immune to disease. Infection with hepatitis A does not progress to chronic disease.
HBV is implicated in both acute and chronic hepatitis. The disease is endemic in Asia, is increasing in prevalence in the U.S. and Europe. Chronic liver disease, resulting in significant morbidity and increased mortality, is sequela of infection in 1-10% of infected individuals. HBV infection is also correlated with the development of primary liver cancer.
HCV was recently shown to be the major causative agent of parenterally transmitted non-A, non-B hepatitis.sup.(1). It is estimated that 0.5-1% of the world population is infected with HCV, and in some developing countries the prevalence rate is up to 40%. Moreover, 40-60% of newly infected patients develop persistent HCV infections.sup.(2) and are at risk of developing acute, fulminant hepatitis and various chronic liver diseases (including cirrhosis, chronic active hepatitis and in some cases hepatocellular carcinoma).
Hepatitis D virus ("Delta Virus") is a defective RNA virus that can only infect the liver in the presence of an active HBV infection. Hepatitis E virus appears to be a single-stranded RNA virus. Infection with hepatitis E virus is not known to progress to chronic liver disease.
Although HBV and HCV have been identified and characterized, the development of new anti-viral strategies has been greatly hampered by the lack of adequate, simple and low cost animal model systems.
Currently, biological assays for HBV and HCV have been limited to the experimental inoculation of chimpanzees.sup.(3,4), which are expensive and limited in numbers. In addition, an in vitro system for the propagation of HCV was developed in the murine retrovirus infected human T cell lines, HPB-Ma.sup.(5) and Molt4-Ma.sup.(6), in which replication of HCV is achieved.
It has recently been demonstrated in several studies that human solid organs such as fetal thymus or fetal liver as well as several types of tumors were successfully grafted into SCID mice under the kidney capsule.sup.(7). In addition, transplantation of other organs such as lymph nodes and bone marrow spicules and engraftment of organs to other sites (i.e. subcutane and peritoneum) have also been reported.
A SCID mouse mutant was reported to support human cell implantation, i.e. single hepatocyte transplantation.sup.(8,9), and was also used as a model for human infectious diseases, i.e. HIV-1 infections.sup.(10).
It has been disclosed that lethally irradiated mice, radio-protected with bone marrow from SCID mice, developed marked immune-deficiency and supported engraftment of human peripheral blood lymphocytes (PBL) for a long period of time.sup.(11). It was also disclosed that human implants of non-hematopoietic origin were accepted and maintained for prolonged periods of time after transplantation under the kidney capsules of these chimeras.sup.(12).
USPTO Backgrounds
USPTO Backgrounds