Liver and bile duct pathology following Cryptosporidium parvum infection of immunodeficient mice

Patients with acquired immune deficiency syndrome (AIDS) and boys with muta tions of the CD154 gene (causing congenital X-linked immunodeficiency with hyper-IgM [XHIM]) are susceptible to chronic infections of the biliary trac t with Cryptosporidium parvum (CP) that may lead to biliary sclerosis and u ltimately to cholangiocarcinoma. To determine whether the CP infection and the consequent immune response contribute independently to this morbidity, we infected mice with severe combined immunodeficiency (SCID) or with disru pted genes for CD154, CD40, or interferon gamma (IFN-gamma) with CP. Even w hen CP infection persisted for 16 weeks, the SCID mice developed only mild triaditis, without apoptosis of biliary epithelial cells (BEC). Fifty perce nt of the CD154 knockout mice developed lobular hepatitis with acute and ch ronic triaditis. The CD40 knockout mice developed marked triaditis, and the IFN-gamma knockouts either succumbed to enteritis or survived to develop m arked triaditis, portal fibrosis, biliary sclerosis, necrosis with dilation of duct-like structures within the porta hepatis, and dysplastic changes. CP-infected SCID mice reconstituted with T cells from IFN-gamma knockout do nors either developed severe enteritis or survived to develop triaditis, ch olangitis, lobular hepatitis with periductular sclerosis, and scarring. Mic e with disruptions of both the CD40 and IFN-gamma genes remained infected b y CP and developed bile duct and liver disease, but not enteritis. Our resu lts suggest that T-cell cytokines are required for the inflammatory and scl erosing responses to CP infection in immunodeficient animals. The response of immunodeficient mice to CP infection may model at least the initial step s toward the development of sclerosing cholangitis or bile duct cancers in XHIM patients.