807 An Animal Model for Kaposi's Sarcoma C.H. Parsons*, D.H. Kedes Univ of Virginia, Charlottesville
Background: Kaposiís sarcoma (KS) is a multicellular angiogenic tumor and the most common AIDS-associated malignancy worldwide. The etiologic agent of KS is KS-associated herpes virus (KSHV or HHV8). KSHV has been identified in both peripheral blood mononuclear cells (PBMC) and a variety of cells within KS lesions. In vitro experiments demonstrate that KSHV can transform certain cell types from both of these compartments into characteristic KS spindle cells that display unique morphologic and cell surface properties. Despite these advances, the exact means of viral spread within an infected individual remains unclear. Insights into this issue and other details regarding KS pathogenesis, depend on the development of an effective in vivo system in which to study the natural history of KSHV infection in the setting of immunosuppression.
Methods: We implanted a novel combination of human fetal tissue grafts, including bone marrow, thymus, and skin, into severe combined immunodeficient mice (a SCID-hu model). We then employed flow cytometry (FACS), ELISA, immunohistochemistry and IFA to characterize the human engraftment and test the overall potential of the model to study KSHV pathogenesis.
Results: Our preliminary findings demonstrate detectable levels of human cells (> 0.1% of total cells, range 0.1%-18%) in the peripheral blood, as well as in murine liver and spleen. Detailed cytometric analysis of the explanted human grafts and peripheral blood reveals discernible subpopulations of human cells, including B cells, monocytes, and hematopoetic progenitor cells-the same cell types infected with KSHV in human patients. Furthermore, the B cells produce detectable amounts of human IgG within the sera of the SCID-hu mice. Finally, the human fetal skin supports KS-like tumor formation following long-term engraftment and then direct viral injection.
Conclusions: Our data indicate that this novel SCID-hu model possesses the potential to act as the first animal system in which to track KSVH pathogenesis. The mice demonstrate sustained maintenance of the human cell types that KSHV infects in patients as well as the tissue (skin) most commonly affected with KS. It is our hope that this model will allow for more effective investigation into the pathogenesis of KS as it relates to primary viral infection, viral spread, and the host immune response, while shedding light on mechanisms for the prevention and treatment of this disease.