Understanding retroviral pathogenesis through the study of intrathymic expression of viral and exogenous antigens / Deborah Jill Marshall.

Marshall, Deborah Jill.
xiv, 267 p. : ill. ; 29 cm.
Medical subjects:
Allergy and Immunology.
Dissertations, Academic.
Local subjects:
Penn dissertations -- Immunology. (search)
Immunology -- Penn dissertations. (search)
Although the exact mechanisms of murine leukemia virus (MuLV)-induced lymphomagenesis have yet to be elucidated, it is clear that the immune response to viral proteins plays a critical role in this disease process. The parameters for lymphomagenesis are governed by an inverse relationship between viral persistence and immune responsiveness. Immunocompetent adult mice are typically resistant to the development of lymphoma. In contrast, neonatal animals and immunosuppressed adults are highly susceptible to MuLV-dependent leukemogenesis. MuLV have evolved ways to avoid immune detection either by altering their own genome or by altering the host environment. The formation of lymphomas in response to murine leukemia virus (MuLV) infection is dependent on MuLV persistence and the avoidance of immune clearance. In addition, the intrathymic replication of MuLV during thymocyte maturation and immune selection plays an important role in T cell repertoire development and immune inhibition. The proposed studies address the hypothesis that replication of MuLV in medullary thymic epithelial cells is an essential component of immune tolerance and leukemogenesis during persistent virus infection. Our studies have investigated the central hypothesis that intrathymic replication of MuLV is an essential component of leukemogenesis through both the induction of immunologic tolerance and persistent replication of MuLV. Our studies utilize a well characterized molecular clone of Gross murine leukemia virus (GMuLV), GD-17. The thymotropism of GD-17 is controlled by unique sequences within the long terminal repeat (LTR). This has been utilized to analyze the mechanism of MuLV persistence and leukemogenesis through the creation and in vivo expression of GMuLV based vectors. During the pre-leukemic phase, integrated virus and virus protein expression is detected predominantly in medullary thymic epithelial cells (mTEC) which are known to regulate negative selection. Most importantly, virus persistence is uniformly linked to inhibition of anti-GMuLV immunity, and lymphoma formation in adult animals. The purpose of this project is to utilize MuLV (murine leukemia viruses) as a model system to understand the biological processes that control the formation of tumors within the immune system.
Supervisor: Glen N. Gaulton.
Thesis (Ph.D. in Immunology) -- University of Pennsylvania, 1997.
Includes bibliographical references.
Local notes:
University Microfilms order no.: 98-00898.
Gaulton, Glen N., advisor.
University of Pennsylvania.
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