All ETDs from UAB

Advisory Committee Chair

Zdenek Hel

Advisory Committee Members

Peter Burrows

John C Kappes

Christopher Klug

Selvarangen Ponnazhagan

Laura Timares

Document Type

Dissertation

Date of Award

2011

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

While each type of cancer and chronic viral infection has its own specific pathology, they share two common mechanisms of immune evasion. The first mechanism is the exhaustion or deletion of antigen-specific T cells. The second mechanism is the formation of an immunosuppressive environment responsible for the block of T cell function. Elicitation of antigen-specific T cells be accomplished by immunotherapy in place of conventional treatments such as HAART and chemotherapy. In addition, immunotherapy can alleviate the side-effects associated with long-term use of conventional therapies while reducing the total cost. The results presented here provide an alternative to conventional methods of T cell elicitation by using antigen-expressing hematopoietic stem cells (HSCs) in order to generate and maintain high levels of antigen-specific T cells, that display a central memory phenotype, efficiently kill target cells in vivo and protect recipients against tumor growth in a preventive setting. Removal of the immunosuppressive environment created in chronic infections is important for future therapies. Research in the last five years has identified MDSC as a primary mechanism responsible for the immunosuppressive environment in a wide variety of tumors. However, what exact role MDSCs play in HIV disease progression is currently unknown. Research presented here assesses the frequency of MDSCs in circulating peripheral blood mononuclear cells (PBMCs) in the blood of HIV-1-infected individuals versus uninfected controls. Altogether, the data indicates that the MDSC population suppresses T cell proliferation, expresses HIV co-receptors, supports viral replication and is reduced in the circulation of HIV-1-infected individuals but retains suppressive function that intensifies with disease progression in those individuals.

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