Date of Award

5-2007

Level of Access

Campus-Only Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biochemistry and Molecular Biology

Advisor

Derry Roopenian

Second Committee Member

Charles E. Moody

Third Committee Member

David Serreze

Abstract

Hematopoietic stem cell transplantation (HSCT) is an affective treatment for many malignant diseases including hematological malignancies, solid tumors that are sensitive to myeloablative therapy, non malignant diseases and severe autoimmune diseases. Graft versus host disease (GVHD) is the most serious and life-threatening complication post HSCT. The immune response that causes GVHD in HSCT between major histocompatibility complex matched donors and recipients are directed mainly against few immunodominant minor histocompatibility antigens (mHAgs) despite the presence of numerous other mHAgs. Remarkably >30% of the total CD8+ T cells immune response to the mHAgs was directed against a single mHAg (H60). The mechanism by which H60 achieves its immunodominance is unknown. A major goal of the study is to investigate the mechanism by which H60 overwhelmingly dominates other mHAgs and determine the kinetics of CD8+ T cells immune response to various immunodominant mHAgs in immunization and GVHD settings. Furthermore, we sought to determine the relative impact of matching or mismatching of a single or multiple mHAgs in development of GVHD following bone marrow (BM) transplantation between MHC matched background disparate mouse strains. We generated H60 transgenic mice and a battery of congenic mice for single and multiple combinations of mHAgs and we performed several immunizations and BM and spleen cell transfers. We hypothesized that the immunodominance of H60 is due to the lack of self analog in the responding mice that cause loss of T cells negative selection in the thymus which lead to presence of high T cell precursor frequency specific for H60. Herein we show that introduction of self analog of H60 in mice that do not express H60 did not ameliorate their immune response to H60, thus we ruled out this mechanism for the immunodominance of H60. Furthermore, we show that any of the tested single mHAgs are not a risk factor for lethal GVHD; however, we show that matching for mHAgs resulted in the attenuation of GVHD. Understanding the mechanism of immunodominance is of importance in transplantation, immunotherapy targeting mHAgs in cancer treatment and vaccine development.

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