Graduation Year
2014
Document Type
Dissertation
Degree
Ph.D.
Degree Granting Department
Medical Sciences
Major Professor
Claudio Anasetti, M.D.
Co-Major Professor
Patricia Kruk, Ph.D.
Committee Member
Xiaohong Zhang, M.S., Ph.D.
Committee Member
Julie Djeu, Ph.D.
Committee Member
Leslie Kean, M.D., Ph.D.
Keywords
graft vs. host disease, immune tolerance, regulatory T cells, sirolimus
Abstract
Current immune suppressive strategies fail to induce donor-recipient immune tolerance after allogeneic hematopoietic cell transplantation. Accordingly, patients suffer morbidity and mortality from graft vs. host disease (GVHD) and prolonged immune suppressive therapy. Biologic insight into transplantation tolerance is needed, and translation of such insight to novel clinical strategies may improve clinical outcomes. We report original investigation at seminal phases of this process including initial prophylactic immune suppression, onset of acute graft vs. host disease, and ultimate immune suppression discontinuation: In a controlled randomized clinical trial, we demonstrate that sirolimus-based immune suppression reduces risk for acute GVHD, ameliorates the severity of subsequent chronic GVHD, and supports reconstitution of functional regulatory T cells. Study of tissue-infiltrating CD4+ T cell subsets in acute GVHD target organs supports a pathogenic role for Th17 cells. Finally, we demonstrate that peripheral blood transcriptional biomarkers provide mechanistic insight into human transplantation tolerance. These data signal progress, and suggest rational translational efforts to achieve transplantation tolerance.
Scholar Commons Citation
Pidala, Joseph, "Achievement of Transplantation Tolerance: Novel Approaches and Mechanistic Insights" (2014). USF Tampa Graduate Theses and Dissertations.
https://digitalcommons.usf.edu/etd/5104
