Graduation Year

2014

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Medical Sciences

Major Professor

Claudio Anasetti

Co-Major Professor

Patricia Kruk

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.

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