Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a life-saving, curative treatment for a range of malignant and non-malignant diseases. However, the efficacy of allo-HSCT is significantly reduced by the development of acute and chronic graft-versus-host disease (GVHD). Current GVHD therapies are incompletely effective, and can increase malignancy recurrence and opportunistic infections. Therefore, new approaches to treat GVHD are required. Here we demonstrate several methods to augment Regulatory T-cell (Treg)-mediated suppression of GVHD. In acute GVHD, we discovered that physical disruption of a novel negative signaling complex in Treg enhances Treg-mediated suppression of GVHD. We show that PKC-θ and vimentin complex together after Treg activation, and that disrupting this complex increases Treg metabolism, and augments Treg suppression of conventional T-cell (Tcon) priming, metabolism and cytokine production. In chronic GVHD, we show that infusions of either IL-2/mAb complexes or Treg were efficacious in treating established cGVHD. Treatment efficacy was dependent upon enhancing Treg-mediated suppression of germinal centers. Importantly, IL-2/mAb complexes had the potential to drive Tcon proliferation, suggesting that Treg infusions may be safer for some cGVHD patients. These studies identify PKC-θ/vimentin complex disruption as a novel means to augment Treg-mediated suppression of acute GVHD, and both Treg infusions and IL-2/mAb complexes as potential methods to enhance Treg-mediated suppression of chronic GVHD.
University of Minnesota Ph.D. dissertation.August 2016. Major: Microbiology, Immunology and Cancer Biology. Advisor: Bruce Blazar. 1 computer file (PDF); ix, 114 pages.
Methods to enhance the efficacy of Regulatory T-cell therapies for acute and chronic Graft-versus-Host Disease.
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