Date of Award

1-1-2020

Embargo Period

2-19-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

College

College of Graduate Studies

First Advisor

Xue-Zhong Yu

Second Advisor

Lynn Schnapp

Third Advisor

Beichu Guo

Fourth Advisor

Carl Atkinson

Fifth Advisor

Bei Liu

Sixth Advisor

Xian Zhang

Abstract

Hematopoietic stem-cell transplantation (HCT) is a curative procedure for hematological malignancies, but chronic graft-versus-host disease (GVHD) remains a major complication after allogeneic HCT. Because donor B cells are essential for chronic GVHD (cGVHD) development and B cells are sensitive to endoplasmic reticulum stress, we hypothesized that the IRE-1α/XBP-1 pathway is required for B-cell activation and function in cGVHD. Here, we used mice deficient of XBP-1 specifically in B cells, and recipients transplanted with grafts containing XBP-1–deficient B cells displayed reduced cGVHD compared with controls that was associated with reduced B-cell activation and production of alloreactive antibodies. Prophylactic administration of B-I09 (an IRE-1α/XBP-1 inhibitor) also reduced cGVHD without compromising GVL effect against chronic myelogenous leukemia. Although B cells play an important role in chronic GVHD development, effector T cells are still primary drivers of the disease. We investigated the T-cell specific role of a second transcription factor, Fli-1, in GVHD pathogenesis. Ablation of two critical exons of the fli-1 gene in donor-derived T cells was associated with significant reduction of disease development in allo-HCT models of cGVHD and aGVHD. This reduction was associated with increased regulatory T cells (Tregs) and decreased IFN-γ+, IL-17A+, and TFH T cells in lymphoid organs. We also demonstrated that low-dose camptothecin exhibits action as a potent Fli-1 inhibitor, both in vitro and in vivo against mouse and human Fli-1. Utilization of drugs that targeted Fli-1 was able to prevent cGVHD development and reverse already established cGVHD. Camptothecin also prevented aGVHD while preserving the GVL effect against P815 mastocytoma. Further, camptothecin reduced human T-cell proliferation both in vitro and in vivo, while also reducing GVHD in a human xenograft model. These findings in combination suggest that XBP-1 is a critical factor regulating the B-cell component of chronic GVHD development while Fli-1 is a critical factor involved in the T-cell component. Many transcription factors are also notoriously difficult to inhibit, however, we identified that both XBP-1 and Fli-1 could be targeted using pharmaceuticals, making these factors promising translational strategies for reducing GVHD in the clinical setting, while also preserving the GVL effect of the donor graft.

Rights

All rights reserved. Copyright is held by the author.

Download

Share

COinS