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Immunobiology and Novel Therapeutics in Acute Graft-versus-Host Disease

Zitzer, Nina Celia
http://rave.ohiolink.edu/etdc/view?acc_num=osu1532003009790858

Abstract Details

2018, Doctor of Philosophy, Ohio State University, Comparative and Veterinary Medicine.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a life-saving therapy both for malignant and non-malignant diseases. The success of allo-HSCTs, however, is limited by acute graft-versus-host disease (aGVHD), a frequent complication that remains a leading causes of non-relapse mortality following allo-HSCT. The pathogenesis of aGVHD involves donor T cells which target human leukocyte antigen mismatched host tissues, causing tissue injury through pro-inflammatory cytokine secretion and direct cytotoxicity. The morbidity and mortality associated with aGVHD pose a major barrier against the wider application of allo-HSCT as a curative modality. Thus, better understanding of aGVHD pathogenesis and novel therapeutics are needed. Modulation of T cell function, broadly, depends on control of gene expression. Two well-studied modes of modulating gene expression are noncoding RNAs and epigenetic modifications. Using unbiased approaches, we identified multiple microRNAs that are upregulated during aGVHD. We validated two of these, T-cell intrinsic miR-155 and serum miR-29a, due to their pivotal role in regulating the adaptive immune system. First, we investigate the molecular mechanisms by which miR-155 modulates T cell function in aGVHD. We identify that miR-155 expression in both donor CD8+ T cells and conventional CD4+ CD25- T cells is pivotal for aGVHD pathogenesis. Furthermore, we show that miR-155 strongly impacts alloreactive T cell expansion through proliferation and exhaustion as well as function by promoting a pro-inflammatory Th1 phenotype. Finally, we demonstrate that miR-155 expression in donor T cells regulates chemokine-dependent migration and infiltration into target organs. These findings provide novel insight into the role of miR-155 in regulating T cell function post-transplant and are convincing biological rationale to justify investigation of novel antagomiR-155 therapeutics to prevent or minimize aGVHD. Next, we strive to identify source, kinetics, and therapeutic potential of serum miR-29a in aGVHD, our second validated miR. We identify that miR-29a is upregulated in serum of mice that develop aGVHD as early as 10 days post-transplant and that the serum miR-29a originates from the host gastrointestinal tract epithelium. Finally, we show that targeting miR-29a using LNA antimiR-29a increases survival in a mouse model of aGVHD without perturbing graft versus leukemia effects. These findings support the pursuance of miR-29a as a biomarker for aGVHD and provide a strong rationale for targeting miR-29a as a novel therapeutic strategy for aGVHD. While the first two projects focus on miRs, another mechanism by which gene expression and T cell function is modulated is through epigenetics. While epigenetic modifiers such as hypomethylating agents have been studied in aGVHD, only recently has arginine methylation been investigated in the context of T cells. Our collaborators demonstrated that protein arginine methyltransferase 5 (PRMT5), which specifically produces symmetric dimethylarginine, promotes the activation and expansion of memory T helper cells following antigen re-exposure and that inhibiting PRMT5 suppresses clinically developed experimental autoimmune encephalomyelitis. Therefore, we sought to investigate the role of PRMT5 in aGVHD pathogenesis. We found that both PRMT5 expression and activity are increased following T cell activation. Furthermore, we show that PRMT5 plays a role T cell proliferation by promoting G1-to-S phase transition and impacts T cell effector IFN¿ production. We also demonstrate that PRMT5 inhibition perturbs T cell signaling by reducing both proximal PLC¿1 and distal ERK1/2 phosphorylation. Finally, treatment with PRMT5 inhibitor improves overall survival in mice with aGVHD, making PRMT5 an exciting therapeutic target for aGVHD.
Ramiro Garzon, MD (Advisor)
Michael Caligiuri, MD (Committee Member)
Renukaradhya Gourapura, DVM, MS, PhD (Committee Member)
M. Judith Radin, DVM, PhD (Committee Member)
176 p.
Immunology; Molecular Biology; Oncology
acute graft-versus-host disease; aGVHD microRNA; miR-155; miR-29a; PRMT5; HSCT; stem cell transplantation; BMT; bone marrow transplantation

Recommended Citations

Citations

  • Zitzer, N. C. (2018). Immunobiology and Novel Therapeutics in Acute Graft-versus-Host Disease [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1532003009790858

    APA Style (7th edition)

  • Zitzer, Nina. Immunobiology and Novel Therapeutics in Acute Graft-versus-Host Disease. 2018. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1532003009790858.

    MLA Style (8th edition)

  • Zitzer, Nina. "Immunobiology and Novel Therapeutics in Acute Graft-versus-Host Disease." Doctoral dissertation, Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1532003009790858

    Chicago Manual of Style (17th edition)

osu1532003009790858
165
© 2018, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.