Author ORCID Identifier

https://orcid.org/0000-0001-6905-0813

Year of Publication

2020

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department

Microbiology, Immunology, and Molecular Genetics

First Advisor

Dr. Gerhard Carl Hildebrandt

Second Advisor

Dr. Subbarao Bondada

Abstract

Hematopoietic stem cell transplantation (HSCT) is most commonly a treatment for inborn defects of hematopoiesis or acute leukemias. Widespread use of HSCT, a potentially curative therapy, is hampered by onset of graft-versus-host-disease (GVHD), a condition wherein the donor cells recognize the patient tissues as non-self. GVHD can manifest anywhere from weeks to decades post-transplant and is classified as either acute or chronic GVHD, both of which are significant causes of transplant-related morbidity and mortality.

However, GVHD is a complex, multifactorial, and enigmatic disease. The factors driving GVHD at the cellular and molecular level are incompletely understood. Immunosuppression targeting T-cells has not always been effective and increases the risk of relapse. Prophylactic immunosuppression can be particularly detrimental in the context of cGVHD, where symptoms can appear even decades after transplant. There is great need to further understand the mechanisms of GVHD pathogenesis in order to more effectively make use of HSCT.

Mast cells are an arm of the immune system that are primarily known for their role in atopic disease. However, recent studies have demonstrated new paradigms for mast cell activity, showing that they can play important roles in tissue homeostasis and wound healing. Therefore, the purpose of this dissertation is to explore the role of mast cells in the onset of fibrotic chronic GVHD. We hypothesized that mast cells, through their interactions with tissue-resident and circulating GVHD effector cells, would be detrimental in chronic GVHD by exerting proinflammatory and profibrotic effects on the surrounding tissue. We examined mast cells in vitro in mono- and co-culture models, finding that they are significantly resistant to conditioning-induced cell death, as well as capable of inducing proliferation of fibroblasts. We further tested our hypothesis in vivo in murine models of allogeneic transplant using both wild type and mast cell-deficient mice. Compared to wild type recipients, mast cell-deficient recipients had significant reductions in GVHD symptomology and skin manifestations, as well as in chemokine levels and immune cell recruitment in the skin. We show that mast cell chemokine production is blocked by drugs currently used clinically to treat chronic GVHD, and that skin from GVHD patients is enriched in mast cells. Lastly, we show that recipient-derived mast cells are capable of surviving after transplant.

Taken together, these data demonstrate a role for mast cells in the onset of dermal chronic GVHD. We therefore outline methods and pathways by which mast cells could be targeted for therapeutic inhibition and discuss future studies that would further clarify the function of mast cells in chronic GVHD pathogenesis.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2020.419

Funding Information

Funding received from 2016-2020 was from laboratory startup funds of Gerhard Hildebrandt, awarded by the University of Kentucky.

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