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THE DEVELOPMENT OF SELECTIVE PHOTOSENSITIZERS TO TARGET PATHOGENIC T CELLS AND PREVENT GRAFT-VERSUS-HOST DISEASE

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abstract
T lymphocytes play a central role in many human immunologic disorders, including autoimmune and alloimmune diseases. In hematopoietic stem cell transplantation, acute graft-versus-host-disease (GVHD) is caused by an attack on the recipient's tissues from donor allogeneic T cells. In cutaneous T cell lymphoma (CTCL), malignant T cells migrate throughout the skin to mediate the disease. Consequently, developing new therapeutics to selectively target pathogenic and malignant T cells may improve clinical outcomes. In the work presented here, we have created a series of photosensitizers with the ability to target oxidative phosphorylation (OXPHOS) in pathogenic and malignant T cells. The photosensitizers are also potent stimulators of P-glycoprotein (P-gp). Enhanced P-gp activity promotes the efficient removal of photosensitizer not sequestered in mitochondria, and protects resting lymphocytes that are essential for antipathogen and antitumor responses. To evaluate the selective depletion of alloimmune responses, donor C57BL/6 splenocytes were cocultured for 5 days with irradiated BALB/c splenocytes and then photodepleted (PD) with the best-in-class photosensitizer, 2-Se-Cl. PD-treated splenocytes were infused into lethally irradiated BALB/c (same-party) or C3H/HeJ (third-party) mice. Same-party mice that received PD-treated splenocytes at the time of transplant lived 100 days without evidence of GVHD. In contrast, all mice that received untreated primed splenocytes and third-party mice that received PD-treated splenocytes died of lethal GVHD. However, 2-Se-Cl was not highly effective in targeting malignant T cells. Consequently, we developed a series of photosensitizers with increased lipophilicity, which facilitated greater selectivity towards malignant T cells. Selenorhodamine 6 was selected as the best-in-class photosensitizer in this series, and was rapidly extruded from resting cells, which resulted in 60 – 80% survival of all resting T cells populations. In contrast, the high retention of selenorhodamine 6 resulted in only a 5% cell survival of malignant T cells after light exposure. Collectively, our work provides insight into the development of selective therapeutics that stimulate P-gp and inhibit OXPHOS, and which may be designed with tissue specificity. The high selectivity of our photosensitizers may have broad applications and provide alternative treatment options for patients with T lymphocyte-mediated diseases.
subject
Graft-versus-host Disease
Immunotherapy
Leukemia
Stem cell transplant
contributor
McIver, Zachariah (author)
Grayson, Jason M (committee chair)
High, Kevin (committee member)
Alexander-Miller, Martha (committee member)
Gautreaux, Michael (committee member)
date
2017-06-15T08:35:51Z (accessioned)
2017-06-15T08:35:51Z (available)
2017 (issued)
degree
Molecular Medicine and Translational Science (discipline)
identifier
http://hdl.handle.net/10339/82184 (uri)
language
en (iso)
publisher
Wake Forest University
title
THE DEVELOPMENT OF SELECTIVE PHOTOSENSITIZERS TO TARGET PATHOGENIC T CELLS AND PREVENT GRAFT-VERSUS-HOST DISEASE
type
Dissertation

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