Hoshitsuki, Keito
(2024)
Investigation of immunologic and hepatic adverse effects of asparaginase.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Asparaginase is a highly effective antileukemic agent that has been used for over 5 decades but has several unique adverse effects, most commonly immunotoxicity and hepatotoxicity. These toxicities can lead to disruption of antileukemic treatment, leading to poorer outcomes. Therefore, investigation of the mechanisms underlying these toxicities and methods to prevent or treat them, could reduce morbidity and mortality associated with asparaginase. Using both human cohorts and murine models, we investigated the potential genetic and mechanistic modifiers of asparaginase immunotoxicity and hepatotoxicity. We performed genomic association studies to identify genetic loci underlying anti- asparaginase antibody formation and confirmed the association with Class II HLA-DRB*07:01 allele previously associated with asparaginase hypersensitivity reactions. We report the results of a clinical trial using anti-CD20 B-cell depletion to reduce anti-asparaginase antibodies. We investigated the mechanism of action of a novel small molecule inhibitor of a previously identified mechanism of asparaginase immunogenicity, showing its effectiveness as an immunosuppressant. Hepatotoxicity was investigated exclusively in murine models of asparaginase-induced liver injury. Our work showed that asparaginase-induced liver injury does not appear to be a direct hepatic insult from asparaginase but rather is associated with lipotoxicity, due to lipolysis of peripheral white adipose tissue and free fatty acid influx into the liver. Finally, our investigation at the single-cell level point to hepatocytes as the main cell types affected in liver injury, with similarities to other human steatotic liver diseases, posing interesting future questions on potential therapeutic interventions for asparaginase-induced liver injury. Taken together, this dissertation contributes original investigations and data towards our understanding of the pathophysiology and potential modifiers of asparaginase-induced immunotoxicity and hepatotoxicity.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
23 July 2024 |
| Date Type: |
Publication |
| Defense Date: |
7 June 2024 |
| Approval Date: |
23 July 2024 |
| Submission Date: |
13 July 2024 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
216 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Drug allergy; drug-induced liver injury; acute lymphoblastic leukemia; chemotherapy |
| Date Deposited: |
23 Jul 2024 16:36 |
| Last Modified: |
23 Jul 2024 16:36 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46471 |
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