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Perturbing Proteostasis to Deplete Plasma Cells

Rossi, Amy
http://orcid.org/0000-0003-0629-0603
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1692203447145032

Abstract Details

2023, PhD, University of Cincinnati, Medicine: Immunology.
Anti-human leukocyte antigen antibodies (aHLA Ab) can form during a humoral immune response to non-self HLA encountered during pregnancy, blood transfusion, or transplantation. Due to shared epitopes across HLA alleles, highly sensitized patients can have aHLA Ab that recognize and would destroy an allograft from >99% of deceased donors; thus, their pool of available organs is severely limited compared to non-sensitized patients. To increase organ availability for highly sensitized patients, aHLA Ab must be sustainably reduced which requires depleting their source: plasma cells (PCs). Our group has focused on PC depletion using proteasome inhibitors as PCs are exquisitely dependent on the proteasome to maintain proteostasis due to their high rate of antibody synthesis. Despite significant PC depletion, proteasome inhibitors alone are insufficient to sustainably reduce aHLA Ab. We hypothesized this was in part due to PC residence in protective bone marrow (BM) microenvironments. Because the CXCR4:CXCL12 axis is instrumental in recruiting and maintaining PCs in the BM, we conducted a proof-of-concept clinical trial to determine if CXCR4 antagonism with the small molecule inhibitor, plerixafor, would mobilize PCs out of the BM. We evaluated the effects of plerixafor on PC residence in blood and BM, its safety profile (alone and in combination with the proteasome inhibitor, bortezomib), and the transcriptional impact on BMPCs in HLA-sensitized kidney transplant candidates. We found that plerixafor indeed mobilized PCs to peripheral blood and had varying effects on BM residence depending on the dose of plerixafor and bortezomib used. Single cell RNA-sequencing on BMPCs pre- and post-treatment revealed multiple populations of PCs, with post-treatment enrichment of oxidative phosphorylation, proteasome assembly, cytoplasmic translation, and autophagy-related genes. Follow up in vitro studies using mouse BMPCs demonstrated that dually inhibiting the proteasome and autophagy resulted in greater BMPC death than did monotherapies. Taken together, our findings suggest the potential utility of plerixafor-based PC mobilization and autophagy- and proteasome-inhibitor-based PC depletion in desensitization regimens.
George Deepe, M.D. (Committee Chair)
David Hildeman, Ph.D. (Committee Member)
Ervin Woodle, M.D. (Committee Member)
Krishna Roskin, PhD (Committee Member)
Kathryn Wikenheiser-Brokamp, M.D. (Committee Member)
David Plas, Ph.D. (Committee Member)
149 p.
Immunology
plasma cells; proteasome inhibitors; antibody mediated rejection; transplantation; desensitization

Recommended Citations

Citations

  • Rossi, A. (2023). Perturbing Proteostasis to Deplete Plasma Cells [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1692203447145032

    APA Style (7th edition)

  • Rossi, Amy. Perturbing Proteostasis to Deplete Plasma Cells. 2023. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1692203447145032.

    MLA Style (8th edition)

  • Rossi, Amy. "Perturbing Proteostasis to Deplete Plasma Cells." Doctoral dissertation, University of Cincinnati, 2023. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1692203447145032

    Chicago Manual of Style (17th edition)

ucin1692203447145032
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© 2023, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.
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