Date: Saturday, June 11, 2016
Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Halls C&D
Sensitized patients comprise a significant proportion (30%) of candidates on the waiting list for transplantation. With recent evidence that the presence of donor-specific antibodies (DSA) leads to decreased graft survival, efforts continue to be made to reduce DSA in these patients. While eliminating DSA is one part of the equation, the other is to improve immunosuppressive therapy for transplant recipients at high risk for antibody-mediated rejection. Here we evaluate the effectiveness of a proteasome inhibitor, bortezomib, in desensitizing rhesus monkeys immunized via skin grafts. We evaluate the impact of the drug on preformed antibodies and also on upstream components of the B cell response to provide a mechanistic insight on using bortezomib as a means of desensitization. Bortezomib i.v. weekly for 1 month (1.3mg/m2 per dose) clearly reduced CD38+CD19+CD20– plasma cells in the bone marrow (p<0.05) and antibody producing cells. However, the donor-specific alloantibody level was not decreased commensurately (Figure 1A). We observed rapid but transient induction of circulating IgG+ B cells and an increased number of proliferating B cells in the lymph nodes. Surprisingly, bortezomib treatment induced germinal center B cell (Figure 1B) and follicular helper T cell expansion (Figure 1C) in the lymph nodes. Finally, we confirmed in situ induction of germinal center (CD20/Ki67/CD3) response after bortezomib treatment through immunohistochemistry (Figure 1D). These data suggest that bortezomib-induced plasma cell depletion triggers humoral compensation. Therefore desensitization regimens incorporating the unique impact of bortezomib should be designed based on its mechanistic effects and limitations.
CITATION INFORMATION: Kwun J, Burghuber C, Iwakoshi N, Gibby A, Knechtle S. Limited Efficacy of Bortezomib on Desensitization via Rapid Humoral Compensation in a Sensitized Rhesus Model. Am J Transplant. 2016;16 (suppl 3).
To cite this abstract in AMA style:Kwun J, Burghuber C, Iwakoshi N, Gibby A, Knechtle S. Limited Efficacy of Bortezomib on Desensitization via Rapid Humoral Compensation in a Sensitized Rhesus Model. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/limited-efficacy-of-bortezomib-on-desensitization-via-rapid-humoral-compensation-in-a-sensitized-rhesus-model/. Accessed January 26, 2020.
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