Session Time: 4:30pm-6:00pm
Presentation Time: 4:42pm-4:54pm
Location: Room 602/603/604
HLA-sensitization is a significant immunologic barrier to successful kidney transplantation (KT). We have shown that proteasome inhibition (PI) in insolation reduces plasma cells (PCs), but does not impact donor-specific antibodies (DSA) due to upstream germinal center (GC) compensation. We hypothesized that PC depletion with carfilzomib (CFZ), a 2nd generation PI, and arrest of differentiation of upstream naive B cells with tabalumab (TAB), an anti-BAFF monoclonal antibody (mAb), would permit successful renal allotransplantation in highly sensitized nonhuman primates.
Maximally MHC-mismatched rhesus pairs were sensitized with two sequential skin transplants and then desensitized with CFZ (20 mg/m2 IV) and TAB (100 mg IV) weekly for one month. Peripheral blood, lymph node (LN), and bone marrow (BM) cells were analyzed pre- and post-desensitization. Anti-CD4 and CD8 depletion was given and swapping KT was performed. Animals were maintained on conventional triple immunosuppression post-transplant and closely monitored.
CFZ/TAB (n=6) reduced mean DSA by 57% (p=0.0173). Peripheral CD4, CD8, and CD20 counts were unchanged by desensitization treatment. However, CFZ/TAB reduced peripheral PCs (mean 4.2% to 2.4% CD3[mdash]CD20[mdash]CD27+CD38+ cells, p=0.0026) and LN Tfh cells (mean 4.4% to 2.7% CD3+CD4+PD1highICOS+ cells, p=0.0393). CFZ/TAB did not change populations of Treg, CD4 Tnaïve, CD4 Tcm, CD4 Tem, CD8 Tnaive, CD8 Tcm, or CD8 Tem cells. CFZ/TAB prolonged median survival to 61 days (vs. 5 days in controls, log rank test p=0.01). CFZ/TAB with anti-CD4/CD8 mAb induction reactivated rhCMV.
CFZ/TAB was associated with a moderate reduction of DSA and prolonged graft survival in a highly sensitized rhesus model of KT. A possible mechanism for prolonged survival includes collapse of the GC by concurrently inhibiting PCs and upstream Tfh cells. This desensitization regimen in combination with T cell depletion impaired protective viral immunity.
CITATION INFORMATION: Ezekian B., Kwun J., Manook M., Schroder P., Yoon J., Mulvihill M., Freischlag K., Park J., Cochran J., Kroning K., Yi J., Knechtle S. Combination Proteasome Inhibition and Anti-BAFF Therapy Permits Highly Sensitized Rhesus Kidney Transplantation Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:Ezekian B, Kwun J, Manook M, Schroder P, Yoon J, Mulvihill M, Freischlag K, Park J, Cochran J, Kroning K, Yi J, Knechtle S. Combination Proteasome Inhibition and Anti-BAFF Therapy Permits Highly Sensitized Rhesus Kidney Transplantation [abstract]. https://atcmeetingabstracts.com/abstract/combination-proteasome-inhibition-and-anti-baff-therapy-permits-highly-sensitized-rhesus-kidney-transplantation/. Accessed February 20, 2020.
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