Purpose:

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 2^nd 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.

Methods:

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.

Results:

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⁺PD1^highICOS⁺ 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.

Conclusion:

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).

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