Highly sensitized candidates on the transplant waitlist remain a significant challenge, as current desensitization protocols have variable success rates of donor-specific antibody (DSA) reduction. Therefore, improved therapies are needed. A proliferation-inducing ligand (APRIL) and B-lymphocyte stimulator (BLyS) are critical survival factors for B-lymphocytes and plasma cells, which are the primary sources of alloantibody production. We examined the effect of APRIL/BLyS blockade on DSA in a murine kidney transplant model as a possible novel desensitization strategy.
C57BL/6 mice were sensitized with intraperitoneal (IP) injections of 2 × 106 BALB/c splenocytes. Twenty-one days following sensitization, animals were treated with 100 μg of BLyS blockade (B-cell activating factor receptor-immunoglobulin) or APRIL/BLyS blockade (transmembrane activator and calcium modulator and cyclophilin ligand interactor-immunoglobulin), administered thrice weekly for an additional 21 days. Animals were then euthanized or randomized to kidney transplant with Control Ig, BLyS blockade, or APRIL/BLyS blockade. Animals were euthanized 7 days posttransplant. B-lymphocytes and DSA of BLyS blockade only or APRIL/BLyS blockade-treated mice were assessed by flow cytometry, immunohistochemistry, and enzyme-linked immunospot.
APRIL/BLyS inhibition resulted in a significant reduction of DSA by flow crossmatch compared with controls (P < 0.01). APRIL/BLyS blockade also significantly depleted IgM- and IgG-secreting cells and B-lymphocyte populations compared to controls (P < 0.0001). APRIL/BLyS blockade in transplanted mice also resulted in decreased B-lymphocyte populations; however, no difference in rejection rates were seen between groups.
APRIL/BLyS blockade with transmembrane activator and calcium modulator and cyclophilin ligand interactor-immunoglobulin significantly depleted B-lymphocytes and reduced DSA in this sensitized murine model. APRIL/BLyS inhibition may be a clinically useful desensitization strategy for sensitized transplant candidates.
1 Division of Nephrology, Department of Medicine, University of Wisconsin–Madison, Madison, WI.
2 Division of Transplant, Department of Surgery, University of Wisconsin–Madison, Madison, WI.
3 Department of Organ Transplantation, Xiangya Hospital, Central South University, Changsha, China.
4 Department of Biology, University of Wisconsin–Platteville, Platteville, WI.
5 Department of Pathology, University of Wisconsin–Madison, Madison, WI.
Received 6 April 2018. Revision received 6 February 2019.
Accepted 8 February 2019.
N.A.W. participated in research design, writing of the article, performance of research, and data analysis. N.M.B. participated in the performance of research, writing of the article, and data analysis. B.M.V. participated in research design, performance of research, and data analysis. B.A.B. and X.D. participated in research design and performance of research. A.S., W.S., and S.E.P. participated in the performance of research. R.R.R. III participated in research design, writing of the article, and data analysis.
Murine TACI-Ig and BAFFR-Ig were generously provided by Merck Serono (R.R.R.). Outside the submitted work, grants and personal fees were received from Genentech, GlaxoSmithKline, Roche. All the other authors declare no conflicts of interest.
This work was supported by a KL2 career development award (4KL2TR000428-10), the American Society of Transplant Surgeons Faculty Development Grant (MSN183242), and the American College of Surgeons Franklin Martin, MD, FACS Faculty Research Fellowship (MSN192116). This publication was supported by the National Institute Of Allergy And Infectious Diseases of the National Institutes of Health under the award number T32AI125231.
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Correspondence: Robert R. Redfield III, MD, University of Wisconsin School of Medicine and Public Health, Division of Transplant, Department of Surgery, University of Wisconsin - Madison, 600 Highland Avenue, H4/761, Madison, WI 53792. (firstname.lastname@example.org).