APRIL/BLyS Blockade Reduces Donor-specific Antibodies in Allosensitized Mice.
Transplantation
; 103(7): 1372-1384, 2019 07.
Article
em En
| MEDLINE
| ID: mdl-30830041
ABSTRACT
BACKGROUND:
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.METHODS:
C57BL/6 mice were sensitized with intraperitoneal (IP) injections of 2 × 10 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.RESULTS:
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.CONCLUSIONS:
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Baço
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Imunoglobulinas
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Linfócitos B
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Subpopulações de Linfócitos T
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Dessensibilização Imunológica
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Transplante de Rim
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Fator Ativador de Células B
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Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral
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Rejeição de Enxerto
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Isoanticorpos
Tipo de estudo:
Guideline
/
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Transplantation
Ano de publicação:
2019
Tipo de documento:
Article