Abstract
Alemtuzumab is a monoclonal antibody that depletes T and B cells and is used as induction therapy for renal transplant recipients. Without long-term calcineurin inhibitor (CNI) therapy, alemtuzumab-treated patients have a propensity to develop alloantibody and may undergo antibody-mediated rejection (AMR). In pursuit of a mechanistic explanation, we analyzed peripheral B cells and serum of these patients for BAFF (Blys) and BAFF-R, factors known to be integral for B-cell activation, survival, and homeostasis. Serum BAFF levels of 22/24 alemtuzumab-treated patients were above normal range, with average levels of 1967 pg/mL compared to 775 pg/mL in healthy controls (p = 0.006). BAFF remained elevated 2 years posttransplant in 78% of these patients. BAFF-R on CD19(+) B cells was significantly downregulated, suggesting ligand/receptor engagement. BAFF mRNA expression was increased 2-7-fold in CD14(+) cells of depleted patients, possibly linking monocytes to the BAFF dysregulation. Addition of recombinant BAFF to mixed lymphocyte cultures increased B-cell activation to alloantigen, as measured by CD25 and CD69 coexpression on CD19(+) cells. Of note, addition of sirolimus (SRL) augmented BAFF-enhanced B-cell activation whereas CNIs blocked it. These data suggest associations between BAFF/BAFF-R and AMR in alemtuzumab-treated patients.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adolescent
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Adult
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Aged
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Alemtuzumab
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Antibodies, Monoclonal / pharmacology
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Antibodies, Monoclonal / therapeutic use*
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Antibodies, Monoclonal, Humanized
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Antibodies, Neoplasm / pharmacology
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Antibodies, Neoplasm / therapeutic use*
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Antigens, CD / metabolism
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Antigens, Differentiation, T-Lymphocyte / metabolism
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B-Cell Activating Factor / blood*
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B-Cell Maturation Antigen / metabolism
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B-Lymphocytes / drug effects
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B-Lymphocytes / pathology
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Case-Control Studies
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Female
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Graft Rejection / pathology
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Graft Rejection / prevention & control*
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Humans
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Interleukin-2 Receptor alpha Subunit / metabolism
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Kidney Transplantation / pathology*
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Lectins, C-Type
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Male
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Middle Aged
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T-Lymphocytes / drug effects
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T-Lymphocytes / pathology
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Transmembrane Activator and CAML Interactor Protein / metabolism
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Tumor Necrosis Factor Ligand Superfamily Member 13 / blood
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Young Adult
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Antibodies, Neoplasm
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Antigens, CD
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Antigens, Differentiation, T-Lymphocyte
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B-Cell Activating Factor
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B-Cell Maturation Antigen
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CD69 antigen
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Interleukin-2 Receptor alpha Subunit
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Lectins, C-Type
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TNFRSF13B protein, human
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TNFRSF17 protein, human
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TNFSF13B protein, human
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Transmembrane Activator and CAML Interactor Protein
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Tumor Necrosis Factor Ligand Superfamily Member 13
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Alemtuzumab