BAFF is increased in renal transplant patients following treatment with alemtuzumab.
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.
Bloom
D
D
Department of Surgery, Division of Solid Organ Transplantation, University of Wisconsin-Madison School of Public Health and Medicine, Madison, WI, USA. bloom@surgery.wisc.edu
Chang
Z
Z
Pauly
K
K
Kwun
J
J
Fechner
J
J
Hayes
C
C
Samaniego
M
M
Knechtle
S
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000494:pharmacology / Q000627:therapeutic use*; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D053264:B-Cell Activating Factor / Q000097:blood*; D053301:B-Cell Maturation Antigen / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology; D016022:Case-Control Studies; D005260:Female; D006084:Graft Rejection / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D016030:Kidney Transplantation / Q000473:pathology*; D037181:Lectins, C-Type; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology; D053303:Transmembrane Activator and CAML Interactor Protein / Q000378:metabolism; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000097:blood; D055815:Young Adult; D000099192:CD69 Antigens
D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D053264:B-Cell Activating Factor; D053301:B-Cell Maturation Antigen; D053645:Interleukin-2 Receptor alpha Subunit; D037181:Lectins, C-Type; D053303:Transmembrane Activator and CAML Interactor Protein; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D000099192:CD69 Antigens; C108467:TNFRSF13B protein, human; C086966:TNFRSF17 protein, human; C505719:TNFSF13B protein, human