BAFF and BAFF-R Levels Are Associated With Risk of Long-Term Kidney Graft Dysfunction and Development of Donor-Specific Antibodies

Abstract

There are lines of evidence that B cells may play a role in transplantation. B cell activating factor, BAFF, is a homotrimer that has been shown to play a role in B cell survival, maturation and activation. To date, little is known of the role of BAFF and its receptors in transplantation. We analyzed the level of BAFF mRNA and its soluble protein, as well as transcripts coding for its receptors, BAFF-R, TACI and BCMA, in the blood of 143 patients with stable kidney transplant function 5 years or more posttransplantation. Three endpoints were analyzed: the time to renal dysfunction, the time to appearance of anti-HLA antibodies and the time to development of donor-specific antibodies. We established threshold values for BAFF and BAFF-R and showed that (1) stable patients with high BAFF-R levels had a higher risk of developing graft dysfunction, (2) patients with lower levels of BAFF transcripts or a higher level of soluble BAFF had a significantly higher risk of developing donor-specific antibodies. These data suggest that BAFF constitutes a risk factor for renal graft dysfunction and development of donor-specific antibodies. They also suggest that agents targeting BAFF-R interactions may offer new therapeutic opportunities in transplantation.

B Cells, Antibodies, and More

“…In addition, dysregulation of BAFF levels, especially after depletion of cells consuming BAFF, contribute to pathogenic antibody responses, indicating that pan-depletion of B cells can have deleterious effects on disease progression (128)(129)(130)(131). Long-lived plasma cells lack CD20, the target of rituximab, and account for alloantibody production even after mature B cells that express CD20 are depleted.…”

“…SLE results from systemic loss of B-cell tolerance, leading to production of high titers of autoantibodies against double-stranded DNA (dsDNA), RNA, and nuclear proteins (143)(144)(145). Dysregulated BAFF levels and augmented signal transduction downstream of the BCR, specifically in the BtK-Lyn-Syk kinase pathway, contribute to increased B-cell activation with increased frequencies of memory and plasma cells in patients with SLE (65,131,144,(146)(147)(148). The presence of anti-dsDNA antibodies identifies patients at risk of lupus nephritis, consistent with experimental evidence that these antibodies have a causative role in GN when deposited as immune complexes in the kidney.…”

Böbrek Naklinde Kullanılan Yeni İmmünsupresif İlaçlar

“…Thibault-Espitia ve ark. yaptığı çalışma daha yüksek solüble BAFF düzeyine sahip hastalarda donör spesifik antikor gelişme riskinin anlamlı olarak daha yüksek olduğunu, bunun greft disfonksiyonu gelişme riskiyle de ilişkili olduğunu göstermiştir (46). Solid organ transplantasyonunda Belimumab'ın kullanımı ile ilgili preklinik ve klinik araştırmalar halen devam etmektedir.…”

The Evolving Roles of Memory Immune Cells in Transplantation

“…(64) In a clinical study that enrolled 143 patients with stable kidney graft function for more than 5 years, elevated serum BATF levels predicted generation of de novo DSA and elevated BAFF-R transcripts represented a higher risk of developing graft dysfunction. (65) Further studies are required to delineate the roles of IL-21 and BAFF in antibody-mediated transplant rejection (AMR).…”