B Cell Receptor Genes Associated With Tolerance Identify a Cohort of Immunosuppressed Patients With Improved Renal Allograft Graft Function

Abstract

We previously reported that two B cell receptor genes, IGKV1D-13 and IGKV4-1, were associated with tolerance following kidney transplantation. To assess the potential utility of this “signature” we conducted a prospective, multicenter study to determine the frequency of patients predicted tolerant within a cohort of patients deemed to be candidates for immunosuppressive minimization. At any single time point 25 – 30% of patients were predicted to be tolerant, while 13.7% consistently displayed the tolerance “signature” over the two-year study. We also examined the relationship of the presence of the tolerance “signature” on drug usage and graft function. Contrary to expectations, the frequency of predicted tolerance was increased in patients receiving tacrolimus and reduced in those receiving corticosteroids, MMF, or Thymoglobulin as induction. Surprisingly, patients consistently predicted to be tolerant displayed a statistically and clinically significant improvement in eGFR that increased over time following transplantation. These findings indicate that the frequency of patients consistently predicted to be tolerant is sufficiently high to be clinically relevant and confirm recent findings by others that immunosuppressive agents impact putative biomarkers of tolerance. The association of a B cell-based “signature” with graft function suggests that B cells may contribute to the function/survival of transplanted kidneys.

B cells in transplant tolerance and rejection: friends or foes?

“…More recent evidence in the operationally tolerant human kidney transplant recipients has identified the same B‐cell signature of tolerance by transcriptional analysis of peripheral blood in both spontaneously tolerant individuals as well as those who underwent specific tolerance induction protocols . In addition, a significant proportion of patients with stable long‐term graft function while on immunosuppression demonstrated this B‐cell tolerance signature . A recent meta‐analysis of the gene signatures of operationally tolerant kidney transplant patients validated the concept that the majority of biomarkers associated with tolerance were in fact B‐cell‐related .…”

Validation Study of an Operational Tolerance Signature in Korean Kidney Transplant Recipients

“…Moreover, it was impossible to compare the prescription patterns of immunosuppressive drugs in patients with LTGS, which might affect the gene expression related to immune cells. A recently published study demonstrated that the expression levels of IGKV1D-13 and IGKV4-1 were increased by tacrolimus and decreased by steroids, mycophenolate mofetil, or thymoglobulin treatment ( 31 ), suggesting the importance of the effects of drugs in the interpretation of transcriptomic data. We could not exclude the possibility that the molecular and phenotypic features of patients with OT simply originated from the lack of immunosuppressive agents, rather than specific immunological characteristics of tolerance.…”

Regulatory B cells: Development, phenotypes, functions, and role in transplantation

“…Tolerance (GAMBIT) study in Europe. 133 Nevertheless, some authors still support the notion that the expression of B-cell receptor genes, IGKV1D-13 and IGKV4-1, is a clinically relevant biomarker in kidney transplantation, 134 whereas others consider that the effect of immunosuppressive drugs is still misleading the results. 129 Their results showed that the percentage of transitional B cells increased significantly after steroid withdrawal, suggesting that the increment of regulatory B cells in tolerant patients could be a consequence of steroid withdrawal rather than a true biomarker of tolerance.…”

“…129 Interestingly, another independent study that evaluated tolerance biomarkers (in particular the expression of IGKV1D-13 and IGKV4-1 genes obtained from Newell et al 125 Having shown that immunosuppressive drugs drastically affect circulating B-cell proportions, it is difficult to conclude with certainty that gene signatures in B cells can be used to indicate operational tolerance in renal transplant recipients. 133 Nevertheless, some authors still support the notion that the expression of B-cell receptor genes, IGKV1D-13 and IGKV4-1, is a clinically relevant biomarker in kidney transplantation, 134 whereas others consider that the effect of immunosuppressive drugs is still misleading the results. 135,136 This interesting debate has allowed the definitions of biomarkers of tolerance to be refined.…”