High numbers of donor-specific IL-21 producing cells predict rejection after kidney transplantation: a cross validation study

N.M. van Besouw, L. Yan, P. de Kuiper, M. Klepper, D. Reijerkerk, D.L. Roelen, F.H.J. Claas, M.C. Clahsen-van Groningen, D.A. Hesselink, C.C. Baan

Thursday 15 march 2018

16:45 - 16:55h at Van Weelde Zaal

Categories: Basic / translational research, Session (parallel)

Parallel session: Parallel session 7: Basic / translational research

Introduction

Both IFN-γ and IL-21 support induction and expansion of highly-reactive cytotoxic CD8⁺ T-cells. In addition, IL-21 is a key cytokine for differentiation of alloantigen activated naïve and memory B-cells into antibody producing plasma cells. We questioned whether the frequency of donor-specific IFN-γ and IL-21 producing cells (pc) can predict kidney transplant rejection, and evaluated these cytokines in a cross-validation study.

Methods

The training group consisted of PBMC samples from 47 patients obtained at 6 months after living-donor kidney transplantation of whom 14 patients developed a late rejection (>6 months). The independent validation group included pre-transplantation samples of 38 patients of whom 17 patients had an early rejection (<3 months). The frequency of donor-reactive circulating IFN-γ and IL-21 pc was determined by Elispot assay.

Results

Remarkably, no relation was found between donor-specific IFN-γ pc frequency and rejection in both groups. However, significantly higher donor-specific IL-21 pc numbers were found in patients who developed rejection compared to those without rejection in both the training (p=0.020) and validation (p=0.024) group. ROC-curve analysis of donor-specific IL-21 pc frequencies distinguished the development of rejection from non-rejection with a specificity of 88% and 80% in the training and validation group, and a sensitivity of 50% and 73%, respectively. Patients with low IL-21 pc frequencies had a significantly increased rejection free survival rate in both the training (p=0.0008) and validation group (p=0.0005) compared to those with high frequencies. In addition, a positive correlation was found between donor-specific IL-21 pc numbers and serum creatinine concentrations at 12 months (training cohort: r_s=0.35, p=0.015) and at 1 and 2 months (validation cohort: r_s=0.41, p=0.013 and r_s=0.34, p=0.047) post-transplantation. Moreover, patients with pre-transplant anti-HLA antibodies had significantly higher numbers of pre-transplant circulating donor-reactive IL-21 pc than patients without antibodies (r_s=0.388, p=0.031).

Conclusion

The frequency of donor-specific IL-21 producing cells is linked to an increased risk of rejection, giving it the potential to be a new biomarker in predicting rejection in different phases of transplantation.