Anti-rejection therapy does not eliminate donor-reactive IFN-γ and IL-21 producing cells
Nicole M. van Besouw1, Derek Reijerkerk1, Aleixandra Mendoza Rojas1, Marian C. Clahsen-van Groningen2, Dennis A. Hesselink1, Carla C. Baan1.
1Internal Medicine - Nephrology & Transplantation, Erasmus MC, Rotterdam, Netherlands; 2Pathology, Erasmus MC, Rotterdam, Netherlands
Introduction: IFN-γ and IL-21 have pro-inflammatory properties and support induction and expansion of aggressive cytotoxic T cells. IL-21 also regulates the differentiation of B cells into antibody producing plasma cells, and high numbers are associated with the occurrence of rejection. We investigated whether successful anti-rejection treatment eliminates circulating donor-reactive cytokine producing cells (pc).
Material and Methods: PBMC samples of 85 stable kidney transplant recipients of whom 30 patients were successfully treated with rejection therapy (high-dose corticosteroids for 3 consecutive days (n=23) followed by ATG treatment (n=7) at median 7 days after transplantation, range: 6-48) were analysed by IFN-γ and IL-21 Elispot after rejection treatment (1.22±0.91 years after transplantation). Patient’s PBMC were stimulated with irradiated donor cells or third-party cells that were completely HLA mismatched.
Results: Significantly higher frequencies of donor-reactive IFN-γ and IL-21 pc were found in patients treated with rejection therapy compared to those without rejection [IFN-γ: median 24/3x10E5 PBMC (6-119) vs. 9/3x10E5 PBMC (3-27), p=0.01; IL-21: 27/3x10E5 PBMC (10-59) vs. 9/3x10E5 PBMC (4-32), p=0.004]. No difference was found between the patient groups after third-party stimulation. Remarkably, the number of donor-reactive IFN-γ and IL-21 pc in the rejection treated group was comparable with the third-party reactivity, while the number of donor-reactive cytokine pc in patients without rejection was significantly lower than the third-party reactivity [IFN-γ: 9/3x10E5 PBMC (3-27) vs. 33/3x10E5 PBMC (15-117), p<0.0001; IL-21: 9/3x10E5 PBMC (4-32) vs. 40/3x10E5 PBMC (19-88) p<0.0001].
Conclusion: High numbers of donor-reactive IFN-γ and IL-21 pc in patients subsequently and successfully treated with anti-rejection therapy appear to be insensitive to therapy. These patients should be more carefully monitored as they are at risk for rejection when their immunosuppressive adherence decreases.
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