Anti-rejection therapy does not eliminate donor-reactive IFN-γ and IL-21 producing cells

N.M. van Besouw, D. Reijerkerk, A. Mendoza Rojas, M.C. Clahsen-van Groningen, D.A. Hesselink, C.C. Baan

Wednesday 4 march 2020

15:10 - 15:20h at Joep Nicolas zaal

Parallel session: Parallel sessie IV – Basale abstracts

Background: 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).

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 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 24/3E5 PBMC (6-119) vs. 9/3E5 PBMC (3-27), p=0.01; IL-21: 27/3E5 PBMC (10-59) vs. 9/3E5 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: 9/3E5 PBMC (3-27) vs. 33/3E5 PBMC (15-117), p<0.0001; IL-21: 9/3E5 PBMC (4-32) vs. 40/3E5 PBMC (19-88) p<0.0001].

Conclusions: 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.