IL-10 promotes chronic BK-virus infection and HLA class I antibody formation in renal transplant recipients
Rolf Weimer1, Nuray Bulut1, Fabrice Renner1, Hartmut Dietrich1, Christian Schüttler2, Caner Süsal3, Volker Daniel3, Demet Celik1, Elisabeth Freitag1, Natascha Gärtner1, Stefan Karoui1, Julia Mark1, Christoph Raatz1, Joern Pons-Kuehnemann4, Winfried Padberg5, Gerhard Opelz3.
1Department of Internal Medicine, University of Giessen, Giessen, Germany; 2Institute of Virology, University of Giessen, Giessen, Germany; 3Institute of Immunology, University of Heidelberg, Heidelberg, Germany; 4Institute of Medical Informatics, University of Giessen, Giessen, Germany; 5Department of Surgery, University of Giessen, Giessen, Germany
Background: In a randomized prospective renal transplant study, we found that IL-10 plays a key role in chronic BKV infection. Tacr/ERL treatment significantly downregulated IL-10 responses and resulted in the lowest BK viremia incidence compared to CsA/MMF and Tacr/MMF treatment. As IL-10 acts as a potent B cell growth and differentiation factor, we wondered whether increased IL-10 responses in chronic BK-virus infection might promote HLA antibody formation.
Materials and Methods: We analyzed intracellular cytokine responses, CD4+ T helper function and in-vitro B cell responses pretransplant and up to 24 months posttransplant. 105 renal transplant recipients were randomized to a CsA/MMF (n=35), Tacr/MMF (n=37) and Tacr/ERL (n=33) regimen, respectively. 18 drop-outs were excluded from analysis. Luminex-based HLA class I and II and MICA antibody screening was performed pretransplant and 1 and 2 years posttransplant.
Results: In patients developing BK viremia, posttransplant HLA and MICA antibody formation was not increased compared to patients without BK viremia (P≥0.256). However, pretransplant increased CD4, CD8 and CD14 cell IL-10 production was significantly related to HLA class I antibody formation in CsA/MMF or Tacr/MMF treated patients (CD4 and CD8 cells: 1 year and 2 years, p<0.0005; CD14 cells: 1 year, p=0.013) but not in Tacr/ERL treated patients. Compared to CsA/MMF and Tacr/MMF patients, Tacr/ERL patients showed downregulated IL-10 responses (CD4 cells: p=0.009, 1 year; CD19 cells: p=0.002, 4 months; CD14 cells: p=0.048, 2 years) and increased T-dependent B cell responses (p=0.004, 4 months; p=0.019, 1 year) posttransplant. Only in Tacr/ERL patients, pretransplant CD8 cell IL-10R expression was significantly associated with HLA class I antibody formation (1 year and 2 years, p<0.0005).
Conclusion: Patients developing BK viremia did not show a generally increased risk of HLA and MICA antibody formation within 2 years posttransplant. However, increased in-vitro IL-10 production pretransplant was significantly associated with posttransplant HLA class I antibody formation, with the exception of Tacr/ERL patients who showed downregulated IL-10 responses posttransplant.
This study was supported by Astellas, Novartis and Roche Pharma..
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