Long-term compromised immune regulation after rituximab induction in blood group incompatible living-donor renal transplantation - 5 year results of a prospective pilot study
Rolf Weimer1, Hristos Karakizlis1, Fabrice Renner1, Hartmut Dietrich1, Volker Daniel2, Caner Suesal2,3, Christian Schüttler4, Daniel Kämper1, Dominik Leicht1, Michael Wörlen1, Lene Renner1, Katrin Milchsack1, Winfried Padberg5, Gerhard Opelz2.
1Department of Internal Medicine, University of Giessen, Giessen, Germany; 2Institute of Immunology, University of Heidelberg, Heidelberg, Germany; 3Transplant Immunology Research Center of Excellence, Koç University , Istanbul, Turkey; 4Institute of Medical Virology, University of Giessen, Giessen, Germany; 5Department of Surgery, University of Giessen, Giessen, Germany
Background: An increased frequency of severe infectious diseases and BK viremia has been described after ABOi renal transplantation. As rituximab induction may alter immunoregulation in these patients, we analyzed clinically relevant immune parameters in a prospective renal transplant study up to 5 years posttransplant.
Materials and Methods: Mononuclear cell subsets (peripheral blood; lymph nodes taken during transplant surgery), intracellular cytokine responses, CD4 helper function and in-vitro B cell responses were assessed pretransplant and up to 5 years posttransplant in 85 renal transplant recipients (living donation: n=25 ABO incompatible (ABOi) and n=30 ABO compatible (ABOc); deceased donation (DD): n=30, all ABO compatible).
Results: Severe infectious diseases occurred more often in ABOi than ABOc recipients within 2 years posttransplant (11/24 (46%) versus 6/30 (20%), P=0.042) but not beyond. The incidence of BK viremia was significantly enhanced in rituximab versus non-rituximab treated patients (1 year: 9/29 (31%) versus 4/54 (7%), P=0.009; 5 years: 10/30 (33%) versus 7/53 (13%), P=0.029). After rituximab induction in ABOi recipients, counts of peripheral blood B cell subsets were profoundly downregulated even 3 years posttransplant and reached the level of non-ABOi recipients after 4 years (memory B cells after 5 years). T-dependent and T-independent B cell responses were significantly impaired in ABOi patients up to 2 years posttransplant (P=0.010 and P=0.053, respectively) whereas CD4 helper activity was not compromised. CD4+ T cell counts were significantly lower in ABOi compared to ABOc recipients at 3 and 6 months (P=0.025 and P=0.046, respectively), but showed no differences in the percentage of Tregs. In regional lymph nodes of ABOi patients, we found a significant downregulation of CD20+ but not CD19+ B cells (P<0.0005), of naive B cells (P=0.031) and short lived plasma cells (P<0.0005) at the time of transplantation.
Conclusion: An increased frequency of severe infectious diseases and BK viremia in rituximab treated ABOi renal transplant recipients may be explained by significantly downregulated CD4+ T cell counts up to 6 months and a profoundly delayed B cell repopulation, most pronounced with regard to memory B cells, together with compromised B cell responses up to 2 years posttransplant. IL-10, as a key player in chronic BK virus infection, was not upregulated in rituximab-treated ABOi transplant recipients.
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