Immune Responses in Renal Transplant Recipients at Risk of BK-Virus Associated Nephropathy – Impact of Three Immunosuppressive Regimens


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Abstract

IntroductionEarly detection of patients at risk of BK virus-associated graft nephropathy (BKAN) would allow prevention by early adjusting immunosuppressive treatment.Materials and MethodsWe analyzed intracellular cytokine responses, CD4+ T helper function and T-cell dependent and independent B cell responses up to 24 months post-transplant in a prospective study of 105 renal transplant recipients, who 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. BK virus (BKV) screening was performed by real time PCR with hybridization probes in serum and urine specimens.ResultsRisk of BK viremia was lowest in Tacr/ERL patients (4/30 (13%), CsA/MMF; 14/36 (39%), Tacr/MMF; 1/21 (5%), Tacr/ERL; p=0.005). BKAN was histologically proven in 6 patients (n=1, CsA/MMF; n=4, Tacr/MMF; n=1, Tacr/ERL). Tacr/ERL patients showed increased T-dependent B cell responses (p=0.004, 4 months; p=0.019, 1 year), increased CD4 cell IL4 (PMA; p=0.032, 1 year), CD14 IL6 (LPS; p=0.044, 4 months) and lowest CD4, CD19 and CD14 cell IL10 responses (CD4: PMA; p=0.009, 1year; CD19: PMA; p=0.002, 4 months; CD14: LPS; p=0.048, 2 years) "compared to CsA/MMF and Tacr/MMF patients".Intracellular CD4 and CD8 cell IL-2, IL-4 and IFN-γ production as well as B cell responses did not differ between patients with and without BK viremia. Pretransplant, increased IL-10R expression was detected in patients developing BK viremia (CD4+ T cells, p=0.005; CD8+ T cells, p=0.004; CD14+ monocytes, p=0.004). Post-transplant, we found an increased CD4 helper activity (p=0.008, 4 months), a decreased IL1β response of CD14+ monocytes (LPS; p=0.008, 4 months) and increased IL10 responses of CD4+ and CD8+ T cells (PMA; CD4: p=0.003, 1 year; p=0.038, 2 years; CD8: p=0.013, 1 year) in these patients.ConclusionOur data demonstrate a significantly lower risk of BK viremia on Tacr/ERL compared to CsA/MMF and Tacr/MMF treatment. The previously reported increased risk of donor-specific antibody (DSA) formation on everolimus treatment is supported by our finding of significantly increased T-dependent B cell responses but not the low CD4, CD8 and CD14 cell IL-10 production. Whereas pretransplant increased IL-10R expression may predict an increased risk of developing BK viremia, the increased post-transplant Th2 responses (CD4 helper activity and IL10 responses) found in these patients may increase the risk of DSA formation.

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