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

Abstract

Introduction Early detection of patients at risk of BK virus-associated graft nephropathy (BKAN) would allow prevention by early adjusting immunosuppressive treatment. Materials and Methods We 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. Results Risk 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. Conclusion Our 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.