Intragraft Blood Dendritic Cell Antigen-1–Positive Myeloid Dendritic Cells Increase during BK Polyomavirus–Associated Nephropathy

Abstract

Although both polyomavirus infection and T cell-mediated rejection (TCMR) are characterized by tubulointerstitial inflammation in the renal allograft, these conditions are treated with opposing therapeutic regimens. To gain more insight into the differences between antiviral and alloimmune responses, we performed a case-control study, in which we immunophenotyped the inflammatory infiltrates in renal biopsy specimens with BK polyomavirus-associated nephropathy (BKPyVAN) and specimens with TCMR. Compared with TCMR, BKPyVAN was diagnosed later after transplantation; therefore, BKPyVAN specimens showed more chronic damage than TCMR specimens showed. However, TCMR and BKPyVAN specimens had comparable levels of tubulointerstitial inflammation. Adjustment for confounders in various multivariable models revealed more blood dendritic cell antigen-1 + (BDCA-1 + ) myeloid dendritic cells (mDCs) present during BKPyVAN (odds ratio, 2.31; 95% confidence interval, 1.03 to 5.16; P=0.04) than during TCMR. Double immunostaining for SV40 and BDCA-1 showed that, during BKPyVAN, BDCA-1 + mDCs localized in proximity to the polyomavirus-infected tubular epithelial cells. We ensured that time of biopsy after transplantation was not a confounding factor by including additional specimens with late TCMR and protocol biopsy specimens matched for biopsy time. These additional specimens showed amounts of BDCA-1 + mDCs comparable with amounts in the early TCMR specimens. These results suggest that BDCA-1 + mDCs, known to be involved in the antiviral immune response during various viral infections, might have a pivotal role during BKPyVAN infection in the grafted kidney.

Non-permissive human conventional CD1c+dendritic cells enabletrans-infection of human primary renal tubular epithelial cells and protect BK polyomavirus from neutralization

“…We demonstrated that although renal CD1c+ DC are refractory to BKPyV infection they remain able to capture virions and trans-infect hRPTEC in vitro. CD1c+ DC are normally present in the human renal interstitium surrounding the proximal tubules and glomeruli (29,34,71) but in PVAN lesions, a significant increase in infiltrating CD1c+ DC is documented (34). Whether the CD1c+ DC infiltrate has a key role in viral spreading in vivo deserves to be investigated through combined multidimensional imaging techniques and spatial RNA/DNA sequencing.…”

“…HRPTEC were shown to negatively regulate cDC activation subsequently leading to the retention of cDC in renal tissues as immature cells (31)(32)(33) putatively decreasing antigen presentation by DC. Early stage PVAN is marked by a CD1c + cDC infiltrate (34) and mild inflammation (30,35,36). Whether cDC play a role in the pathophysiology of the BKPyV infection apart from their ability to trigger and sustain specific immune responses is still unclear.…”

Analysis of dendritic cells and ischemia-reperfusion changes in postimplantation renal allograft biopsies may serve as predictors of subsequent rejection episodes

“…[31][32][33] Myeloid DCs outnumber plasmacytoid DCs in noninflamed as well as in inflamed biopsies. [31][32][33] Although none of the DC immune markers has perfect sensitivity or specificity, BDCA-1 (CD1c) and DC-SIGN (CD209) are both considered acceptable markers to identify kidney myeloid DCs, 32,34,35 with the former being more specific if one were to exclude inflammatory DCs, which constitute a less defined subtype of leukocytes that accumulate during inflammatory conditions.…”

“…For the purpose of this study, total DCs, myeloid DCs, and plasmacytoid DCs were identified by circumferential cellular HLA-DR, BDCA-1, and CD123 immunostaining, respectively. 32,35,[38][39][40] Immunostaining was performed on formalin-fixed, paraffin-embedded tissue (detailed in Supplementary Material), and DCs were manually assessed as follows:…”

BK Polyomavirus and the Transplanted Kidney

“…102 Hackstein and colleagues 104 demonstrated that all DC subtypes were lower in patients treated with long term immunosuppression (more than a year) in kidney transplant recipients compared to age and sex matched controls, independently of total leucocyte count. Despite this possible DC deficiency, Yapici and colleagues 105 found significant amount of myeloid DC in PVAN biopsies and those cells were found closely to BK virus infected tubules, suggesting a role in PVAN physiopathology.…”