Background: Long-term renal allograft survival continues to lag behind the progress seen in short-term transplant outcomes. Dendritic cells (DCs) are the most efficient antigen-presenting cells, but surprisingly little attention has been paid to them in transplanted kidneys.

Design: We used DC-SIGN as a marker of DCs in allograft biopsies of 105 kidney transplant recipients. Average number of DC-SIGN+ cells per high power field (hpf) was recorded. Biopsies were also stratified as having high vs. low DC-SIGN+ cell density based on the presence of more than 2 standard deviations from the mean of DC-SIGN+ cell density in control nephrectomy samples. DCs were correlated with clinical and histologic variables, with immunohistochemical staining, and with in situ hybridization data.

Results: Patients with high DCs density were associated with poor allograft survival (P<0.001), which was independent of clinical variables and interstitial fibrosis/tubular atrophy (IFTA) [[HR (95% CI): 7.06 (1.48 – 33.55), P= 0.006]. In patients with high total inflammation scores (ti>2), DCs density correlated with T cell proliferation activity as assessed by CD3/Ki67 double immunostaining (r=0.45, P=0.013) and was capable of predicting poor outcomes (ROC curve, AUC: 0.72, 95% CI: 0.56-0.88, P=0.01). Multivariate analysis indicated an independent association between the densities of T cells and DCs (P=0.02). Furthermore, ultrastructural analysis revealed direct physical contact between DCs and infiltrating lymphocytes in 12/16 (75%) of biopsies with high DCs density that had material available for electron microscopic evaluation. To understand the dynamics of this process, the origin of graft DCs was assessed in 9 sex-mismatched recipients using XY fluorescence in situ hybridization. Whereas donor DCs predominated initially, the majority of DCs in late allograft biopsies were of recipient origin.

Conclusions: Our data highlight the importance of assessing DC-SIGN+ cells in allograft biopsies, suggest a new role for DCs in shaping allograft inflammation likely by stimulating an in situ immune response, and provide a rationale for targeting DCs' recruitment to improve long-term allograft survival.

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