Dendritic Cells in Kidney Transplant Biopsy Samples Are Associated with T Cell Infiltration and Poor Allograft Survival

Abstract

Progress in long-term renal allograft survival continues to lag behind the progress in short-term transplant outcomes. Dendritic cells are the most efficient antigen-presenting cells, but surprisingly little attention has been paid to their presence in transplanted kidneys. We used dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin as a marker of dendritic cells in 105 allograft biopsy samples from 105 kidney transplant recipients. High dendritic cell density was associated with poor allograft survival independent of clinical variables. Moreover, high dendritic cell density correlated with greater T cell proliferation and poor outcomes in patients with high total inflammation scores, including inflammation in areas of tubular atrophy. We then explored the association between dendritic cells and histologic variables associated with poor prognosis. Multivariate analysis revealed an independent association between the densities of dendritic cells and T cells. In biopsy samples with high dendritic cell density, electron microscopy showed direct physical contact between infiltrating lymphocytes and cells that have the ultrastructural morphologic characteristics of dendritic cells. The origin of graft dendritic cells was sought in nine sex-mismatched recipients using XY fluorescence in situ hybridization. Whereas donor dendritic cells predominated initially, the majority of dendritic cells in late allograft biopsy samples were of recipient origin. Our data highlight the prognostic value of dendritic cell density in allograft biopsy samples, suggest a new role for these cells in shaping graft inflammation, and provide a rationale for targeting dendritic cell recruitment to promote long-term allograft survival.

High renal DC‐SIGN+ cell density is associated with severe renal lesions and poor prognosis in patients with immunoglobulin A nephropathy

“…Cross‐talk between T cells and DCs in kidneys is well recognised in mouse models, and evidence from human kidney samples suggests that a similar inter‐relationship is involved in the initiation of immunological responses in the kidney. Biopsy tissues from renal allograft and patients with ANCA‐associated vasculitis both revealed a close proximity between CD3 + T cells and DC‐SIGN + DCs . We found that DC‐SIGN + DCs clustered with CD4 + or CD8 + T cells or ICAM‐3 + T cells in renal interstitium, and we also found that most CD4 + or CD8 + T cells expressed ICAM‐3.…”

“…Moreover, the density of DC‐SIGN + cells was positively correlated with the density of CD4 + cells, CD8 + cells and ICAM‐3 + cells. These data suggest that renal DC‐SIGN + cells may induce kidney injury in IgAN by activating T cells …”

“…9,10 Although none of the DC immune markers has perfect sensitivity or specificity, DC-SIGN, also known as CD209, a 44-kDa type II membrane protein with an external mannose-binding, which participates in T cell stimulation, [11][12][13] is considered reliable in distinguishing myeloid DCs from macrophages. 14,15 In kidney transplant biopsy samples, high DC-SIGN + dendritic cell density correlated with greater T cell proliferation and poor outcomes in patients with high total inflammation scores, including inflammation in areas of tubular atrophy. 14 DC-SIGN + cells have also been found in the kidney of different types of human glomerulonephritis, 9,16 but their detailed role has not been fully assessed in IgAN patients.…”

Innate allorecognition by monocytic cells and its role in graft rejection

“…Third, whether human monocytic cells show the same features of alloreactivity, including reliance on sensing donor SIRPα polymorphism, deserves careful investigation. In fact, DCs and macrophages are present in significant numbers in chronically rejected transplants in humans, and the degree to which they are present correlates with poor kidney allograft outcomes (22). …”

Current status of alloimmunity

“…The authors observed that DC-SIGN + cell density (3.8>hpf) was adversely associated with allograft function and survival (2-yr after biopsy, r=-0.36, p<0.001), and with increased proliferation of T cells (Ki67 + ) and higher inflammation scores (ti 2-3). Interestingly, DC-SIGN + cells clustered with lymphocytes were predominantly of recipient origin, especially at the later time points (8). This observation implies a possibly harmful effect of in situ DC-SIGN + DCs on the alloimmune response and provides a rationale for targeting DCs to halt allograft inflammation.…”