Infiltration of Macrophages Correlates with Severity of Allograft Rejection and Outcome in Human Kidney Transplantation

Abstract

ObjectiveDespite substantial progress in recent years, graft survival beyond the first year still requires improvement. Since modern immunosuppression addresses mainly T-cell activation and proliferation, we studied macrophage infiltration into the allografts of 103 kidney transplant recipients during acute antibody and T-cell mediated rejection. Macrophage infiltration was correlated with both graft function and graft survival until month 36 after transplantation.ResultsMacrophage infiltration was significantly elevated in antibody-mediated and T-cell mediated rejection, but not in kidneys with established IFTA. Treatment of rejection with steroids was less successful in patients with more prominent macrophage infiltration into the allografts. Macrophage infiltration was accompanied by increased cell proliferation as well as antigen presentation. With regard to the compartmental distribution severity of T-cell-mediated rejection was correlated to the amount of CD68+ cells especially in the peritubular and perivascular compartment, whereas biopsies with ABMR showed mainly peritubular CD68 infiltration. Furthermore, severity of macrophage infiltration was a valid predictor of resulting creatinine values two weeks as well as two and three years after renal transplantation as illustrated by multivariate analysis. Additionally performed ROC curve analysis showed that magnitude of macrophage infiltration (below vs. above the median) was a valid predictor for the necessity to restart dialysis. Having additionally stratified biopsies in accordance to the magnitude of macrophage infiltration, differential CD68+ cell infiltration was reflected by striking differences in overall graft survival.ConclusionThe differences in acute allograft rejection have not only been reflected by different magnitudes of macrophage infiltration, but also by compartment-specific infiltration pattern and subsequent impact on resulting allograft function as well as need for dialysis initiation. There is a robust relationship between macrophage infiltration, accompanying antigen-presentation and resulting allograft function.

Landscape of innate immune system transcriptome and acute T cell–mediated rejection of human kidney allografts

“…The role of APCs is also played by macrophages (8, 11). Our finding of increased macrophages in TCMR is consistent with immunohistochemical data demonstrating increased CD68 + macrophages in allograft biopsies of kidney recipients with TCMR (4,55). We found increased M1 macrophages in TCMR, which are activated by IFN-γ, are proinflammatory, and act as an APC (56).…”

Neutrophil derived CSF1 induces macrophage polarization and promotes transplantation tolerance

“…1 Early after transplantation, macrophage precursors infiltrate the allograft and represent the major cell subset during antibody and T-cell mediated rejection. 2,3 These inflammatory macrophages are characterized phenotypically by their high expression of Ly6C (Ly6C hi or M1). 4 Recent evidence suggests that macrophages are also important during the induction of transplantation tolerance.…”

Inflammatory macrophage–associated 3-gene signature predicts subclinical allograft injury and graft survival

“…Macrophage infiltration has been implicated in both AR (13) and chronic graft failure (10,11), yet a precise role for this cell type in organ transplantation remains unclear (12). Macrophages take on diverse phenotypic states in response to environmental stimuli, with activation characterized by a spectrum of transcriptional reprogramming (14), ranging from an antiinflammatory phenotype in the presence of IL-4 or IL-10 to a proinflammatory phenotype in the presence of IFN-γ, referred to as M(IL-4), M(IL-10), and M(IFN-γ), respectively (15).…”