Chronic antibody-mediated rejection (CAMR) represents the main cause of kidney graft loss. To uncover the molecular mechanisms underlying this condition, we characterized the molecular signature of peripheral blood mononuclear cells (PBMCs) and, separately, of CD4(+) T lymphocytes isolated from CAMR patients, compared to kidney transplant recipients with normal graft function and histology. We enrolled 29 patients with biopsy-proven CAMR, 29 stable transplant recipients (controls), and 8 transplant recipients with clinical and histological evidence of interstitial fibrosis/tubular atrophy. Messenger RNA and microRNA profiling of PBMCs and CD4(+) T lymphocytes was performed using Agilent microarrays in eight randomly selected patients per group from CAMR and control subjects. Results were evaluated statistically and by functional pathway analysis (Ingenuity Pathway Analysis) and validated in the remaining subjects. In PBMCs, 45 genes were differentially expressed between the two groups, most of which were up-regulated in CAMR and were involved in type I interferon signalling. In the same patients, 16 microRNAs were down-regulated in CAMR subjects compared to controls: four were predicted modulators of six mRNAs identified in the transcriptional analysis. In silico functional analysis supported the involvement of type I interferon signalling. To further confirm this result, we investigated the transcriptomic profiles of CD4(+) T lymphocytes in an independent group of patients, observing that the activation of type I interferon signalling was a specific hallmark of CAMR. In addition, in CAMR patients, we detected a reduction of circulating BDCA2(+) dendritic cells, the natural type I interferon-producing cells, and their recruitment into the graft along with increased expression of MXA, a type I interferon-induced protein, at the tubulointerstitial and vascular level. Finally, interferon alpha mRNA expression was significantly increased in CAMR compared to control biopsies. We conclude that type I interferon signalling may represent the molecular signature of CAMR.
One of the major concerns in organ transplantation is the early detection of humoral rejection, through improved diagnostic and prognostic biomarkers. Long-term survival of renal allografts is significantly lower in recipients developing donor-specific anti-HLA antibodies (DSAs) either pretransplant or posttransplant. Patients can form antibodies following blood transfusions, pregnancies or previous transplants. DSAs can lead to endothelial damage through complement-dependent or independent pathways. Universal testing of kidney transplant patients and careful monitoring of graft function if DSAs are detected are recommended. Since there are different techniques to detect DSAs presence and serum levels, nephrologists have to face challenges in their interpretation due to variable sensitivity and specificity. Moreover, other biomarkers of rejection (T-cell reactivity, gene expression pattern modulation, early features of immunological damage in protocol renal biopsies) may be adopted together with DSAs detection tools, thus providing a global approach to the issue. To date, however, there are no well-defined strategies of intervention in cases of humoral graft damage. Future resolution of both interpretative and therapeutic concerns will make DSAs monitoring a very effective way to predict incoming immunological events. Therefore, an operative protocol for DSAs detection in renal recipients has been illustrated.
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