Dataset Information

The role of C4d deposition in the diagnosis of antibody-mediated rejection after lung transplantation.

ABSTRACT: Antibody-mediated rejection (AMR) is an increasingly recognized form of lung rejection. C4d deposition has been an inconsistent finding in previous reports and its role in the diagnosis has been controversial. We conducted a retrospective single-center study to characterize cases of C4d-negative probable AMR and to compare these to cases of definite (C4d-positive) AMR. We identified 73 cases of AMR: 28 (38%) were C4d-positive and 45 (62%) were C4d-negative. The two groups had a similar clinical presentation, and although more patients in the C4d-positive group had neutrophilic capillaritis (54% vs. 29%, P = .035), there was no significant difference in the presence of other histologic findings. Despite aggressive antibody-depleting therapy, 19 of 73 (26%) patients in the overall cohort died within 30 days, but there was no significant difference in freedom from chronic lung allograft dysfunction (CLAD) or survival between the two groups. We conclude that AMR may cause allograft failure, but that the diagnosis requires a multidisciplinary approach and a high index of suspicion. C4d deposition does not appear to be a necessary criterion for the diagnosis, and although some cases may respond initially to therapy, there is a high incidence of CLAD and poor survival after AMR.

SUBMITTER: Aguilar PR

PROVIDER: S-EPMC5878693 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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The role of C4d deposition in the diagnosis of antibody-mediated rejection after lung transplantation.

Aguilar P R PR Carpenter D D Ritter J J Yusen R D RD Witt C A CA Byers D E DE Mohanakumar T T Kreisel D D Trulock E P EP Hachem R R RR

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20171111 4

Antibody-mediated rejection (AMR) is an increasingly recognized form of lung rejection. C4d deposition has been an inconsistent finding in previous reports and its role in the diagnosis has been controversial. We conducted a retrospective single-center study to characterize cases of C4d-negative probable AMR and to compare these to cases of definite (C4d-positive) AMR. We identified 73 cases of AMR: 28 (38%) were C4d-positive and 45 (62%) were C4d-negative. The two groups had a similar clinical ...[more]

PMID: 28992372

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Project description:Chronic antibody-mediated rejection (CAMR) represents the main cause of kidney graft loss, but its pathogenesis is unclear. In order to uncover the molecular mechanisms underlying this condition, we characterized the molecular signature of circulating peripheral blood mononuclear cells and, separately, of CD4+ T lymphocytes isolated from CAMR patients compared to kidney transplant recipients with normal graft function and histology. In total peripheral lympho-monocytes, forty-five genes resulted differentially expressed between the two groups, most of them were up-regulated in CAMR and were involved in type I interferon signaling. In addition, in the same set of patients, 16 microRNAs resulted down-regulated in CAMR subjects compared to controls: 4 were predicted modulators of 6 mRNAs identified in the transcriptional analysis. In silico functional analysis supported the involvement of type I interferon signaling. To further confirm this hypothesis, we investigated the transcriptomic profiles of CD4+ T lymphocytes in an independent group of patients and we observed that the activation of type I interferon signaling 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 an increased expression of MXA, a type I interferon-induced protein, at tubulointerstitial and vascular level. In conclusion, our data suggest that type I interferon signaling may represent the molecular signature of CAMR. For microarray analysis, we studied 5 patients included into the control-group and 4 included into the study group. The control group was represented by renal transplant recipients undergoing protocol graft biopsies, with normal renal function and histology, in the absence of circulating anti-HLA antibodies. Study group patients showed clinical and histological evidence of CAMR according to Banff 2011 criteria.

Project description:Chronic antibody-mediated rejection (CAMR) represents the main cause of kidney graft loss, but its pathogenesis is unclear. In order to uncover the molecular mechanisms underlying this condition, we characterized the molecular signature of circulating peripheral blood mononuclear cells and, separately, of CD4+ T lymphocytes isolated from CAMR patients compared to kidney transplant recipients with normal graft function and histology. In total peripheral lympho-monocytes, forty-five genes resulted differentially expressed between the two groups, most of them were up-regulated in CAMR and were involved in type I interferon signaling. In addition, in the same set of patients, 16 microRNAs resulted down-regulated in CAMR subjects compared to controls: 4 were predicted modulators of 6 mRNAs identified in the transcriptional analysis. In silico functional analysis supported the involvement of type I interferon signaling. To further confirm this hypothesis, we investigated the transcriptomic profiles of CD4+ T lymphocytes in an independent group of patients and we observed that the activation of type I interferon signaling 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 an increased expression of MXA, a type I interferon-induced protein, at tubulointerstitial and vascular level. In conclusion, our data suggest that type I interferon signaling may represent the molecular signature of CAMR. For microarray analysis, we studied 8 patients included into the control-group and 10 included into the study group. The control group was represented by renal transplant recipients undergoing protocol graft biopsies, with normal renal function and histology, in the absence of circulating anti-HLA antibodies. Study group patients showed clinical and histological evidence of CAMR according to Banff 2011 criteria.

Project description:Antibody-mediated rejection (AMR) remains a refractory rejection after donor-specific antibody (DSA)-positive or blood-type incompatible liver transplantation (LT), even in the era of pre-transplant rituximab desensitization. This is due to the lack of not only effective post-transplant treatments but also robust animal models to develop/validate new interventions. Orthotopic LT from male Dark Agouti (DA) to male Lewis (LEW) rats was used to develop a rat LT-AMR model. LEW were pre-sensitized by a preceding skin transplantation from DA 4-6 weeks before LT (Group-PS), while sham procedure was performed in non-sensitized controls (Group-NS). Tacrolimus was daily administered until post-transplant day (PTD)-7 or sacrifice to suppress cellular rejections. Using this model, we validated the efficacy of anti-C5 antibody (Anti-C5) for LT-AMR. Group-PS+Anti-C5 received Anti-C5 intravenously on PTD-0 and -3. Group-PS showed increased anti-donor (DA) antibody-titers (P <0.001) and more C4d deposition in transplanted livers than in Group-NS (P <0.001). Alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bile acid (TBA), and total bilirubin (T-Bil) were all significantly higher in Group-PS than in Group-NS (all P <0.01). Thrombocytopenia (P <0.01), coagulopathies (PT-INR, P =0.04), and histopathological deterioration (C4d+h-score, P <0.001) were also confirmed in Group-PS. Anti-C5 administration significantly lowered anti-DA IgG (P <0.05), resulting in decreased ALP, TBA, and T-Bil on PTD-7 than in Group-PS (all P <0.01). Histopathological improvement was also confirmed on PTD-1, -3, and -7 (all P <0.001). Of the 9,543 genes analyzed by RNA sequencing, 575 genes were upregulated in LT-AMR (Group-PS vs. Group-NS). Of these, 6 were directly associated with the complement cascades. In particular, Ptx3, Tfpi2, and C1qtnf6 were specific to the classical pathway. Volcano plot analysis identified 22 genes that were downregulated by Anti-C5 treatment (Group-PS+Anti-C5 vs. Group-PS). Of these, Anti-C5 significantly down-regulated Nfkb2, Ripk2, Birc3, and Map3k1, the key genes that were amplified in LT-AMR. Notably, just two doses of Anti-C5 only on PTD-0 and -3 significantly improved biliary injury and liver fibrosis up to PTD-100, leading to better long-term animal survival (P =0.02). We newly developed a rat model of LT-AMR that meets all the Banff diagnostic criteria and demonstrated the efficacy of Anti-C5 antibody for LT-AMR.

Dataset Information

The role of C4d deposition in the diagnosis of antibody-mediated rejection after lung transplantation.

Publications

The role of C4d deposition in the diagnosis of antibody-mediated rejection after lung transplantation.

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