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Pathways to acute humoral rejection.

ABSTRACT: Acute humoral rejection, also known as acute vascular rejection, is a devastating condition of organ transplants and a major barrier to clinical application of organ xenotransplantation. Although initiation of acute humoral or vascular rejection is generally linked to the action of antibodies and complement on the graft, other factors such as ischemia, platelets, T cells, natural killer cells, and macrophages have also been implicated. Central to any understanding of the pathogenesis of acute humoral rejection, and to developing means of preventing it, is to know whether these factors injure the graft independently or through one or few pathways. We addressed this question by examining early events in a severe model of vascular rejection in which guinea pig hearts transplanted heterotopically into rats treated with cobra venom factor (CVF) develop disease over 72 hours. The early steps in acute vascular rejection were associated with expression of a set of inflammatory genes, which appeared to be controlled by availability of interleukin (IL)-1. Interruption of IL-1 signaling by IL-1 receptor antagonist (IL-1ra) averted expression of these genes and early tissue changes, including coagulation and influx of inflammatory cells. These findings suggest IL-1 plays an important role in initiation of acute humoral rejection.

SUBMITTER: Saadi S

PROVIDER: S-EPMC1614720 | biostudies-literature | 2004 Mar

REPOSITORIES: biostudies-literature

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Pathways to acute humoral rejection.

Saadi Soheyla S Takahashi Takao T Holzknecht Robert A RA Platt Jeffrey L JL

The American journal of pathology 20040301 3

Acute humoral rejection, also known as acute vascular rejection, is a devastating condition of organ transplants and a major barrier to clinical application of organ xenotransplantation. Although initiation of acute humoral or vascular rejection is generally linked to the action of antibodies and complement on the graft, other factors such as ischemia, platelets, T cells, natural killer cells, and macrophages have also been implicated. Central to any understanding of the pathogenesis of acute hu ...[more]

PMID: 14982860

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Project description:Acute cellular rejection (ACR) and hepatitis C virus (HCV) recurrence (HCVrec) are common complications after liver transplantation (LT) in HCV patients, who share common clinical and histological features, making a differential diagnosis difficult. Fifty-three liver allograft samples from unique HCV LT recipients were studied using microarrays, including a training set (n = 32) and a validation set (n = 19). Two no-HCV-ACR samples from LT recipients were also included. Probe set intensity values were obtained using the robust multiarray average method (RMA) method. Analysis of variance identified statistically differentially expressed genes (P ? 0.005). The limma package was used to fit the mixed-effects models using a restricted maximum likelihood procedure. The last absolute shrinkage and selection operator (LASSO) model was fit with HCVrec versus ACR as the dependent variable predicted. N-fold cross-validation was performed to provide an unbiased estimate of generalization error. A total of 179 probe sets were differentially expressed among groups, with 71 exclusive genes between HCVrec and HCV-ACR. No differences were found within ACR group (HCV-ACR vs. no-HCV-ACR). Supervised clustering analysis displayed two clearly independent groups, and no-HCV-ACR clustered within HCV-ACR. HCVrec-related genes were associated with a cytotoxic T-cell profile, and HCV-ACR-related genes were associated with the inflammatory response. The best-fitting LASSO model classifier accuracy, including 15 genes, has an accuracy of 100% in the training set. N-fold cross-validation accuracy was 78.1%, and sensitivity, specificity and positive and negative predictive values were 50.0%, 90.9%, 71.4% and 80.0%, respectively. Arginase type II (ARG2), ethylmalonic encephalopathy 1 (ETHE1), transmembrane protein 176A (TMEM176A) and TMEM176B genes were significantly confirmed in the validation set. A molecular signature capable of distinguishing HCVrec and ACR in HCV LT recipients was identified and validated.

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Pathways to acute humoral rejection.

Publications

Pathways to acute humoral rejection.

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