Novel Insights into Lung Transplant Rejection by Microarray Analysis

Abstract

Gene expression microarrays can estimate the prevalence of mRNA for thousands of genes in a small sample of cells or tissue. Organ transplant researchers are increasingly using microarrays to identify specific patterns of gene expression that predict and characterize acute and chronic rejection, and to improve our understanding of the mechanisms underlying organ allograft dysfunction. We used microarrays to assess gene expression in bronchoalveolar lavage cell samples from lung transplant recipients with and without acute rejection on simultaneous lung biopsies. These studies showed increased expression during acute rejection of genes involved in inflammation, apoptosis, and T-cell activation and proliferation. We also studied gene expression during the evolution of airway obliteration in a murine heterotopic tracheal transplant model of chronic rejection. These studies demonstrated specific patterns of gene expression at defined time points after transplantation in allografts, whereas gene expression in isografts reverted back to that of native tracheas within 2 wk after transplantation. These studies demonstrate the potential power of microarrays to identify biomarkers of acute and chronic lung rejection. The application of new genetic, genomic, and proteomic technologies is in its infancy, and the microarray-based studies described here are clearly only the beginning of their application to lung transplantation. The massive amount of data generated per tissue or cell sample has spawned an outpouring of invention in the bioinformatics field, which is developing methodologies to turn data into meaningful and reproducible clinical and mechanistic inferences. Keywords: allograft rejection; lung transplantation; microarrayLung and heart-lung transplants, introduced into clinical practice in 1981, have now been performed in over 20,000 individuals worldwide for whom effective medical therapy was not available (1). These procedures have been highly beneficial for many recipients, with 2-yr survival rates of approximately 70% and dramatic improvements in quality of life. Despite these remarkable successes, problems remain, and long-term survival rates for lung transplant recipients are considerably lower than those observed in kidney, heart, and liver recipients. This is due, in large part, to the development of chronic allograft rejection despite administration of immunosuppressive medications.

MicroRNA Signature of Intestinal Acute Cellular Rejection in Formalin-Fixed Paraffin-Embedded Mucosal Biopsies

“…Recent advances in genetic information using high throughput microarray analysis has revealed that there are quite different transcriptome patterns according to the rejection status after solid organ transplantation (5)(6)(7)(8). We already revealed that small bowel allografts undergoing ACR show distinct mRNA expression profiles involving immune, inflammatory and apoptosis genes reflect the histopathological changes in bowel biopsies and provided novel insights into these pathways operative in alloreactive inflammation (9).…”

Automatic Event Detection in Lung Transplant Recipients Based on Home Monitoring of Spirometry and Symptoms

“…14 Records of transbronchial lung biopsies with graded acute rejection and infections 15 were combined into the event list. The absence of events was determined by the lack of evidence of event occurrence.…”

Lung Transplantation: Advances and Roadblocks in Treatment

“…(Madsen et al 2010) A 2007 study by Lande et al describes the use of microarray analysis to observe relative gene expression levels of cytokines thought in be involved in acute rejection in the BAL fluid of AR patients. (Lande et al 2007) …”