The physiopathology of immune-mediated tissue injury of acute allograft rejection is not completely understood. Although several mechanicistic experiments have been conducted in vitro and in animal models, only few hypotheses have been confirmed in humans and, paradoxically, findings in humans often lack mechanistic explanations. Before high throughput gene expression analysis advent (microarrays), the use of optic microscopy, immunohistochemistry and reverse transcriptase protein chain reaction (RT-PCR), allowed the in situ evaluation of only a few variables simultaneously. Conversely, the integration of the aforementioned methodologies with microarrays has cast new lights on unrecognized mechanisms that are now deemed as central for the development of the alloresponse. Pari passu with underlining the molecular heterogeneity between apparently similar lesions, this approach has also unveiled the activation of common mechanisms among clinically and histopathologically different lesions. Universal standardization procedures were slowly and incompletely developed while microarray methodology was at its dawn and in continuing evolution. Moreover, the lack of uniformity among different investigating groups (in terms of sample collection, microarray platforms, genes coverage, bioinformatic analysis and study design) has probably been one of the reasons accounting for the relatively small overlap in the relevant genes detected by individual studies. Nevertheless, in spite of the aforementioned limitations, it is difficult to ignore the relevance of those gene/gene pathways consistently detected as simultaneously upregulated among independent studies even in the presence of such technical and analytic limitations. The aim of this chapter is to shed some light on the physiopathology of allorejection, pointing at the activation of genes and molecular pathways thought to play a leading role in the development and/or maintenance of the tissue destructive process, which characterizes acute rejection. Rather than trying to explain the cause of the activation of this acute response, we will try to depict a molecular fresco of the battlefield where tissue destruction is fought. To this purpose, we will focus on human microarray studies performed on tissue biopsies taken during episodes of acute allograft rejection, providing also a brief description of the results obtained with other approaches (RT-PCR or immunohistochemistry). We will apply the knowledge derived from mechanicistic studies and from inductive and deductive reasoning to explain the possible roles and relations of the described pathways.
|Title of host publication||Immunologic Signatures of Rejection|
|Publisher||Springer New York|
|Number of pages||41|
|Publication status||Published - 1 Jan 2011|
ASJC Scopus subject areas