Referenced in: none

Automatically associated channels: Kv10.1

Title: Immunosuppression in cardiac graft rejection: a human in vitro model to study the potential use of new immunomodulatory drugs.

Authors: Clara Crescioli, Roberta Squecco, Lorenzo Cosmi, Mariangela Sottili, Stefania Gelmini, Elisa Borgogni, Erica Sarchielli, Sabino Scolletta, Fabio Francini, Francesco Annunziato, Gabriella Barbara Vannelli, Mario Serio

Journal, date & volume: Exp. Cell Res., 2008 Apr 1 , 314, 1337-50

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/18291365

Abstract
CXCL10-CXCR3 axis plays a pivotal role in cardiac allograft rejection, so that targeting CXCL10 without inducing generalized immunosuppression may be of therapeutic significance in allotransplantation. Since the role of resident cells in cardiac rejection is still unclear, we aimed to establish reliable human cardiomyocyte cultures to investigate Th1 cytokine-mediated response in allograft rejection. We used human fetal cardiomyocytes (Hfcm) isolated from fetal hearts, obtained after legal abortions. Hfcm expressed specific cardiac lineage markers, specific cardiac structural proteins, typical cardiac currents and generated ventricular action potentials. Thus, Hfcm represent a reliable in vitro tool for allograft rejection research, since they resemble the features of mature cells. Hfcm secreted CXCL10 in response to IFNgamma and TNFalphaalpha; this effect was magnified by cytokine combination. Cytokine synergy was associated to a significant TNFalpha-induced up-regulation of IFNgammaR. The response of Hfcm to some currently used immunosuppressive drugs compared to rosiglitazone, a peroxisome proliferator-activated receptor gamma agonist and Th1-mediated response inhibitor, was also evaluated. Only micophenolic acid and rosiglitazone halved CXCL10 secretion by Hfcm. Given the pivotal role of IFNgamma-induced chemokines in Th1-mediated allograft rejection, these preliminary results suggest that the combined effects of immunosuppressive agents and rosiglitazone could be potentially beneficial to patients receiving heart transplants.