title: Immunosuppression in cardiac graft rejection: a human in vitro model to study the potential use of new immunomodulatory drugs.
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.
authors.affiliation: Center for Research Transfer and High Education DENOthe, University of Florence, Florence, Italy. c.crescioli@dfc.unifi.it
authors.forename: Clara
authors.initials: C
authors.lastname: Crescioli
authors.forename: Roberta
authors.initials: R
authors.lastname: Squecco
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Cosmi
authors.forename: Mariangela
authors.initials: M
authors.lastname: Sottili
authors.forename: Stefania
authors.initials: S
authors.lastname: Gelmini
authors.forename: Elisa
authors.initials: E
authors.lastname: Borgogni
authors.forename: Erica
authors.initials: E
authors.lastname: Sarchielli
authors.forename: Sabino
authors.initials: S
authors.lastname: Scolletta
authors.forename: Fabio
authors.initials: F
authors.lastname: Francini
authors.forename: Francesco
authors.initials: F
authors.lastname: Annunziato
authors.forename: Gabriella Barbara
authors.initials: GB
authors.lastname: Vannelli
authors.forename: Mario
authors.initials: M
authors.lastname: Serio
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D019070:Cell Lineage / Q000187:drug effects; D002469:Cell Separation; D048430:Cell Shape / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D025802:Electric Capacitance; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D016207:Cytokines; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma