Current immunosuppressive protocols have reduced rejection occurrence in heart transplantation; nevertheless, management of heart transplant recipients is accompanied by major adverse effects, due to drug doses close to toxic range. In allograft rejection, characterized by T-helper 1 (Th1) cell-mediated response, the CXCL10-CXCR3 axis plays a pivotal role in triggering a self-promoting inflammatory loop. Indeed, CXCL10 intragraft production, required for initiation and development of graft failure, supports organ infiltration by Th1 cells. Thus, targeting the CXCL10-CXCR3 axis while avoiding generalized immunosuppression, may be of therapeutic significance. Based on preclinical evidence for immunoregulatory properties of vitamin D receptor agonists, we propose that a less hypercalcemic vitamin D analogue, BXL-01-0029, might have the potential to contribute to rejection management. We investigated the effect of BXL-01-0029 on CXCL10 secretion induced by proinflammatory stimuli, both in human isolated cardiomyocytes (Hfcm) and purified CD4+ T cells. Mycophenolic acid (MPA), the active agent of mycophenolate mofetil, was used for comparison. BXL-01-0029 inhibited IFNγ and TNFα-induced CXCL10 secretion by Hfcm more potently than MPA, impairing cytokine synergy and pathways. BXL-01-0029 reduced also CXCL10 protein secretion and gene expression by CD4+ T cells. Furthermore, BXL-01-0029 did not exert any toxic effect onto both cell types, suggesting its possible use as a dose-reducing agent for conventional immunosuppressive drugs in clinical transplantation. © 2008 Elsevier Inc. All rights reserved.

Immunomodulatory effects of BXL-01-0029, a non hypercalcemic vitamin D analogue, in human cardiomyocytes and T cells / M. SOTTILI; L. COSMI; E. BORGOGNI; E. SARCHIELLI; L. MAGGI; M. FRANCALANCI; G.B VANNELLI; E. RONCONI; L. ADORINI; F. ANNUNZIATO; P. ROMAGNANI; M. SERIO; C. CRESCIOLI. - In: EXPERIMENTAL CELL RESEARCH. - ISSN 0014-4827. - STAMPA. - 315:(2009), pp. 264-273. [10.1016/j.yexcr.2008.10.025]

Immunomodulatory effects of BXL-01-0029, a non hypercalcemic vitamin D analogue, in human cardiomyocytes and T cells.

SOTTILI, MARIANGELA;COSMI, LORENZO;MAGGI, LAURA;VANNELLI, GABRIELLA;RONCONI, ELISA;ANNUNZIATO, FRANCESCO;ROMAGNANI, PAOLA;SERIO, MARIO;
2009

Abstract

Current immunosuppressive protocols have reduced rejection occurrence in heart transplantation; nevertheless, management of heart transplant recipients is accompanied by major adverse effects, due to drug doses close to toxic range. In allograft rejection, characterized by T-helper 1 (Th1) cell-mediated response, the CXCL10-CXCR3 axis plays a pivotal role in triggering a self-promoting inflammatory loop. Indeed, CXCL10 intragraft production, required for initiation and development of graft failure, supports organ infiltration by Th1 cells. Thus, targeting the CXCL10-CXCR3 axis while avoiding generalized immunosuppression, may be of therapeutic significance. Based on preclinical evidence for immunoregulatory properties of vitamin D receptor agonists, we propose that a less hypercalcemic vitamin D analogue, BXL-01-0029, might have the potential to contribute to rejection management. We investigated the effect of BXL-01-0029 on CXCL10 secretion induced by proinflammatory stimuli, both in human isolated cardiomyocytes (Hfcm) and purified CD4+ T cells. Mycophenolic acid (MPA), the active agent of mycophenolate mofetil, was used for comparison. BXL-01-0029 inhibited IFNγ and TNFα-induced CXCL10 secretion by Hfcm more potently than MPA, impairing cytokine synergy and pathways. BXL-01-0029 reduced also CXCL10 protein secretion and gene expression by CD4+ T cells. Furthermore, BXL-01-0029 did not exert any toxic effect onto both cell types, suggesting its possible use as a dose-reducing agent for conventional immunosuppressive drugs in clinical transplantation. © 2008 Elsevier Inc. All rights reserved.
2009
315
264
273
M. SOTTILI; L. COSMI; E. BORGOGNI; E. SARCHIELLI; L. MAGGI; M. FRANCALANCI; G.B VANNELLI; E. RONCONI; L. ADORINI; F. ANNUNZIATO; P. ROMAGNANI; M. SERIO; C. CRESCIOLI
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/321943
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