Immunomodulatory effects of BXL-01-0029, a less hypercalcemic vitamin D analogue, in human cardiomyocytes and T cells.
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 IFNgamma and TNFalpha-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.
Sottili
M
M
Excellence Center for Research Transfer and High Education DENOthe, University of Florence, Italy.
Cosmi
L
L
Borgogni
E
E
Sarchielli
E
E
Maggi
L
L
Francalanci
M
M
Vannelli
G B
GB
Ronconi
E
E
Adorini
L
L
Annunziato
F
F
Romagnani
P
P
Serio
M
M
Crescioli
C
C
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D002762:Cholecalciferol / Q000031:analogs & derivatives / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D009173:Mycophenolic Acid / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D018167:Receptors, Calcitriol / Q000819:agonists; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D000096743:Interferon gamma Receptor
D054357:Chemokine CXCL10; D002762:Cholecalciferol; D007166:Immunosuppressive Agents; D007371:Interferon-gamma; D015759:Ionomycin; D009173:Mycophenolic Acid; D016328:NF-kappa B; D018167:Receptors, Calcitriol; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D013755:Tetradecanoylphorbol Acetate; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor; C494079:STAT1 protein, human