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Suppressed calcineurin‐dependent gene expression identifies lung allograft recipients at increased risk of infection
Author(s) -
Greenland John R.,
Chong Tiffany,
Wang Angelia S.,
Martinez Emily,
Shrestha Pavan,
Kukreja Jasleen,
Hays Steven R.,
Golden Jeffrey A.,
Singer Jonathan P.,
Tang Qizhi
Publication year - 2018
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.14886
Subject(s) - tacrolimus , calcineurin , medicine , immunosuppression , immunology , lung transplantation , whole blood , ex vivo , lung , cytokine , transplantation , in vivo , pharmacology , gastroenterology , biology , microbiology and biotechnology
Lung transplant immunosuppression regimens generally include the calcineurin inhibitor tacrolimus. We hypothesized that mean residual expression (MRE) of calcineurin‐dependent genes assesses rejection and infection risk better than does tacrolimus trough. We prospectively followed 44 lung allograft recipients at 2 to 18 months posttransplant and measured changes in whole blood interleukin‐2, interferon‐γ, and granulocyte‐macrophage colony‐stimulating factor gene expression following a tacrolimus dose. Posttransplant duration, immunosuppressive medication levels, and bronchoscopic rejection and infection assessments were compared with MRE by using generalized‐estimating equation–adjusted models. Prednisolone effect on MRE was assessed ex vivo in blood samples from nontransplanted controls. Tacrolimus concentration inhibiting 50% of cytokine production (IC 50 ) was measured in a pretransplant subset. Results showed that MRE did not change with diagnosis of rejection but that airway infection was associated with a 20% absolute decrease (95% confidence interval 11%‐29%). MRE increased with time after transplant but was not associated with tacrolimus trough. Interestingly, MRE correlated inversely with corticosteroid dose in the study cohort and ex vivo. Pretransplant tacrolimus IC 50 depended on the cytokine measured and varied between individuals, suggesting a range in baseline responses to tacrolimus. We conclude that MRE identifies infection risk in lung allograft recipients, potentially integrating calcineurin inhibitor and steroid effects on lymphocyte effector function.