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Distinct peripheral blood molecular signature emerges with successful tacrolimus withdrawal in kidney transplant recipients
Author(s) -
Cravedi Paolo,
Fribourg Miguel,
Zhang Weijia,
Yi Zhengzi,
Zaslavsky Elena,
Nudelman German,
Anderson Lisa,
Hartzell Susan,
Brouard Sophie,
Heeger Peter S.
Publication year - 2020
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.15979
Subject(s) - medicine , tacrolimus , immunosuppression , peripheral blood mononuclear cell , immune system , prednisone , kidney transplantation , immunology , transplantation , kidney , transplant rejection , biology , biochemistry , in vitro
Tacrolimus (Tac) is an effective anti‐rejection agent in kidney transplantation, but its off‐target effects make withdrawal desirable. Although studies indicate that Tac can be safely withdrawn in a subset of kidney transplant recipients, immune mechanisms that underlie successful vs unsuccessful Tac removal are unknown. We performed microarray analyses of peripheral blood mononuclear cells (PBMC) RNA from subjects enrolled in the Clinical Trials in Organ Transplantation‐09 study in which we randomized stable kidney transplant recipients to Tac withdrawal or maintenance of standard immunosuppression beginning 6 months after transplant. Eight of 14 subjects attempted but failed withdrawal, while six developed stable graft function for ≥2 years on mycophenolate mofetil plus prednisone. Whereas failed withdrawal upregulated immune activation genes, successful Tac withdrawal was associated with a downregulatory and proapoptotic gene program enriched within T cells. Functional analyses suggested stronger donor‐reactive immunity in subjects who failed withdrawal without evidence of regulatory T cell dysfunction. Together, our data from a small, but unique, patient cohort support the conclusion that successful Tac withdrawal is not simply due to absence of donor‐reactive immunity but rather is associated with an active immunological process.