Danazol induces prolonged survival of fully allogeneic cardiac grafts and maintains the generation of regulatory CD4(+) cells in mice

Uchiyama M, Masateru Uchiyama, Xiangyuan Jin, Zhang Q, Qi Zhang, Hirai T, Toshihito Hirai, Bashuda H, Hisashi Bashuda, Watanabe T, Toshiaki Watanabe, Amano A, Atsushi Amano, Niimi M, Masanori Niimi
Transplant international : official journal of the European Society for Organ Transplantation · 2012 · vol. 25(3) , pp. 357–365 · doi:10.1111/j.1432-2277.2011.01427.x · PMID:22239184 · W1509507280
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Danazol treatment prolonged cardiac allograft survival in mice by suppressing cell proliferation and interferon-gamma, while upregulating interleukin-4 and 10 and increasing regulatory CD4+ CD25+ Foxp3+ cells.

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Abstract

Danazol, a derivative of testosterone, is useful for treatment of endometriosis as well as pretreatment for in vitro fertilization and embryo transfer, although its mechanisms of action are unclear. The aim of this study was to investigate the effect of danazol on alloimmune responses in murine heart transplantation. CBA male mice (H2(k) ) underwent transplantation of C57BL/6 male (H2(b) ) hearts and received a single dose of danazol (0.4, 1.2 or 4mg/kg/day) by intraperitoneal injection on the day of transplantation and for 6days thereafter. An adoptive transfer study was performed to determine whether regulatory cells were generated. The median survival time (MST) of allografts in danazol-treated (1.2 and 4mg/kg/day) mice was 28 and 63days, respectively, compared with 7days in untreated mice. Moreover, secondary CBA recipients given whole splenocytes or CD4(+) cells from primary danazol-treated (4mg/kg/day) CBA recipients 30days after transplantation had prolonged allograft survival (MSTs, 29 and 60days, respectively). Cell proliferation, interleukin (IL)-2 and interferon-γ were suppressed in danazol-treated mice, whereas IL-4 and IL-10 were up-regulated. Moreover, danazol directly suppressed allo-proliferation in a mixed leukocyte culture. Flow cytometry showed an increased CD4(+) CD25(+) Foxp3(+) cell population in splenocytes from danazol-treated mice. Danazol prolongs cardiac allograft survival and generates regulatory CD4(+) cells.

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Condition tags

endometriosis

MeSH descriptors

Danazol Graft Survival Heart Transplantation Immunosuppressive Agents T-Lymphocytes, Regulatory Adoptive Transfer Adoptive Transfer Animals Animals Biomarkers Biomarkers Biomarkers Cytokines Cytokines Cytokines Danazol Danazol Danazol Drug Administration Schedule Drug Administration Schedule

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