RT Journal Article
SR Electronic
T1 Aldehyde Dehydrogenase Expression Drives Human Regulatory T Cell Resistance to Posttransplantation Cyclophosphamide
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP 211ra157
OP 211ra157
DO 10.1126/scitranslmed.3006960
VO 5
IS 211
A1 Kanakry, Christopher G.
A1 Ganguly, Sudipto
A1 Zahurak, Marianna
A1 Bolaños-Meade, Javier
A1 Thoburn, Christopher
A1 Perkins, Brandy
A1 Fuchs, Ephraim J.
A1 Jones, Richard J.
A1 Hess, Allan D.
A1 Luznik, Leo
YR 2013
UL http://stm.sciencemag.org/content/5/211/211ra157.abstract
AB High-dose, posttransplantation cyclophosphamide (PTCy) is an effective strategy for preventing graft-versus-host disease (GVHD) after allogeneic blood or marrow transplantation (alloBMT). However, the mechanisms by which PTCy modulates alloimmune responses are not well understood. We studied early T cell reconstitution in patients undergoing alloBMT with PTCy and the effects of mafosfamide, a cyclophosphamide (Cy) analog, on CD4+ T cells in allogeneic mixed lymphocyte reactions (MLRs) in vitro. Patients exhibited reductions in naïve, potentially alloreactive conventional CD4+ T cells with relative preservation of memory CD4+Foxp3+ T cells. In particular, CD4+CD45RA−Foxp3+hi effector regulatory T cells (Tregs) recovered rapidly after alloBMT and, unexpectedly, were present at higher levels in patients with GVHD. CD4+Foxp3+ T cells from patients and from allogeneic MLRs expressed relatively high levels of aldehyde dehydrogenase (ALDH), the major in vivo mechanism of Cy resistance. Treatment of MLR cultures with the ALDH inhibitor diethylaminobenzaldehyde reduced the activation and proliferation of CD4+ T cells and sensitized Tregs to mafosfamide. Finally, removing Tregs from peripheral blood lymphocyte grafts obviated PTCy’s GVHD-protective effect in a xenogeneic transplant model. Together, these findings suggest that Treg resistance to Cy through expression of ALDH may contribute to the clinical activity of PTCy in preventing GVHD.