Aldehyde dehydrogenase expression drives human regulatory T cell resistance to posttransplantation cyclophosphamide
Christopher G Kanakry, Sudipto Ganguly, Marianna Zahurak, Javier Bolaños-Meade, Christopher Thoburn, Brandy Perkins, Ephraim J Fuchs, Richard J Jones, Allan D Hess, Leo Luznik, Christopher G Kanakry, Sudipto Ganguly, Marianna Zahurak, Javier Bolaños-Meade, Christopher Thoburn, Brandy Perkins, Ephraim J Fuchs, Richard J Jones, Allan D Hess, Leo Luznik
Abstract
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.
Conflict of interest statement
Competing interests: R.J.J. holds the patent for Aldefluor and, under a licensing agreement between Aldagen and Johns Hopkins University, is entitled to a share of royalties received by the University. The terms of this arrangement are managed by Johns Hopkins University in accordance with its conflict of interest policies. No other authors have competing interests.
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Source: PubMed