In vivo engineering of mobilized stem cell grafts with the immunomodulatory drug FTY720 for allogeneic transplantation

Abstract

The immunological attributes of stem cell grafts play an important role in the outcome of allogeneic stem cell transplants. Currently, ex vivo manipulation techniques such as bulk T-cell depletion or positive selection of CD34 + cells are utilized to improve the immunological attributes of grafts and minimize the potential for graft-versus-host disease (GvHD). Here, we demonstrate a novel graft engineering technique, which utilizes the immunomodulatory drug FTY720 for in vivo depletion of naïve T (T N ) cells from donor G-CSF-mobilized grafts without ex vivo manipulation. We show that treatment of donor mice with FTY720 during mobilization depletes grafts of T N cells and prevents lethal GvHD following transplantation in a major mismatch setting. Importantly, both stem cells and NK cells are retained in the FTY720-treated grafts. FTY720 treatment does not negatively affect the engraftment potential of stem cells as demonstrated in our congenic transplants or the functionality of NK cells. In addition, potentially useful memory T cells may be retained in the graft. These findings suggest that FTY720 may be used to optimize the immunological attributes of G-CSF-mobilized grafts by removing potentially deleterious T N cells which can contribute to GvHD, and by retaining useful cells which can promote immunity in the recipient.Keywords: Allogeneic stem cell transplantation r Graft engineering r Graft-versus-host disease r Stem cell mobilization r T cellsAdditional supporting information may be found in the online version of this article at the publisher's web-siteCorrespondence: Dr. Julius G. Juarez e-mail: juliusgjuarez@gmail.com * These authors contributed equally to this work. * * These authors contributed equally to this work as senior co-authors.C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2016. 46: 1758-1769 Transplantation and tolerance 1759 IntroductionGraft engineering has played a crucial role in improving allogeneic stem cell transplantation (ASCT) and also broadening its potential application [1]. This has been underpinned by our greater understanding of the different cells that constitute the graft and their contribution to alloresponses [2]. Naïve T (T N ) cells from grafts are the major cells responsible for graft-versus-host disease (GvHD), whereas other cells, such as effector memory T (T EM ), central memory T (T CM ), and NK cells, have potential for promoting immunity and antitumor activity, respectively [1,[3][4][5][6]. In order to mitigate alloresponses by donor T N cells, current graftengineering techniques utilize ex vivo bulk T-cell depletion or positive selection of CD34 + cells. These techniques, however, can leave the graft devoid of useful immune cells, potentially making the recipient more susceptible to infection and relapse [1,2].Techniques specifically targeting depletion of T N cells from grafts could potentially help maximize the capacity of grafts for immune reconstitution, antitumor activity as well as prevention of GvHD in recipients [1,[...