Donor CD4+ Foxp3+ regulatory T cells are necessary for posttransplantation cyclophosphamide-mediated protection against GVHD in mice

Posttransplantation cyclophosphamide (PTCy) is an effective prophylaxis against graft-versus-host disease (GVHD). However, it is unknown whether PTCy works singularly by eliminating alloreactive T cells via DNA alkylation or also by restoring the conventional (Tcon)/regulatory (Treg) T-cell balance....

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Bibliographic Details
Published in:Blood Vol. 124; no. 13; pp. 2131 - 2141
Main Authors: Ganguly, Sudipto, Ross, Duncan B., Panoskaltsis-Mortari, Angela, Kanakry, Christopher G., Blazar, Bruce R., Levy, Robert B., Luznik, Leo
Format: Journal Article
Language:English
Published: United States Elsevier Inc 25-09-2014
American Society of Hematology
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Summary:Posttransplantation cyclophosphamide (PTCy) is an effective prophylaxis against graft-versus-host disease (GVHD). However, it is unknown whether PTCy works singularly by eliminating alloreactive T cells via DNA alkylation or also by restoring the conventional (Tcon)/regulatory (Treg) T-cell balance. We studied the role of Tregs in PTCy-mediated GVHD prophylaxis in murine models of allogeneic blood or marrow transplantation (alloBMT). In 2 distinct MHC-matched alloBMT models, infusing Treg-depleted allografts abrogated the GVHD-prophylactic activity of PTCy. Using allografts in which Foxp3+ Tregs could be selectively depleted in vivo, either pre- or post-PTCy ablation of donor thymus–derived Tregs (tTregs) abolished PTCy protection against GVHD. PTCy treatment was associated with relative preservation of donor Tregs. Experiments using combinations of Foxp3– Tcons and Foxp3+ Tregs sorted from different Foxp3 reporter mice indicated that donor Treg persistence after PTCy treatment was predominantly caused by survival of functional tTregs that retained Treg-specific demethylation and also induction of peripherally derived Tregs. Finally, adoptive transfer of tTregs retrieved from PTCy-treated chimeras rescued PTCy-treated, Treg-depleted recipients from lethal GVHD. Our findings indicate that PTCy-mediated protection against GVHD is not singularly dependent on depletion of donor alloreactive T cells but also requires rapidly recovering donor Tregs to initiate and maintain alloimmune regulation. •The prophylactic efficacy of posttransplantation cyclophosphamide (PTCy) against GVHD is dependent on donor CD4+ Foxp3+ Tregs.•PTCy treatment was associated with recovery of epigenetically stable and suppressive donor thymus–derived Tregs in secondary lymphoid organs.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2013-10-525873