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

Sudipto Ganguly, Duncan B. Ross, Angela Panoskaltsis-Mortari, Christopher G. Kanakry, Bruce R. Blazar, Robert B. Levy, Leo Luznik

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2131-2141
Number of pages11
JournalBlood
Volume124
Issue number13
DOIs
StatePublished - Sep 25 2014

Fingerprint

T-cells
Graft vs Host Disease
Regulatory T-Lymphocytes
Grafts
Cyclophosphamide
Thymus
Thymus Gland
Allografts
Blood
Transplantation
Bone Marrow
T-Lymphocytes
Adoptive Transfer
Alkylation
Ablation

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology
  • Medicine(all)

Cite this

Donor CD4+Foxp3+regulatory T cells are necessary for posttransplantation cyclophosphamide-mediated protection against GVHD in mice. / Ganguly, Sudipto; Ross, Duncan B.; Panoskaltsis-Mortari, Angela; Kanakry, Christopher G.; Blazar, Bruce R.; Levy, Robert B.; Luznik, Leo.

In: Blood, Vol. 124, No. 13, 25.09.2014, p. 2131-2141.

Research output: Contribution to journalArticle

Ganguly, Sudipto ; Ross, Duncan B. ; Panoskaltsis-Mortari, Angela ; Kanakry, Christopher G. ; Blazar, Bruce R. ; Levy, Robert B. ; Luznik, Leo. / Donor CD4+Foxp3+regulatory T cells are necessary for posttransplantation cyclophosphamide-mediated protection against GVHD in mice. In: Blood. 2014 ; Vol. 124, No. 13. pp. 2131-2141.
@article{6e683b14548c40d0819a4a523c127db9,
title = "Donor CD4+Foxp3+regulatory T cells are necessary for posttransplantation cyclophosphamide-mediated protection against GVHD in mice",
abstract = "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.",
author = "Sudipto Ganguly and Ross, {Duncan B.} and Angela Panoskaltsis-Mortari and Kanakry, {Christopher G.} and Blazar, {Bruce R.} and Levy, {Robert B.} and Leo Luznik",
year = "2014",
month = "9",
day = "25",
doi = "10.1182/blood-2013-10-525873",
language = "English (US)",
volume = "124",
pages = "2131--2141",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "13",

}

TY - JOUR

T1 - Donor CD4+Foxp3+regulatory T cells are necessary for posttransplantation cyclophosphamide-mediated protection against GVHD in mice

AU - Ganguly, Sudipto

AU - Ross, Duncan B.

AU - Panoskaltsis-Mortari, Angela

AU - Kanakry, Christopher G.

AU - Blazar, Bruce R.

AU - Levy, Robert B.

AU - Luznik, Leo

PY - 2014/9/25

Y1 - 2014/9/25

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84907535297&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84907535297&partnerID=8YFLogxK

U2 - 10.1182/blood-2013-10-525873

DO - 10.1182/blood-2013-10-525873

M3 - Article

C2 - 25139358

AN - SCOPUS:84907535297

VL - 124

SP - 2131

EP - 2141

JO - Blood

JF - Blood

SN - 0006-4971

IS - 13

ER -