Antigen and lymphopenia-driven donor T cells are differentially diminished by post-transplantation administration of cyclophosphamide after hematopoietic cell transplantation

Duncan Ross, Monica Jones, Krishna V Komanduri, Robert B Levy

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39 Citations (Scopus)

Abstract

Administration of cyclophosphamide after transplantation (post-transplantation cyclophosphamide, PTC) has shown promise in the clinic as a prophylactic agent against graft-versus-host disease (GVHD). An important issue with regard to recipient immune function and reconstitution after PTC is the extent to which, in addition to diminution of antihost allo-reactive donor T cells, the remainder of the nonhost allo-reactive donor T cell pool may be affected. To investigate PTC's effects on nonhost reactive donor CD8T cells, ova-specific (OT-I) and gp100-specific Pmel-1T cells were labeled with proliferation dyes and transplanted into syngeneic and allogeneic recipients. Notably, an intermediate dose (66mg/kg) of PTC, which abrogated GVHD after allogeneic HSCT, did not significantly diminish these peptide-specific donor T cell populations. Analysis of the rate of proliferation after transplantation illustrated that lymphopenic-driven, donor nonhost reactive TCR TgT cells in syngeneic recipients underwent slow division, resulting in significant sparing of these donor populations. In contrast, after exposure to specific antigens at the time of transplantation, these same T cells were significantly depleted by PTC, demonstrating the global susceptibility of rapidly dividing T cells after an encounter with cognate antigen. In total, our results, employing both syngeneic and allogeneic minor antigen-mismatched T cell replete models of transplantation, demonstrate a concentration of PTC that abrogates GVHD can preserve most cells that are dividing because of the accompanying lymphopenia after exposure. These findings have important implications with regard to immune function and reconstitution in recipients after allogeneic hematopoietic stem cell transplantation.

Original languageEnglish
Pages (from-to)1430-1438
Number of pages9
JournalBiology of Blood and Marrow Transplantation
Volume19
Issue number10
DOIs
StatePublished - Oct 1 2013

Fingerprint

Lymphopenia
Cell Transplantation
Cyclophosphamide
Transplantation
T-Lymphocytes
Antigens
Graft vs Host Disease
Factor IX
Hematopoietic Stem Cell Transplantation
Population
Ovum
Coloring Agents
Peptides

Keywords

  • Alkylating agent
  • Allogeneic-hematopoietic stem cell transplantation (HSCT)
  • Graft-versus-host disease (GVHD)
  • Lymphopenia-induced proliferation
  • Myeloablative conditioning
  • Post-transplantation cyclophosphamide

ASJC Scopus subject areas

  • Transplantation
  • Hematology

Cite this

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title = "Antigen and lymphopenia-driven donor T cells are differentially diminished by post-transplantation administration of cyclophosphamide after hematopoietic cell transplantation",
abstract = "Administration of cyclophosphamide after transplantation (post-transplantation cyclophosphamide, PTC) has shown promise in the clinic as a prophylactic agent against graft-versus-host disease (GVHD). An important issue with regard to recipient immune function and reconstitution after PTC is the extent to which, in addition to diminution of antihost allo-reactive donor T cells, the remainder of the nonhost allo-reactive donor T cell pool may be affected. To investigate PTC's effects on nonhost reactive donor CD8T cells, ova-specific (OT-I) and gp100-specific Pmel-1T cells were labeled with proliferation dyes and transplanted into syngeneic and allogeneic recipients. Notably, an intermediate dose (66mg/kg) of PTC, which abrogated GVHD after allogeneic HSCT, did not significantly diminish these peptide-specific donor T cell populations. Analysis of the rate of proliferation after transplantation illustrated that lymphopenic-driven, donor nonhost reactive TCR TgT cells in syngeneic recipients underwent slow division, resulting in significant sparing of these donor populations. In contrast, after exposure to specific antigens at the time of transplantation, these same T cells were significantly depleted by PTC, demonstrating the global susceptibility of rapidly dividing T cells after an encounter with cognate antigen. In total, our results, employing both syngeneic and allogeneic minor antigen-mismatched T cell replete models of transplantation, demonstrate a concentration of PTC that abrogates GVHD can preserve most cells that are dividing because of the accompanying lymphopenia after exposure. These findings have important implications with regard to immune function and reconstitution in recipients after allogeneic hematopoietic stem cell transplantation.",
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T1 - Antigen and lymphopenia-driven donor T cells are differentially diminished by post-transplantation administration of cyclophosphamide after hematopoietic cell transplantation

AU - Ross, Duncan

AU - Jones, Monica

AU - Komanduri, Krishna V

AU - Levy, Robert B

PY - 2013/10/1

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N2 - Administration of cyclophosphamide after transplantation (post-transplantation cyclophosphamide, PTC) has shown promise in the clinic as a prophylactic agent against graft-versus-host disease (GVHD). An important issue with regard to recipient immune function and reconstitution after PTC is the extent to which, in addition to diminution of antihost allo-reactive donor T cells, the remainder of the nonhost allo-reactive donor T cell pool may be affected. To investigate PTC's effects on nonhost reactive donor CD8T cells, ova-specific (OT-I) and gp100-specific Pmel-1T cells were labeled with proliferation dyes and transplanted into syngeneic and allogeneic recipients. Notably, an intermediate dose (66mg/kg) of PTC, which abrogated GVHD after allogeneic HSCT, did not significantly diminish these peptide-specific donor T cell populations. Analysis of the rate of proliferation after transplantation illustrated that lymphopenic-driven, donor nonhost reactive TCR TgT cells in syngeneic recipients underwent slow division, resulting in significant sparing of these donor populations. In contrast, after exposure to specific antigens at the time of transplantation, these same T cells were significantly depleted by PTC, demonstrating the global susceptibility of rapidly dividing T cells after an encounter with cognate antigen. In total, our results, employing both syngeneic and allogeneic minor antigen-mismatched T cell replete models of transplantation, demonstrate a concentration of PTC that abrogates GVHD can preserve most cells that are dividing because of the accompanying lymphopenia after exposure. These findings have important implications with regard to immune function and reconstitution in recipients after allogeneic hematopoietic stem cell transplantation.

AB - Administration of cyclophosphamide after transplantation (post-transplantation cyclophosphamide, PTC) has shown promise in the clinic as a prophylactic agent against graft-versus-host disease (GVHD). An important issue with regard to recipient immune function and reconstitution after PTC is the extent to which, in addition to diminution of antihost allo-reactive donor T cells, the remainder of the nonhost allo-reactive donor T cell pool may be affected. To investigate PTC's effects on nonhost reactive donor CD8T cells, ova-specific (OT-I) and gp100-specific Pmel-1T cells were labeled with proliferation dyes and transplanted into syngeneic and allogeneic recipients. Notably, an intermediate dose (66mg/kg) of PTC, which abrogated GVHD after allogeneic HSCT, did not significantly diminish these peptide-specific donor T cell populations. Analysis of the rate of proliferation after transplantation illustrated that lymphopenic-driven, donor nonhost reactive TCR TgT cells in syngeneic recipients underwent slow division, resulting in significant sparing of these donor populations. In contrast, after exposure to specific antigens at the time of transplantation, these same T cells were significantly depleted by PTC, demonstrating the global susceptibility of rapidly dividing T cells after an encounter with cognate antigen. In total, our results, employing both syngeneic and allogeneic minor antigen-mismatched T cell replete models of transplantation, demonstrate a concentration of PTC that abrogates GVHD can preserve most cells that are dividing because of the accompanying lymphopenia after exposure. These findings have important implications with regard to immune function and reconstitution in recipients after allogeneic hematopoietic stem cell transplantation.

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KW - Myeloablative conditioning

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