Long-term survival of limb allografts induced by pharmacologically conditioned, donor alloantigen-pulsed dendritic cells without maintenance immunosuppression

Ryosuke Ikeguchi, Justin Michael Sacks, Jignesh V. Unadkat, Mario Solari, Elaine K. Horibe, Angus W. Thomson, W P Andrew Lee, Maryam Feili-Hariri

Research output: Contribution to journalArticle

Abstract

BACKGROUND. We showed recently that limb allograft survival could be enhanced by administration of alloantigen (Ag)-pulsed immature dendritic cells (DC) after transplantation. Since indefinite graft survival was not achieved, we have further modified the DC by pharmacologic (rapamycin; Rapa) conditioning and ascertained their influence on graft survival, without continued immunosuppressive therapy. METHODS. We compared the ability of donor Ag-pulsed, Rapa-conditioned rat myeloid DC (Rapa DC) and control DC (CTR DC) to inhibit alloreactive T-cell responses after limb transplantation in antilymphocyte serum (ALS)-treated recipients given a short postoperative course of cyclosporine (CsA). RESULTS. Both DC populations expressed similar levels of major histocompatibility complex (MHC) II, CD40 and CD54, but Rapa DC expressed lower CD86. After toll-like receptor activation, both populations produced minimal interleukin (IL)-12p70, but Rapa DC secreted lower levels of IL-6 and IL-10. The capacity of DCs to stimulate T-cell proliferation in mixed leukocyte reactions was very low. Pulsing of the DC with donor Ag did not alter their phenotype or function. Interestingly, posttransplant administration of donor Ag-pulsed Rapa DC to rats given perioperative ALS and 21 days CsA significantly delayed graft rejection and promoted long-term (>125 days) graft survival. AlloAg-pulsed Rapa DC induced T-cell hyporesponsiveness and promoted the generation of IL-10-secreting CD4 T cells upon ex vivo challenge. CONCLUSIONS. Infusion of donor Ag-pulsed, Rapa-conditioned DC after composite tissue transplantation can prevent rejection of the grafts, including skin, across a full MHC mismatch and in the absence of continued immunosuppressive therapy.

Original languageEnglish (US)
Pages (from-to)237-246
Number of pages10
JournalTransplantation
Volume85
Issue number2
DOIs
StatePublished - Jan 2008
Externally publishedYes

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Isoantigens
Immunosuppression
Dendritic Cells
Allografts
Extremities
Maintenance
Graft Survival
T-Lymphocytes
Antilymphocyte Serum
Graft Rejection
Immunosuppressive Agents
Major Histocompatibility Complex
Interleukin-10
Tissue Transplantation
Mixed Lymphocyte Culture Test
Toll-Like Receptors
Interleukins
Cell Transplantation
Myeloid Cells
Sirolimus

Keywords

  • Composite tissue transplantation
  • Dendritic cells
  • Rapamycin
  • Rat
  • Tolerance

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Long-term survival of limb allografts induced by pharmacologically conditioned, donor alloantigen-pulsed dendritic cells without maintenance immunosuppression. / Ikeguchi, Ryosuke; Sacks, Justin Michael; Unadkat, Jignesh V.; Solari, Mario; Horibe, Elaine K.; Thomson, Angus W.; Lee, W P Andrew; Feili-Hariri, Maryam.

In: Transplantation, Vol. 85, No. 2, 01.2008, p. 237-246.

Research output: Contribution to journalArticle

Ikeguchi, Ryosuke ; Sacks, Justin Michael ; Unadkat, Jignesh V. ; Solari, Mario ; Horibe, Elaine K. ; Thomson, Angus W. ; Lee, W P Andrew ; Feili-Hariri, Maryam. / Long-term survival of limb allografts induced by pharmacologically conditioned, donor alloantigen-pulsed dendritic cells without maintenance immunosuppression. In: Transplantation. 2008 ; Vol. 85, No. 2. pp. 237-246.
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T1 - Long-term survival of limb allografts induced by pharmacologically conditioned, donor alloantigen-pulsed dendritic cells without maintenance immunosuppression

AU - Ikeguchi, Ryosuke

AU - Sacks, Justin Michael

AU - Unadkat, Jignesh V.

AU - Solari, Mario

AU - Horibe, Elaine K.

AU - Thomson, Angus W.

AU - Lee, W P Andrew

AU - Feili-Hariri, Maryam

PY - 2008/1

Y1 - 2008/1

N2 - BACKGROUND. We showed recently that limb allograft survival could be enhanced by administration of alloantigen (Ag)-pulsed immature dendritic cells (DC) after transplantation. Since indefinite graft survival was not achieved, we have further modified the DC by pharmacologic (rapamycin; Rapa) conditioning and ascertained their influence on graft survival, without continued immunosuppressive therapy. METHODS. We compared the ability of donor Ag-pulsed, Rapa-conditioned rat myeloid DC (Rapa DC) and control DC (CTR DC) to inhibit alloreactive T-cell responses after limb transplantation in antilymphocyte serum (ALS)-treated recipients given a short postoperative course of cyclosporine (CsA). RESULTS. Both DC populations expressed similar levels of major histocompatibility complex (MHC) II, CD40 and CD54, but Rapa DC expressed lower CD86. After toll-like receptor activation, both populations produced minimal interleukin (IL)-12p70, but Rapa DC secreted lower levels of IL-6 and IL-10. The capacity of DCs to stimulate T-cell proliferation in mixed leukocyte reactions was very low. Pulsing of the DC with donor Ag did not alter their phenotype or function. Interestingly, posttransplant administration of donor Ag-pulsed Rapa DC to rats given perioperative ALS and 21 days CsA significantly delayed graft rejection and promoted long-term (>125 days) graft survival. AlloAg-pulsed Rapa DC induced T-cell hyporesponsiveness and promoted the generation of IL-10-secreting CD4 T cells upon ex vivo challenge. CONCLUSIONS. Infusion of donor Ag-pulsed, Rapa-conditioned DC after composite tissue transplantation can prevent rejection of the grafts, including skin, across a full MHC mismatch and in the absence of continued immunosuppressive therapy.

AB - BACKGROUND. We showed recently that limb allograft survival could be enhanced by administration of alloantigen (Ag)-pulsed immature dendritic cells (DC) after transplantation. Since indefinite graft survival was not achieved, we have further modified the DC by pharmacologic (rapamycin; Rapa) conditioning and ascertained their influence on graft survival, without continued immunosuppressive therapy. METHODS. We compared the ability of donor Ag-pulsed, Rapa-conditioned rat myeloid DC (Rapa DC) and control DC (CTR DC) to inhibit alloreactive T-cell responses after limb transplantation in antilymphocyte serum (ALS)-treated recipients given a short postoperative course of cyclosporine (CsA). RESULTS. Both DC populations expressed similar levels of major histocompatibility complex (MHC) II, CD40 and CD54, but Rapa DC expressed lower CD86. After toll-like receptor activation, both populations produced minimal interleukin (IL)-12p70, but Rapa DC secreted lower levels of IL-6 and IL-10. The capacity of DCs to stimulate T-cell proliferation in mixed leukocyte reactions was very low. Pulsing of the DC with donor Ag did not alter their phenotype or function. Interestingly, posttransplant administration of donor Ag-pulsed Rapa DC to rats given perioperative ALS and 21 days CsA significantly delayed graft rejection and promoted long-term (>125 days) graft survival. AlloAg-pulsed Rapa DC induced T-cell hyporesponsiveness and promoted the generation of IL-10-secreting CD4 T cells upon ex vivo challenge. CONCLUSIONS. Infusion of donor Ag-pulsed, Rapa-conditioned DC after composite tissue transplantation can prevent rejection of the grafts, including skin, across a full MHC mismatch and in the absence of continued immunosuppressive therapy.

KW - Composite tissue transplantation

KW - Dendritic cells

KW - Rapamycin

KW - Rat

KW - Tolerance

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