Prolongation of composite tissue allograft survival by immature recipient dendritic cells pulsed with donor antigen and transient low-dose immunosuppression

Justin M. Sacks, Yur Ren Kuo, Aurele Taieb, Jeremy Breitinger, Vu T. Nguyen, Angus W. Thomson, Maryam Feili-Hariri, W. P.Andrew Lee

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

BACKGROUND: Composite tissue allograft transplantation is limited by risks of long-term immunosuppression. The authors investigated whether short-term immunosuppression combined with recipient immature dendritic cells pulsed with donor antigens promotes composite tissue allograft survival. METHODS: Orthotopic hind-limb transplants were performed (day 0) from Wistar-Furth (RT1) to Lewis (RT1) rats. Recipient dendritic cells were propagated from bone marrow with granulocyte-macrophage colony-stimulating factor (bone marrow-derived dendritic cells) and pulsed with or without donor splenic cell lysate. Recipients were as follows: group I, control; group II, cyclosporine (10 mg/kg/day, days 0 through 6, intraperitoneally); group III, antilymphocyte serum plus cyclosporine (days -4 and +1, intraperitoneally); and groups IV and V, cyclosporine plus antilymphocyte serum, combined with 7 × 10 untreated or donor cell lysate-pulsed bone marrow-derived dendritic cells (days +7 and +14, intravenously), respectively. Epidermolysis/desquamation of donor skin defined rejection. Mixed leukocyte reaction determined recipient T-cell reactivity to donor. Tissue samples were obtained at 3 weeks and on the day of rejection. Groups comprised six or seven rats. RESULTS: Donor alloantigen-pulsed bone marrow-derived dendritic cells (group V) significantly prolonged median composite tissue allograft survival time (32.0 days) compared with groups II (18.0 days, p = 0.0012), III (22.5 days, p = 0.0043), and IV (26.5 days, p = 0.0043). Splenic T cells in group V exhibited hyporesponsiveness to donor alloantigen in mixed leukocyte reaction. Interestingly, the graft muscle component in the bone marrow-derived dendritic cell-treated group (group V) showed significant reduction in mononuclear cell infiltration relative to group II (p = 0.0317). CONCLUSIONS: Donor alloantigen-pulsed recipient bone marrow-derived dendritic cells combined with transient T-cell-directed immunosuppression significantly prolonged composite tissue allograft survival across a full major histocompatibility complex barrier. This may represent the basis for a novel, clinically applicable strategy to promote composite tissue allograft survival with reduced systemic immunosuppression.

Original languageEnglish (US)
Pages (from-to)37-49
Number of pages13
JournalPlastic and reconstructive surgery
Volume121
Issue number1
DOIs
StatePublished - Jan 1 2008
Externally publishedYes

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Composite Tissue Allografts
Tissue Survival
Immunosuppression
Dendritic Cells
Antigens
Bone Marrow
Isoantigens
Cyclosporine
Mixed Lymphocyte Culture Test
Antilymphocyte Serum
T-Lymphocytes
Transplants
Tissue Transplantation
Granulocyte-Macrophage Colony-Stimulating Factor
Major Histocompatibility Complex
Extremities
Muscles
Control Groups
Skin

ASJC Scopus subject areas

  • Surgery

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Prolongation of composite tissue allograft survival by immature recipient dendritic cells pulsed with donor antigen and transient low-dose immunosuppression. / Sacks, Justin M.; Kuo, Yur Ren; Taieb, Aurele; Breitinger, Jeremy; Nguyen, Vu T.; Thomson, Angus W.; Feili-Hariri, Maryam; Lee, W. P.Andrew.

In: Plastic and reconstructive surgery, Vol. 121, No. 1, 01.01.2008, p. 37-49.

Research output: Contribution to journalArticle

Sacks, Justin M. ; Kuo, Yur Ren ; Taieb, Aurele ; Breitinger, Jeremy ; Nguyen, Vu T. ; Thomson, Angus W. ; Feili-Hariri, Maryam ; Lee, W. P.Andrew. / Prolongation of composite tissue allograft survival by immature recipient dendritic cells pulsed with donor antigen and transient low-dose immunosuppression. In: Plastic and reconstructive surgery. 2008 ; Vol. 121, No. 1. pp. 37-49.
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abstract = "BACKGROUND: Composite tissue allograft transplantation is limited by risks of long-term immunosuppression. The authors investigated whether short-term immunosuppression combined with recipient immature dendritic cells pulsed with donor antigens promotes composite tissue allograft survival. METHODS: Orthotopic hind-limb transplants were performed (day 0) from Wistar-Furth (RT1) to Lewis (RT1) rats. Recipient dendritic cells were propagated from bone marrow with granulocyte-macrophage colony-stimulating factor (bone marrow-derived dendritic cells) and pulsed with or without donor splenic cell lysate. Recipients were as follows: group I, control; group II, cyclosporine (10 mg/kg/day, days 0 through 6, intraperitoneally); group III, antilymphocyte serum plus cyclosporine (days -4 and +1, intraperitoneally); and groups IV and V, cyclosporine plus antilymphocyte serum, combined with 7 × 10 untreated or donor cell lysate-pulsed bone marrow-derived dendritic cells (days +7 and +14, intravenously), respectively. Epidermolysis/desquamation of donor skin defined rejection. Mixed leukocyte reaction determined recipient T-cell reactivity to donor. Tissue samples were obtained at 3 weeks and on the day of rejection. Groups comprised six or seven rats. RESULTS: Donor alloantigen-pulsed bone marrow-derived dendritic cells (group V) significantly prolonged median composite tissue allograft survival time (32.0 days) compared with groups II (18.0 days, p = 0.0012), III (22.5 days, p = 0.0043), and IV (26.5 days, p = 0.0043). Splenic T cells in group V exhibited hyporesponsiveness to donor alloantigen in mixed leukocyte reaction. Interestingly, the graft muscle component in the bone marrow-derived dendritic cell-treated group (group V) showed significant reduction in mononuclear cell infiltration relative to group II (p = 0.0317). CONCLUSIONS: Donor alloantigen-pulsed recipient bone marrow-derived dendritic cells combined with transient T-cell-directed immunosuppression significantly prolonged composite tissue allograft survival across a full major histocompatibility complex barrier. This may represent the basis for a novel, clinically applicable strategy to promote composite tissue allograft survival with reduced systemic immunosuppression.",
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AU - Sacks, Justin M.

AU - Kuo, Yur Ren

AU - Taieb, Aurele

AU - Breitinger, Jeremy

AU - Nguyen, Vu T.

AU - Thomson, Angus W.

AU - Feili-Hariri, Maryam

AU - Lee, W. P.Andrew

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N2 - BACKGROUND: Composite tissue allograft transplantation is limited by risks of long-term immunosuppression. The authors investigated whether short-term immunosuppression combined with recipient immature dendritic cells pulsed with donor antigens promotes composite tissue allograft survival. METHODS: Orthotopic hind-limb transplants were performed (day 0) from Wistar-Furth (RT1) to Lewis (RT1) rats. Recipient dendritic cells were propagated from bone marrow with granulocyte-macrophage colony-stimulating factor (bone marrow-derived dendritic cells) and pulsed with or without donor splenic cell lysate. Recipients were as follows: group I, control; group II, cyclosporine (10 mg/kg/day, days 0 through 6, intraperitoneally); group III, antilymphocyte serum plus cyclosporine (days -4 and +1, intraperitoneally); and groups IV and V, cyclosporine plus antilymphocyte serum, combined with 7 × 10 untreated or donor cell lysate-pulsed bone marrow-derived dendritic cells (days +7 and +14, intravenously), respectively. Epidermolysis/desquamation of donor skin defined rejection. Mixed leukocyte reaction determined recipient T-cell reactivity to donor. Tissue samples were obtained at 3 weeks and on the day of rejection. Groups comprised six or seven rats. RESULTS: Donor alloantigen-pulsed bone marrow-derived dendritic cells (group V) significantly prolonged median composite tissue allograft survival time (32.0 days) compared with groups II (18.0 days, p = 0.0012), III (22.5 days, p = 0.0043), and IV (26.5 days, p = 0.0043). Splenic T cells in group V exhibited hyporesponsiveness to donor alloantigen in mixed leukocyte reaction. Interestingly, the graft muscle component in the bone marrow-derived dendritic cell-treated group (group V) showed significant reduction in mononuclear cell infiltration relative to group II (p = 0.0317). CONCLUSIONS: Donor alloantigen-pulsed recipient bone marrow-derived dendritic cells combined with transient T-cell-directed immunosuppression significantly prolonged composite tissue allograft survival across a full major histocompatibility complex barrier. This may represent the basis for a novel, clinically applicable strategy to promote composite tissue allograft survival with reduced systemic immunosuppression.

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