Daily topical tacrolimus therapy prevents skin rejection in a rodent hind limb allograft model

W P Andrew Lee, Mario G. Solari, Kia M. Washington, Justin Michael Sacks, Theresa Hautz, Jignesh V. Unadkat, Elaine K. Horibe, Raman Venkataramanan, Adriana T. Larregina, Angus W. Thomson

Research output: Contribution to journalArticle

Abstract

Background: Skin is the most immunogenic component of a composite tissue allograft. Topical immunotherapy is an attractive therapeutic modality with which to provide local immunosuppression, with minimal systemic toxicity. The present study was performed to investigate the potential of topical tacrolimus to prolong survival of the skin component of a composite tissue allograft. Methods: Wistar Furth-to-Lewis rat orthotopic hind limb transplants were performed. Group I consisted of rats treated with topical tacrolimus; group II, antilymphocyte serum plus 21 days cyclosporine; and group III, antilymphocyte serum plus 21 days of cyclosporine plus topical tacrolimus. In group IV, tacrolimus levels in blood, skin, and muscle were measured in an autograft control group. Results: All animals in group I (n = 8) developed grade III clinical rejection by postoperative day 9. In group II (n = 9), the median onset of grade III rejection was postoperative day 40 (range, postoperative days 34 to 44). In group III (n = 6), two animals developed focal grade III rejection on postoperative days 35 and 56. The remaining four animals reached the 100-day endpoint without grade III rejection. In group IV, tacrolimus levels were low or undetectable in blood, whereas skin levels were 100-fold higher than underlying muscle. Conclusions: Topical tacrolimus therapy has the potential to prevent skin rejection in a composite tissue allograft. Preoperative depletion of T cells with antilymphocyte serum, along with a short course of systemic immunosuppression, prevents acute rejection, whereas topical tacrolimus inhibits immune cell function in the skin. Concentrations of tacrolimus are substantially higher in skin compared with underlying muscle and peripheral blood. Topical immunotherapy could reduce the morbidity associated with systemic immunosuppression in clinical composite tissue allografts.

Original languageEnglish (US)
JournalPlastic and Reconstructive Surgery
Volume123
Issue numberSUPPL.2S
DOIs
StatePublished - 2009
Externally publishedYes

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Tacrolimus
Allografts
Rodentia
Composite Tissue Allografts
Extremities
Skin
Antilymphocyte Serum
Immunosuppression
Therapeutics
Muscles
Immunotherapy
Cyclosporine
Autografts
Morbidity
T-Lymphocytes
Transplants
Control Groups

ASJC Scopus subject areas

  • Surgery

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Daily topical tacrolimus therapy prevents skin rejection in a rodent hind limb allograft model. / Lee, W P Andrew; Solari, Mario G.; Washington, Kia M.; Sacks, Justin Michael; Hautz, Theresa; Unadkat, Jignesh V.; Horibe, Elaine K.; Venkataramanan, Raman; Larregina, Adriana T.; Thomson, Angus W.

In: Plastic and Reconstructive Surgery, Vol. 123, No. SUPPL.2S, 2009.

Research output: Contribution to journalArticle

Lee, WPA, Solari, MG, Washington, KM, Sacks, JM, Hautz, T, Unadkat, JV, Horibe, EK, Venkataramanan, R, Larregina, AT & Thomson, AW 2009, 'Daily topical tacrolimus therapy prevents skin rejection in a rodent hind limb allograft model', Plastic and Reconstructive Surgery, vol. 123, no. SUPPL.2S. https://doi.org/10.1097/PRS.0b013e318191bcbd
Lee, W P Andrew ; Solari, Mario G. ; Washington, Kia M. ; Sacks, Justin Michael ; Hautz, Theresa ; Unadkat, Jignesh V. ; Horibe, Elaine K. ; Venkataramanan, Raman ; Larregina, Adriana T. ; Thomson, Angus W. / Daily topical tacrolimus therapy prevents skin rejection in a rodent hind limb allograft model. In: Plastic and Reconstructive Surgery. 2009 ; Vol. 123, No. SUPPL.2S.
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abstract = "Background: Skin is the most immunogenic component of a composite tissue allograft. Topical immunotherapy is an attractive therapeutic modality with which to provide local immunosuppression, with minimal systemic toxicity. The present study was performed to investigate the potential of topical tacrolimus to prolong survival of the skin component of a composite tissue allograft. Methods: Wistar Furth-to-Lewis rat orthotopic hind limb transplants were performed. Group I consisted of rats treated with topical tacrolimus; group II, antilymphocyte serum plus 21 days cyclosporine; and group III, antilymphocyte serum plus 21 days of cyclosporine plus topical tacrolimus. In group IV, tacrolimus levels in blood, skin, and muscle were measured in an autograft control group. Results: All animals in group I (n = 8) developed grade III clinical rejection by postoperative day 9. In group II (n = 9), the median onset of grade III rejection was postoperative day 40 (range, postoperative days 34 to 44). In group III (n = 6), two animals developed focal grade III rejection on postoperative days 35 and 56. The remaining four animals reached the 100-day endpoint without grade III rejection. In group IV, tacrolimus levels were low or undetectable in blood, whereas skin levels were 100-fold higher than underlying muscle. Conclusions: Topical tacrolimus therapy has the potential to prevent skin rejection in a composite tissue allograft. Preoperative depletion of T cells with antilymphocyte serum, along with a short course of systemic immunosuppression, prevents acute rejection, whereas topical tacrolimus inhibits immune cell function in the skin. Concentrations of tacrolimus are substantially higher in skin compared with underlying muscle and peripheral blood. Topical immunotherapy could reduce the morbidity associated with systemic immunosuppression in clinical composite tissue allografts.",
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T1 - Daily topical tacrolimus therapy prevents skin rejection in a rodent hind limb allograft model

AU - Lee, W P Andrew

AU - Solari, Mario G.

AU - Washington, Kia M.

AU - Sacks, Justin Michael

AU - Hautz, Theresa

AU - Unadkat, Jignesh V.

AU - Horibe, Elaine K.

AU - Venkataramanan, Raman

AU - Larregina, Adriana T.

AU - Thomson, Angus W.

PY - 2009

Y1 - 2009

N2 - Background: Skin is the most immunogenic component of a composite tissue allograft. Topical immunotherapy is an attractive therapeutic modality with which to provide local immunosuppression, with minimal systemic toxicity. The present study was performed to investigate the potential of topical tacrolimus to prolong survival of the skin component of a composite tissue allograft. Methods: Wistar Furth-to-Lewis rat orthotopic hind limb transplants were performed. Group I consisted of rats treated with topical tacrolimus; group II, antilymphocyte serum plus 21 days cyclosporine; and group III, antilymphocyte serum plus 21 days of cyclosporine plus topical tacrolimus. In group IV, tacrolimus levels in blood, skin, and muscle were measured in an autograft control group. Results: All animals in group I (n = 8) developed grade III clinical rejection by postoperative day 9. In group II (n = 9), the median onset of grade III rejection was postoperative day 40 (range, postoperative days 34 to 44). In group III (n = 6), two animals developed focal grade III rejection on postoperative days 35 and 56. The remaining four animals reached the 100-day endpoint without grade III rejection. In group IV, tacrolimus levels were low or undetectable in blood, whereas skin levels were 100-fold higher than underlying muscle. Conclusions: Topical tacrolimus therapy has the potential to prevent skin rejection in a composite tissue allograft. Preoperative depletion of T cells with antilymphocyte serum, along with a short course of systemic immunosuppression, prevents acute rejection, whereas topical tacrolimus inhibits immune cell function in the skin. Concentrations of tacrolimus are substantially higher in skin compared with underlying muscle and peripheral blood. Topical immunotherapy could reduce the morbidity associated with systemic immunosuppression in clinical composite tissue allografts.

AB - Background: Skin is the most immunogenic component of a composite tissue allograft. Topical immunotherapy is an attractive therapeutic modality with which to provide local immunosuppression, with minimal systemic toxicity. The present study was performed to investigate the potential of topical tacrolimus to prolong survival of the skin component of a composite tissue allograft. Methods: Wistar Furth-to-Lewis rat orthotopic hind limb transplants were performed. Group I consisted of rats treated with topical tacrolimus; group II, antilymphocyte serum plus 21 days cyclosporine; and group III, antilymphocyte serum plus 21 days of cyclosporine plus topical tacrolimus. In group IV, tacrolimus levels in blood, skin, and muscle were measured in an autograft control group. Results: All animals in group I (n = 8) developed grade III clinical rejection by postoperative day 9. In group II (n = 9), the median onset of grade III rejection was postoperative day 40 (range, postoperative days 34 to 44). In group III (n = 6), two animals developed focal grade III rejection on postoperative days 35 and 56. The remaining four animals reached the 100-day endpoint without grade III rejection. In group IV, tacrolimus levels were low or undetectable in blood, whereas skin levels were 100-fold higher than underlying muscle. Conclusions: Topical tacrolimus therapy has the potential to prevent skin rejection in a composite tissue allograft. Preoperative depletion of T cells with antilymphocyte serum, along with a short course of systemic immunosuppression, prevents acute rejection, whereas topical tacrolimus inhibits immune cell function in the skin. Concentrations of tacrolimus are substantially higher in skin compared with underlying muscle and peripheral blood. Topical immunotherapy could reduce the morbidity associated with systemic immunosuppression in clinical composite tissue allografts.

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