FTY720 in corneal concordant xenotransplantation

K Sedlakova, E Muckersie, M Robertson, M Filipec, J V Forrester

Research output: Contribution to journalArticle

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Abstract

Background. Currently, there are no effective treatments for the control of corneal xenograft rejection. We evaluated the efficacy and mode of action of a novel immunosuppressant, FTY720, in a model of corneal xenograft transplantation. Methods. Rat-to-mouse corneal xenografts were performed and the effects of treatment with daily intraperitoneal injections of FTY720 (0.5 or 3.0 mg/kg/day) or saline from 2 days pretransplantation were assessed clinically. Immunohistochemical studies of the grafts and flow cytometry of the draining lymph node subpopulations were performed at the time of clinical rejection. Results. Treatment with FTY720 delayed the onset of corneal rejection, from 8 days postgraft in saline-treated mice to 12.0 +/- 0.89 days for low-dose FTY720 treatment and 15.6 +/- 3.1 days for high-dose FTY720 treatment (both P<0.001). Histologically, FTY-treated animals had a markedly reduced inflammatory response in the anterior chamber and cornea after replacement of the xenograft epithelium with normal healthy host epithelium. In contrast, saline-treated xenografts had persisting corneal epithelial defects and ulceration. In the draining lymph nodes, FTY720 not only inhibited the increase in the cell number observed in saline-treated recipients of xenografts, but also reduced the expression of activation markers on B cells (MHC class II and CD86). Conclusions. FTY720 treatment significantly delayed rejection and decreased its severity in a dose-dependent manner in a rat-to-mouse model of corneal xenotransplantation. Since corneal xenograft rejection is mediated not by natural antibodies or CD8+ T cells directly, but by CD4+ T cells, the data from these experiments imply that FTY720 mediated its effect via CD4+ T cells.

Original languageEnglish
Pages (from-to)297-303
Number of pages7
JournalTransplantation
Volume79
Issue number3
DOIs
Publication statusPublished - 15 Feb 2005

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Heterologous Transplantation
Heterografts
T-Lymphocytes
Therapeutics
Epithelium
Lymph Nodes
Corneal Transplantation
Fingolimod Hydrochloride
Anterior Chamber
Immunosuppressive Agents
Intraperitoneal Injections
Cornea
Flow Cytometry
B-Lymphocytes
Cell Count
Transplants
Antibodies

Keywords

  • xenotransplantation
  • cornea
  • FTY720
  • mouse
  • rat
  • epithelium
  • circulating mature lymphocytes
  • CD4(+) T-Cells
  • immunosuppressant FTY720
  • sphingosine 1-phosphate
  • xenograft rejection
  • allograft survival
  • graft-rejection
  • murine model
  • RAT MODEL
  • mice

Cite this

Sedlakova, K., Muckersie, E., Robertson, M., Filipec, M., & Forrester, J. V. (2005). FTY720 in corneal concordant xenotransplantation. Transplantation, 79(3), 297-303. https://doi.org/10.1097/01.TP.0000151005.37985.DE

FTY720 in corneal concordant xenotransplantation. / Sedlakova, K ; Muckersie, E ; Robertson, M ; Filipec, M ; Forrester, J V .

In: Transplantation, Vol. 79, No. 3, 15.02.2005, p. 297-303.

Research output: Contribution to journalArticle

Sedlakova, K, Muckersie, E, Robertson, M, Filipec, M & Forrester, JV 2005, 'FTY720 in corneal concordant xenotransplantation' Transplantation, vol. 79, no. 3, pp. 297-303. https://doi.org/10.1097/01.TP.0000151005.37985.DE
Sedlakova K, Muckersie E, Robertson M, Filipec M, Forrester JV. FTY720 in corneal concordant xenotransplantation. Transplantation. 2005 Feb 15;79(3):297-303. https://doi.org/10.1097/01.TP.0000151005.37985.DE
Sedlakova, K ; Muckersie, E ; Robertson, M ; Filipec, M ; Forrester, J V . / FTY720 in corneal concordant xenotransplantation. In: Transplantation. 2005 ; Vol. 79, No. 3. pp. 297-303.
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AU - Robertson, M

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AU - Forrester, J V

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N2 - Background. Currently, there are no effective treatments for the control of corneal xenograft rejection. We evaluated the efficacy and mode of action of a novel immunosuppressant, FTY720, in a model of corneal xenograft transplantation. Methods. Rat-to-mouse corneal xenografts were performed and the effects of treatment with daily intraperitoneal injections of FTY720 (0.5 or 3.0 mg/kg/day) or saline from 2 days pretransplantation were assessed clinically. Immunohistochemical studies of the grafts and flow cytometry of the draining lymph node subpopulations were performed at the time of clinical rejection. Results. Treatment with FTY720 delayed the onset of corneal rejection, from 8 days postgraft in saline-treated mice to 12.0 +/- 0.89 days for low-dose FTY720 treatment and 15.6 +/- 3.1 days for high-dose FTY720 treatment (both P<0.001). Histologically, FTY-treated animals had a markedly reduced inflammatory response in the anterior chamber and cornea after replacement of the xenograft epithelium with normal healthy host epithelium. In contrast, saline-treated xenografts had persisting corneal epithelial defects and ulceration. In the draining lymph nodes, FTY720 not only inhibited the increase in the cell number observed in saline-treated recipients of xenografts, but also reduced the expression of activation markers on B cells (MHC class II and CD86). Conclusions. FTY720 treatment significantly delayed rejection and decreased its severity in a dose-dependent manner in a rat-to-mouse model of corneal xenotransplantation. Since corneal xenograft rejection is mediated not by natural antibodies or CD8+ T cells directly, but by CD4+ T cells, the data from these experiments imply that FTY720 mediated its effect via CD4+ T cells.

AB - Background. Currently, there are no effective treatments for the control of corneal xenograft rejection. We evaluated the efficacy and mode of action of a novel immunosuppressant, FTY720, in a model of corneal xenograft transplantation. Methods. Rat-to-mouse corneal xenografts were performed and the effects of treatment with daily intraperitoneal injections of FTY720 (0.5 or 3.0 mg/kg/day) or saline from 2 days pretransplantation were assessed clinically. Immunohistochemical studies of the grafts and flow cytometry of the draining lymph node subpopulations were performed at the time of clinical rejection. Results. Treatment with FTY720 delayed the onset of corneal rejection, from 8 days postgraft in saline-treated mice to 12.0 +/- 0.89 days for low-dose FTY720 treatment and 15.6 +/- 3.1 days for high-dose FTY720 treatment (both P<0.001). Histologically, FTY-treated animals had a markedly reduced inflammatory response in the anterior chamber and cornea after replacement of the xenograft epithelium with normal healthy host epithelium. In contrast, saline-treated xenografts had persisting corneal epithelial defects and ulceration. In the draining lymph nodes, FTY720 not only inhibited the increase in the cell number observed in saline-treated recipients of xenografts, but also reduced the expression of activation markers on B cells (MHC class II and CD86). Conclusions. FTY720 treatment significantly delayed rejection and decreased its severity in a dose-dependent manner in a rat-to-mouse model of corneal xenotransplantation. Since corneal xenograft rejection is mediated not by natural antibodies or CD8+ T cells directly, but by CD4+ T cells, the data from these experiments imply that FTY720 mediated its effect via CD4+ T cells.

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KW - rat

KW - epithelium

KW - circulating mature lymphocytes

KW - CD4(+) T-Cells

KW - immunosuppressant FTY720

KW - sphingosine 1-phosphate

KW - xenograft rejection

KW - allograft survival

KW - graft-rejection

KW - murine model

KW - RAT MODEL

KW - mice

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JO - Transplantation

JF - Transplantation

SN - 0041-1337

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ER -