Presensitization accelerates chronic allograft rejection in a heterotopic rat tracheal allograft model with immunosuppression

Tatsuo Okumoto, Masaomi Yamane, Yoshifumi Sano, Motoi Aoe, Hiroshi Date, Nobuyoshi Shimizu

Research output: Contribution to journalArticle

Abstract

Background: In the field of organ transplantation, the effect of pretransplant humoral allosensitization on the organ transplant outcome has been highlighted. To clarify the correlation of presensitization with chronic rejection that can lead to a poor prognosis in transplant recipients, we examined humoral alloreactivity and allograft rejection in sensitized recipients by using a rat heterotopic tracheal transplant model. Methods: An MHC fully incompatible combination strain was used in this study. Lewis (LEW) rats sensitized by transplantation with Brown Norway (BN) skin grafts received tracheal segments from BN rats in the dorsal subcutaneous pouch. Four allogenic groups (n = 5) were investigated. Group1, non-sensitized recipients without cyclosporine A (CsA) administration; group 2, non-sensitized recipients with CsA administration; group 3, sensitized recipients without CsA administration; and group 4, sensitized recipients with CsA administration. In the immunosuppressant groups (groups 2 and 4), the recipients were administered a subcutaneous injection of CsA (25 mg·kg- 1·day- 1) for 3 days from the day of operation. All recipients were sacrificed 21 days after transplantation. Tracheal segments were extracted from the recipients and histologically evaluated with regard to the following parameters: (1) airway lining epithelial loss, (2) lymphocyte/plasma cell infiltration, and (3) luminal obliteration due to granulation tissue formation and/or fibrosis. In order to analyze alloantibody (allo-Ab) responses, sera samples were tested by the flow cytometric cross-match (FCXM) technique. Results: Histological findings revealed that the chronic rejection score in sensitized recipients treated with CsA was significantly higher than that in non-sensitized recipients treated with CsA (9.0 ± 1.2 vs. 3.0 ± 0.54, p <0.05). In other words, CsA therapy reduced the rejection score in non-sensitized recipients, but not in sensitized recipients. No significant differences were observed in the level of IgM Abs among the groups. However, donor-specific IgG Abs were induced after presensitization by donor skin grafting prior to tracheal transplantation. Heterotopic tracheal implantation also induced IgG Ab production. This elevation in the Ab levels was inhibited by CsA treatment in non-sensitized recipients. Conversely, the Ab levels were significantly higher in sensitized recipients than in non-sensitized recipients, regardless of CsA administration. Conclusions: Our data showed that presensitization accelerates chronic allograft rejection with a marked elevation in the level of donor specific IgG Abs. These results suggest that presensitization will be a significant risk factor for the lung transplant recipient, furthermore, the effect of immunosuppression might be insufficient in sensitized recipients.

Original languageEnglish
Pages (from-to)249-254
Number of pages6
JournalTransplant Immunology
Volume17
Issue number4
DOIs
Publication statusPublished - Jun 2007

Fingerprint

Immunosuppression
Cyclosporine
Allografts
Immunoglobulin G
Transplantation
Tissue Donors
Transplants
Isoantibodies
Skin Transplantation
Granulation Tissue
Organ Transplantation
Subcutaneous Injections
Norway
Immunosuppressive Agents
Plasma Cells
Immunoglobulin M
Fibrosis
Lymphocytes
Lung
Skin

Keywords

  • Alloantibody
  • Chronic rejection
  • Flow cytometric cross-match
  • Lung transplantation
  • Presensitization

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Transplantation

Cite this

Presensitization accelerates chronic allograft rejection in a heterotopic rat tracheal allograft model with immunosuppression. / Okumoto, Tatsuo; Yamane, Masaomi; Sano, Yoshifumi; Aoe, Motoi; Date, Hiroshi; Shimizu, Nobuyoshi.

In: Transplant Immunology, Vol. 17, No. 4, 06.2007, p. 249-254.

Research output: Contribution to journalArticle

Okumoto, Tatsuo ; Yamane, Masaomi ; Sano, Yoshifumi ; Aoe, Motoi ; Date, Hiroshi ; Shimizu, Nobuyoshi. / Presensitization accelerates chronic allograft rejection in a heterotopic rat tracheal allograft model with immunosuppression. In: Transplant Immunology. 2007 ; Vol. 17, No. 4. pp. 249-254.
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abstract = "Background: In the field of organ transplantation, the effect of pretransplant humoral allosensitization on the organ transplant outcome has been highlighted. To clarify the correlation of presensitization with chronic rejection that can lead to a poor prognosis in transplant recipients, we examined humoral alloreactivity and allograft rejection in sensitized recipients by using a rat heterotopic tracheal transplant model. Methods: An MHC fully incompatible combination strain was used in this study. Lewis (LEW) rats sensitized by transplantation with Brown Norway (BN) skin grafts received tracheal segments from BN rats in the dorsal subcutaneous pouch. Four allogenic groups (n = 5) were investigated. Group1, non-sensitized recipients without cyclosporine A (CsA) administration; group 2, non-sensitized recipients with CsA administration; group 3, sensitized recipients without CsA administration; and group 4, sensitized recipients with CsA administration. In the immunosuppressant groups (groups 2 and 4), the recipients were administered a subcutaneous injection of CsA (25 mg·kg- 1·day- 1) for 3 days from the day of operation. All recipients were sacrificed 21 days after transplantation. Tracheal segments were extracted from the recipients and histologically evaluated with regard to the following parameters: (1) airway lining epithelial loss, (2) lymphocyte/plasma cell infiltration, and (3) luminal obliteration due to granulation tissue formation and/or fibrosis. In order to analyze alloantibody (allo-Ab) responses, sera samples were tested by the flow cytometric cross-match (FCXM) technique. Results: Histological findings revealed that the chronic rejection score in sensitized recipients treated with CsA was significantly higher than that in non-sensitized recipients treated with CsA (9.0 ± 1.2 vs. 3.0 ± 0.54, p <0.05). In other words, CsA therapy reduced the rejection score in non-sensitized recipients, but not in sensitized recipients. No significant differences were observed in the level of IgM Abs among the groups. However, donor-specific IgG Abs were induced after presensitization by donor skin grafting prior to tracheal transplantation. Heterotopic tracheal implantation also induced IgG Ab production. This elevation in the Ab levels was inhibited by CsA treatment in non-sensitized recipients. Conversely, the Ab levels were significantly higher in sensitized recipients than in non-sensitized recipients, regardless of CsA administration. Conclusions: Our data showed that presensitization accelerates chronic allograft rejection with a marked elevation in the level of donor specific IgG Abs. These results suggest that presensitization will be a significant risk factor for the lung transplant recipient, furthermore, the effect of immunosuppression might be insufficient in sensitized recipients.",
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AU - Okumoto, Tatsuo

AU - Yamane, Masaomi

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AU - Aoe, Motoi

AU - Date, Hiroshi

AU - Shimizu, Nobuyoshi

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N2 - Background: In the field of organ transplantation, the effect of pretransplant humoral allosensitization on the organ transplant outcome has been highlighted. To clarify the correlation of presensitization with chronic rejection that can lead to a poor prognosis in transplant recipients, we examined humoral alloreactivity and allograft rejection in sensitized recipients by using a rat heterotopic tracheal transplant model. Methods: An MHC fully incompatible combination strain was used in this study. Lewis (LEW) rats sensitized by transplantation with Brown Norway (BN) skin grafts received tracheal segments from BN rats in the dorsal subcutaneous pouch. Four allogenic groups (n = 5) were investigated. Group1, non-sensitized recipients without cyclosporine A (CsA) administration; group 2, non-sensitized recipients with CsA administration; group 3, sensitized recipients without CsA administration; and group 4, sensitized recipients with CsA administration. In the immunosuppressant groups (groups 2 and 4), the recipients were administered a subcutaneous injection of CsA (25 mg·kg- 1·day- 1) for 3 days from the day of operation. All recipients were sacrificed 21 days after transplantation. Tracheal segments were extracted from the recipients and histologically evaluated with regard to the following parameters: (1) airway lining epithelial loss, (2) lymphocyte/plasma cell infiltration, and (3) luminal obliteration due to granulation tissue formation and/or fibrosis. In order to analyze alloantibody (allo-Ab) responses, sera samples were tested by the flow cytometric cross-match (FCXM) technique. Results: Histological findings revealed that the chronic rejection score in sensitized recipients treated with CsA was significantly higher than that in non-sensitized recipients treated with CsA (9.0 ± 1.2 vs. 3.0 ± 0.54, p <0.05). In other words, CsA therapy reduced the rejection score in non-sensitized recipients, but not in sensitized recipients. No significant differences were observed in the level of IgM Abs among the groups. However, donor-specific IgG Abs were induced after presensitization by donor skin grafting prior to tracheal transplantation. Heterotopic tracheal implantation also induced IgG Ab production. This elevation in the Ab levels was inhibited by CsA treatment in non-sensitized recipients. Conversely, the Ab levels were significantly higher in sensitized recipients than in non-sensitized recipients, regardless of CsA administration. Conclusions: Our data showed that presensitization accelerates chronic allograft rejection with a marked elevation in the level of donor specific IgG Abs. These results suggest that presensitization will be a significant risk factor for the lung transplant recipient, furthermore, the effect of immunosuppression might be insufficient in sensitized recipients.

AB - Background: In the field of organ transplantation, the effect of pretransplant humoral allosensitization on the organ transplant outcome has been highlighted. To clarify the correlation of presensitization with chronic rejection that can lead to a poor prognosis in transplant recipients, we examined humoral alloreactivity and allograft rejection in sensitized recipients by using a rat heterotopic tracheal transplant model. Methods: An MHC fully incompatible combination strain was used in this study. Lewis (LEW) rats sensitized by transplantation with Brown Norway (BN) skin grafts received tracheal segments from BN rats in the dorsal subcutaneous pouch. Four allogenic groups (n = 5) were investigated. Group1, non-sensitized recipients without cyclosporine A (CsA) administration; group 2, non-sensitized recipients with CsA administration; group 3, sensitized recipients without CsA administration; and group 4, sensitized recipients with CsA administration. In the immunosuppressant groups (groups 2 and 4), the recipients were administered a subcutaneous injection of CsA (25 mg·kg- 1·day- 1) for 3 days from the day of operation. All recipients were sacrificed 21 days after transplantation. Tracheal segments were extracted from the recipients and histologically evaluated with regard to the following parameters: (1) airway lining epithelial loss, (2) lymphocyte/plasma cell infiltration, and (3) luminal obliteration due to granulation tissue formation and/or fibrosis. In order to analyze alloantibody (allo-Ab) responses, sera samples were tested by the flow cytometric cross-match (FCXM) technique. Results: Histological findings revealed that the chronic rejection score in sensitized recipients treated with CsA was significantly higher than that in non-sensitized recipients treated with CsA (9.0 ± 1.2 vs. 3.0 ± 0.54, p <0.05). In other words, CsA therapy reduced the rejection score in non-sensitized recipients, but not in sensitized recipients. No significant differences were observed in the level of IgM Abs among the groups. However, donor-specific IgG Abs were induced after presensitization by donor skin grafting prior to tracheal transplantation. Heterotopic tracheal implantation also induced IgG Ab production. This elevation in the Ab levels was inhibited by CsA treatment in non-sensitized recipients. Conversely, the Ab levels were significantly higher in sensitized recipients than in non-sensitized recipients, regardless of CsA administration. Conclusions: Our data showed that presensitization accelerates chronic allograft rejection with a marked elevation in the level of donor specific IgG Abs. These results suggest that presensitization will be a significant risk factor for the lung transplant recipient, furthermore, the effect of immunosuppression might be insufficient in sensitized recipients.

KW - Alloantibody

KW - Chronic rejection

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KW - Lung transplantation

KW - Presensitization

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