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Abstract
Inhibition of the costimulatory molecules B7 and CD40L with CTLA4Ig and anti-CD40L administered only during the first week after transplantation induces indefinite survival of allo- and xenogeneic heart transplants and significantly prolongs skin grafts in C3H mice. However, this treatment protocol is not as effective in C57BL/6 mice which reject skin transplants with nearly the same median survival time as untreated controls. This has been shown to be due to the ability of CD8+ T cells to be activated autonomously of B7 or CD40L costimulation. LFA-1 is an important signaling molecule for CD8+ T cell function and we therefore hypothesized that its inhibition may compliment B7 and CD40L blockade and induce indefinite survival of transplants in mice.
Anti-LFA-1 combined with CTLA4Ig induced indefinite survival of heart transplants after one week of treatment. Anti-LFA-1 also prevented immune responses and chronic vasculopathy in CD40L -/- mice. When CTLA4Ig was combined with anti-LFA-1 and given to CD40L -/- mice, dopaminergic porcine xenografts were accepted without any signs of rejection. The combination of anti-CD40L, CTLA4Ig and anti-LFA-1 induced permanent acceptance of dopaminergic porcine grafts in wild-type C57BL/6 mice. Surprisingly these recipients could be induced to rejected their grafts if challenged with glia cells of donor origin indicating that regulatory T cells maybe involved in the acceptance of these transplants. In order to ascertain the importance of regulatory T cells, IL-10 deficient mice were transplanted with allogeneic heart transplants and treated with costimulation blockade. A majority of these hearts stopped beating two days after transplantation succumbing to a massive neutrophilic infiltrate resembling myocardial infarction. The remaining hearts were rejected with in 50 days after transplantation. These results indicate that anti-LFA-1 can compliment CTLA4Ig and anti-CD40L in the induction of operational tolerance and that this state is facilitated by IL-10 and indirectly regulatory T cells.
Anti-LFA-1 combined with CTLA4Ig induced indefinite survival of heart transplants after one week of treatment. Anti-LFA-1 also prevented immune responses and chronic vasculopathy in CD40L -/- mice. When CTLA4Ig was combined with anti-LFA-1 and given to CD40L -/- mice, dopaminergic porcine xenografts were accepted without any signs of rejection. The combination of anti-CD40L, CTLA4Ig and anti-LFA-1 induced permanent acceptance of dopaminergic porcine grafts in wild-type C57BL/6 mice. Surprisingly these recipients could be induced to rejected their grafts if challenged with glia cells of donor origin indicating that regulatory T cells maybe involved in the acceptance of these transplants. In order to ascertain the importance of regulatory T cells, IL-10 deficient mice were transplanted with allogeneic heart transplants and treated with costimulation blockade. A majority of these hearts stopped beating two days after transplantation succumbing to a massive neutrophilic infiltrate resembling myocardial infarction. The remaining hearts were rejected with in 50 days after transplantation. These results indicate that anti-LFA-1 can compliment CTLA4Ig and anti-CD40L in the induction of operational tolerance and that this state is facilitated by IL-10 and indirectly regulatory T cells.
| Original language | English |
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| Qualification | Doctor |
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| Award date | 2002 Nov 25 |
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| ISBN (Print) | 91-628-5444-5 |
| Publication status | Published - 2002 |
Bibliographical note
Defence detailsDate: 2002-11-25
Time: 09:15
Place: Kirurgens föreläsningssal kl 9.15, 25 november 2002
External reviewer(s)
Name: Wood, Kathryn
Title: Prof
Affiliation: University of Oxford, Nuffield Department of Surgery
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Article: I. Matthias Corbascio, Helene Ekstrand, Cecilia Österholm, Zhongquan Qi, Mecislovas Simanaitis, Christian P. Larsen, Thomas C. Pearson, Kristian Riesbeck, Henrik Ekberg. CTLA4Ig combined with anti-LFA-1 prolongs cardiac allograft survival indefinitely. Transplant Immunology. 2002 Jun:10(1);55-61.
Article: II. Matthias Corbascio, Harish Mahanty, Cecilia Österholm, Zhongquan Qi, Thomas C Pearson, Christian P. Larsen, Chris E. Freise, Henrik Ekberg. Anti-lymphocyte function-associated antigen-1 inhibits CD40 ligand-independent immune responses and prevents chronic vasculopathy in CD40 ligand-deficient mice. Transplantation. 2002 Jul15;74(1):35-41.
Article: III. Lena C. Larsson *, Matthias Corbascio *, Håkan Widner, Thomas C. Pearson,Christian P. Larsen, Henrik Ekberg. Simultaneous inhibition of B7 and LFA-1 signaling prevents rejection of discordant neural xenografts in mice lacking CD40L. Xenotransplantation. 2002 Jan;9(1):68-76.* These authors contributed equally to this study.
Article: IV. Lena C. Larsson* , Matthias Corbascio *, Christian P. Larsen, Thomas C. Pearson,Henrik Ekberg, Håkan Widner. Induction of operational tolerance to discordant dopaminergic porcine xenografts. Accepted for publication in Transplantation.* These authors contributed equally to this study.
Article: V. Matthias Corbascio, Zhongquan Qi, Cecilia Österholm, Bela Veras, Thomas C. Pearson, Christian P. Larsen, Henrik Ekberg. Operational tolerance induced by costimulation blockade is facilitated by IL-10. Manuscript.
The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Emergency medicine/Medicine/Surgery (013240200)
Subject classification (UKÄ)
- Clinical Medicine
Free keywords
- transplantation
- Immunologi
- serologi
- serology
- Immunology
- allograft
- xenograft
- heart transplantation
- tolerance
- anti-LFA-1
- CTLA4Ig
- anti-CD40L
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Dive into the research topics of 'Induction of operational tolerance to allografts and xenografts'. Together they form a unique fingerprint.Research output
- 4 Article
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Induction of operational tolerance to discordant dopaminergic porcine xenografts.
Larsson, L. C., Corbascio, M., Pearson, T. C., Larsen, C. P., Ekberg, H. & Widner, H., 2003, In: Transplantation. 75, 9, p. 1448-1454Research output: Contribution to journal › Article › peer-review
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Anti-lymphocyte function-associated antigen-1 monoclonal antibody inhibits CD40 ligand-independent immune responses and prevents chronic vasculopathy in CD40 ligand-deficient mice.
Corbascio, M., Mahanty, H., Österholm, C., Qi, Z., Pearson, T. C., Larsen, C. P., Freise, C. E. & Ekberg, H., 2002, In: Transplantation. 74, 1, p. 35-41Research output: Contribution to journal › Article › peer-review
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CTLA4Ig combined with anti-LFA-1 prolongs cardiac allograft survival indefinitely.
Corbascio, M., Ekstrand, H., Österholm, C., Qi, Z., Simanaitis, M., Larsen, C. P., Pearson, T. C., Riesbeck, K. & Ekberg, H., 2002, In: Transplant Immunology. 10, 1, p. 55-61Research output: Contribution to journal › Article › peer-review