Differential effects of costimulatory pathway modulation on corneal allograft survival
PURPOSE: T lymphocytes have a central role in allograft rejection. On engagement of the T cell receptor by antigenic peptide-major histocompatibility complex (MHC) complex, a second "costimulatory" signal is critical to full T-cell activation or downregulation. In this study, the effect on corneal allograft survival of modulation of the costimulatory molecules programmed death-1 (PD-1) and inducible costimulatory (ICOS) molecule was examined. These molecules are known to modulate, respectively, negative or positive T-cell activation signals.
METHODS: A dimeric PD-L1 immunoglobulin (Ig) fusion protein was generated to stimulate the inhibitory receptor PD-1, and a monoclonal antibody was used to block ICOS. The effect of PD-1 engagement and ICOS blockade on lymphocyte activation by in vitro T-cell proliferation and the effect on orthotopic corneal allograft survival in BALB/c mice were determined.
RESULTS: Both reagents demonstrated T-cell inhibition in vitro. PD-L1.Ig treatment of BALB/c mice prolonged fully MHC-mismatched C3H donor corneal allograft survival, with a median survival time (MST) of 21 days. This was significantly prolonged compared to isotype control protein-treated recipients (MST 13 days, P < 0.003). Allograft survival in BALB/c recipients treated with anti-ICOS antibody showed no prolongation of survival compared with the isotype control antibody (MST, 12 days in both groups).
CONCLUSIONS: Augmented ligation of the PD-1 negative costimulatory molecule significantly prolongs corneal allograft survival. However, in contrast to findings in other allograft models, signaling through the positive costimulatory molecule ICOS appears to be less important in allogeneic rejection of cornea.
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2006 |
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| Erschienen: |
2006 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:47 |
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| Enthalten in: |
Investigative ophthalmology & visual science - 47(2006), 8 vom: 22. Aug., Seite 3417-22 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Watson, Martin P [VerfasserIn] |
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| Anmerkungen: |
Date Completed 31.08.2006 Date Revised 17.11.2011 published: Print Citation Status MEDLINE |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM164477918 |
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| 100 | 1 | |a Watson, Martin P |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Differential effects of costimulatory pathway modulation on corneal allograft survival |
| 264 | 1 | |c 2006 | |
| 336 | |a Text |b txt |2 rdacontent | ||
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| 338 | |a Band |b nc |2 rdacarrier | ||
| 500 | |a Date Completed 31.08.2006 | ||
| 500 | |a Date Revised 17.11.2011 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a PURPOSE: T lymphocytes have a central role in allograft rejection. On engagement of the T cell receptor by antigenic peptide-major histocompatibility complex (MHC) complex, a second "costimulatory" signal is critical to full T-cell activation or downregulation. In this study, the effect on corneal allograft survival of modulation of the costimulatory molecules programmed death-1 (PD-1) and inducible costimulatory (ICOS) molecule was examined. These molecules are known to modulate, respectively, negative or positive T-cell activation signals | ||
| 520 | |a METHODS: A dimeric PD-L1 immunoglobulin (Ig) fusion protein was generated to stimulate the inhibitory receptor PD-1, and a monoclonal antibody was used to block ICOS. The effect of PD-1 engagement and ICOS blockade on lymphocyte activation by in vitro T-cell proliferation and the effect on orthotopic corneal allograft survival in BALB/c mice were determined | ||
| 520 | |a RESULTS: Both reagents demonstrated T-cell inhibition in vitro. PD-L1.Ig treatment of BALB/c mice prolonged fully MHC-mismatched C3H donor corneal allograft survival, with a median survival time (MST) of 21 days. This was significantly prolonged compared to isotype control protein-treated recipients (MST 13 days, P < 0.003). Allograft survival in BALB/c recipients treated with anti-ICOS antibody showed no prolongation of survival compared with the isotype control antibody (MST, 12 days in both groups) | ||
| 520 | |a CONCLUSIONS: Augmented ligation of the PD-1 negative costimulatory molecule significantly prolongs corneal allograft survival. However, in contrast to findings in other allograft models, signaling through the positive costimulatory molecule ICOS appears to be less important in allogeneic rejection of cornea | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Antigens, Differentiation, T-Lymphocyte |2 NLM | |
| 650 | 7 | |a Antigens, Surface |2 NLM | |
| 650 | 7 | |a Apoptosis Regulatory Proteins |2 NLM | |
| 650 | 7 | |a Icos protein, mouse |2 NLM | |
| 650 | 7 | |a Inducible T-Cell Co-Stimulator Protein |2 NLM | |
| 650 | 7 | |a Pdcd1 protein, mouse |2 NLM | |
| 650 | 7 | |a Programmed Cell Death 1 Receptor |2 NLM | |
| 650 | 7 | |a Recombinant Fusion Proteins |2 NLM | |
| 700 | 1 | |a George, Andrew J T |e verfasserin |4 aut | |
| 700 | 1 | |a Larkin, Daniel F P |e verfasserin |4 aut | |
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