Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig dosing regimen
IntroductionIn de-novo kidney transplantation, the CTLA4-Ig fusion protein belatacept is associated with improved graft function but also an increased risk of acute rejection compared to calcineurin inhibitor therapy. The combination with a second costimulation blocker could potentially improve outc...
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| Format: | Article |
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1060576/full |
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| author | Lukas W. Unger Lukas W. Unger Moritz Muckenhuber Benedikt Mahr Christoph Schwarz Christoph Schwarz Nina Pilat Nicolas Granofszky Heinz Regele Thomas Wekerle |
| author_facet | Lukas W. Unger Lukas W. Unger Moritz Muckenhuber Benedikt Mahr Christoph Schwarz Christoph Schwarz Nina Pilat Nicolas Granofszky Heinz Regele Thomas Wekerle |
| author_sort | Lukas W. Unger |
| collection | DOAJ |
| description | IntroductionIn de-novo kidney transplantation, the CTLA4-Ig fusion protein belatacept is associated with improved graft function but also an increased risk of acute rejection compared to calcineurin inhibitor therapy. The combination with a second costimulation blocker could potentially improve outcome while avoiding calcineurin inhibitor toxicity. The aim of this study was to define the conditions under which the combination of CTLA4-Ig and CD40L blockade leads to rejection-free permanent graft survival in a stringent murine heart transplantation model.MethodsNaïve wild-type or CD40L (CD154) knock-out mice received a fully mismatched BALB/c cardiac allograft. Selected induction and maintenance protocols for CTLA4-Ig and blocking αCD40L monoclonal antibodies (mAB) were investigated. Graft survival, rejection severity and donor-specific antibody (DSA) formation were assessed during a 100-day follow-up period.Results and DiscussionAdministering αCD40L mAb as monotherapy at the time of transplantation significantly prolonged heart allograft survival but did not further improve the outcome when given in addition to chronic CTLA4-Ig therapy (which prolongs graft survival to a median of 22 days). Likewise, chronic αCD40L mAb therapy (0.5mg) combined with perioperative CTLA4-Ig led to rejection in a proportion of mice and extensive histological damage, despite abrogating DSA formation. Only the permanent interruption of CD40-CD40L signaling by using CD40L-/- recipient mice or by chronic αCD40L administration synergized with chronic CTLA4-Ig to achieve long-term allograft survival with preserved histological graft integrity in all recipients without DSA formation. The combination of α-CD40L and CTLA4-Ig works most effectively when both therapeutics are administered chronically. |
| first_indexed | 2024-04-11T06:11:15Z |
| format | Article |
| id | doaj.art-cf0b9771b7fe450e935b274c5ec19e8b |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-11T06:11:15Z |
| publishDate | 2022-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-cf0b9771b7fe450e935b274c5ec19e8b2022-12-22T04:41:17ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-12-011310.3389/fimmu.2022.10605761060576Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig dosing regimenLukas W. Unger0Lukas W. Unger1Moritz Muckenhuber2Benedikt Mahr3Christoph Schwarz4Christoph Schwarz5Nina Pilat6Nicolas Granofszky7Heinz Regele8Thomas Wekerle9Department of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, AustriaDepartment of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, AustriaDepartment of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, AustriaDepartment of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, AustriaDepartment of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, AustriaDepartment of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, AustriaDepartment of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, AustriaDepartment of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, AustriaClinical Institute of Pathology, Medical University of Vienna, Vienna, AustriaDepartment of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, AustriaIntroductionIn de-novo kidney transplantation, the CTLA4-Ig fusion protein belatacept is associated with improved graft function but also an increased risk of acute rejection compared to calcineurin inhibitor therapy. The combination with a second costimulation blocker could potentially improve outcome while avoiding calcineurin inhibitor toxicity. The aim of this study was to define the conditions under which the combination of CTLA4-Ig and CD40L blockade leads to rejection-free permanent graft survival in a stringent murine heart transplantation model.MethodsNaïve wild-type or CD40L (CD154) knock-out mice received a fully mismatched BALB/c cardiac allograft. Selected induction and maintenance protocols for CTLA4-Ig and blocking αCD40L monoclonal antibodies (mAB) were investigated. Graft survival, rejection severity and donor-specific antibody (DSA) formation were assessed during a 100-day follow-up period.Results and DiscussionAdministering αCD40L mAb as monotherapy at the time of transplantation significantly prolonged heart allograft survival but did not further improve the outcome when given in addition to chronic CTLA4-Ig therapy (which prolongs graft survival to a median of 22 days). Likewise, chronic αCD40L mAb therapy (0.5mg) combined with perioperative CTLA4-Ig led to rejection in a proportion of mice and extensive histological damage, despite abrogating DSA formation. Only the permanent interruption of CD40-CD40L signaling by using CD40L-/- recipient mice or by chronic αCD40L administration synergized with chronic CTLA4-Ig to achieve long-term allograft survival with preserved histological graft integrity in all recipients without DSA formation. The combination of α-CD40L and CTLA4-Ig works most effectively when both therapeutics are administered chronically.https://www.frontiersin.org/articles/10.3389/fimmu.2022.1060576/fullcostimulation blockadeCTLA4IgCD40L blockademurine cardiac allotransplanttransplantation |
| spellingShingle | Lukas W. Unger Lukas W. Unger Moritz Muckenhuber Benedikt Mahr Christoph Schwarz Christoph Schwarz Nina Pilat Nicolas Granofszky Heinz Regele Thomas Wekerle Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig dosing regimen Frontiers in Immunology costimulation blockade CTLA4Ig CD40L blockade murine cardiac allotransplant transplantation |
| title | Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig dosing regimen |
| title_full | Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig dosing regimen |
| title_fullStr | Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig dosing regimen |
| title_full_unstemmed | Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig dosing regimen |
| title_short | Chronic CD40L blockade is required for long-term cardiac allograft survival with a clinically relevant CTLA4-Ig dosing regimen |
| title_sort | chronic cd40l blockade is required for long term cardiac allograft survival with a clinically relevant ctla4 ig dosing regimen |
| topic | costimulation blockade CTLA4Ig CD40L blockade murine cardiac allotransplant transplantation |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1060576/full |
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