Use of Post-transplant Cyclophosphamide Treatment to Build a Tolerance Platform to Prevent Liquid and Solid Organ Allograft Rejection
Corneal transplantation (CT) is the most frequent type of solid organ transplant (SOT) performed worldwide. Unfortunately, immunological rejection is the primary cause of graft failure for CT and therefore advances in immune regulation to induce tolerance remains an unmet medical need. Recently, our...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.636789/full |
| _version_ | 1818942741669740544 |
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| author | Casey O. Lightbourn Dietlinde Wolf Sabrina N. Copsel Ying Wang Brent J. Pfeiffer Henry Barreras Cameron S. Bader Krishna V. Komanduri Krishna V. Komanduri Victor L. Perez Victor L. Perez Robert B. Levy Robert B. Levy Robert B. Levy Robert B. Levy |
| author_facet | Casey O. Lightbourn Dietlinde Wolf Sabrina N. Copsel Ying Wang Brent J. Pfeiffer Henry Barreras Cameron S. Bader Krishna V. Komanduri Krishna V. Komanduri Victor L. Perez Victor L. Perez Robert B. Levy Robert B. Levy Robert B. Levy Robert B. Levy |
| author_sort | Casey O. Lightbourn |
| collection | DOAJ |
| description | Corneal transplantation (CT) is the most frequent type of solid organ transplant (SOT) performed worldwide. Unfortunately, immunological rejection is the primary cause of graft failure for CT and therefore advances in immune regulation to induce tolerance remains an unmet medical need. Recently, our work and others in pre-clinical studies found that cyclophosphamide (Cy) administered after (“post-transplant,” PTCy) hematopoietic stem cell transplantation (HSCT), i.e., liquid transplants is effective for graft vs. host disease prophylaxis and enhances overall survival. Importantly, within the past 10 years, PTCy has been widely adopted for clinical HSCT and the results at many centers have been extremely encouraging. The present studies found that Cy can be effectively employed to prolong the survival of SOT, specifically mouse corneal allografts. The results demonstrated that the timing of PTCy administration is critical for these CT and distinct from the kinetics employed following allogeneic HSCT. PTCy was observed to interfere with neovascularization, a process critically associated with immune rejection of corneal tissue that ensues following the loss of ocular “immune privilege.” PTCy has the potential to delete or directly suppress allo-reactive T cells and treatment here was shown to diminish T cell rejection responses. These PTCy doses were observed to spare significant levels of CD4+ FoxP3+ (Tregs) which were found to be functional and could readily receive stimulating signals leading to their in vivo expansion via TNFRSF25 and CD25 agonists. In total, we posit future studies can take advantage of Cy based platforms to generate combinatorial strategies for long-term tolerance induction. |
| first_indexed | 2024-12-20T07:16:15Z |
| format | Article |
| id | doaj.art-b85242069f5e4dfaabbc863841896873 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-20T07:16:15Z |
| publishDate | 2021-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-b85242069f5e4dfaabbc8638418968732022-12-21T19:48:47ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-03-011210.3389/fimmu.2021.636789636789Use of Post-transplant Cyclophosphamide Treatment to Build a Tolerance Platform to Prevent Liquid and Solid Organ Allograft RejectionCasey O. Lightbourn0Dietlinde Wolf1Sabrina N. Copsel2Ying Wang3Brent J. Pfeiffer4Henry Barreras5Cameron S. Bader6Krishna V. Komanduri7Krishna V. Komanduri8Victor L. Perez9Victor L. Perez10Robert B. Levy11Robert B. Levy12Robert B. Levy13Robert B. Levy14Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, United StatesSylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, United StatesDepartment of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, United StatesDepartment of Ophthalmology, Miller School of Medicine, University of Miami, Miami, FL, United StatesDepartment of Pediatrics, Miller School of Medicine, University of Miami, Miami, FL, United StatesDepartment of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, United StatesDepartment of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, United StatesSylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, United StatesDepartment of Medicine, Miller School of Medicine, University of Miami, Miami, FL, United StatesDepartment of Ophthalmology, Miller School of Medicine, University of Miami, Miami, FL, United StatesFoster Center for Ocular Immunology at Duke Eye Center, Duke University, Durham, NC, United StatesDepartment of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL, United StatesSylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, United StatesDepartment of Pediatrics, Miller School of Medicine, University of Miami, Miami, FL, United StatesDepartment of Medicine, Miller School of Medicine, University of Miami, Miami, FL, United StatesCorneal transplantation (CT) is the most frequent type of solid organ transplant (SOT) performed worldwide. Unfortunately, immunological rejection is the primary cause of graft failure for CT and therefore advances in immune regulation to induce tolerance remains an unmet medical need. Recently, our work and others in pre-clinical studies found that cyclophosphamide (Cy) administered after (“post-transplant,” PTCy) hematopoietic stem cell transplantation (HSCT), i.e., liquid transplants is effective for graft vs. host disease prophylaxis and enhances overall survival. Importantly, within the past 10 years, PTCy has been widely adopted for clinical HSCT and the results at many centers have been extremely encouraging. The present studies found that Cy can be effectively employed to prolong the survival of SOT, specifically mouse corneal allografts. The results demonstrated that the timing of PTCy administration is critical for these CT and distinct from the kinetics employed following allogeneic HSCT. PTCy was observed to interfere with neovascularization, a process critically associated with immune rejection of corneal tissue that ensues following the loss of ocular “immune privilege.” PTCy has the potential to delete or directly suppress allo-reactive T cells and treatment here was shown to diminish T cell rejection responses. These PTCy doses were observed to spare significant levels of CD4+ FoxP3+ (Tregs) which were found to be functional and could readily receive stimulating signals leading to their in vivo expansion via TNFRSF25 and CD25 agonists. In total, we posit future studies can take advantage of Cy based platforms to generate combinatorial strategies for long-term tolerance induction.https://www.frontiersin.org/articles/10.3389/fimmu.2021.636789/fullcyclophosphamideTregcorneal transplantationhematopoietic stem cell transplantationtolerance |
| spellingShingle | Casey O. Lightbourn Dietlinde Wolf Sabrina N. Copsel Ying Wang Brent J. Pfeiffer Henry Barreras Cameron S. Bader Krishna V. Komanduri Krishna V. Komanduri Victor L. Perez Victor L. Perez Robert B. Levy Robert B. Levy Robert B. Levy Robert B. Levy Use of Post-transplant Cyclophosphamide Treatment to Build a Tolerance Platform to Prevent Liquid and Solid Organ Allograft Rejection Frontiers in Immunology cyclophosphamide Treg corneal transplantation hematopoietic stem cell transplantation tolerance |
| title | Use of Post-transplant Cyclophosphamide Treatment to Build a Tolerance Platform to Prevent Liquid and Solid Organ Allograft Rejection |
| title_full | Use of Post-transplant Cyclophosphamide Treatment to Build a Tolerance Platform to Prevent Liquid and Solid Organ Allograft Rejection |
| title_fullStr | Use of Post-transplant Cyclophosphamide Treatment to Build a Tolerance Platform to Prevent Liquid and Solid Organ Allograft Rejection |
| title_full_unstemmed | Use of Post-transplant Cyclophosphamide Treatment to Build a Tolerance Platform to Prevent Liquid and Solid Organ Allograft Rejection |
| title_short | Use of Post-transplant Cyclophosphamide Treatment to Build a Tolerance Platform to Prevent Liquid and Solid Organ Allograft Rejection |
| title_sort | use of post transplant cyclophosphamide treatment to build a tolerance platform to prevent liquid and solid organ allograft rejection |
| topic | cyclophosphamide Treg corneal transplantation hematopoietic stem cell transplantation tolerance |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.636789/full |
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