Ex Vivo Alloanergization with Belatacept: A Strategy to Selectively Modulate Alloresponses after Transplantation
Ex vivo alloanergization of human immune cells, via allostimulation in the presence of costimulatory blockade with either a combination of anti-B7.1 and anti-B7.2 antibodies or first-generation cytotoxic T-lymphocyte antigen 4-immunoglobulin (CTLA4-Ig), induces alloantigen-specific hyporesponsivenes...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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SAGE Publishing
2012-09-01
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| Series: | Cell Transplantation |
| Online Access: | https://doi.org/10.3727/096368912X637479 |
| _version_ | 1811327890001756160 |
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| author | Jeff K. Davies Christine M. Barbon Annie Voskertchian Lee M. Nadler Eva C. Guinan |
| author_facet | Jeff K. Davies Christine M. Barbon Annie Voskertchian Lee M. Nadler Eva C. Guinan |
| author_sort | Jeff K. Davies |
| collection | DOAJ |
| description | Ex vivo alloanergization of human immune cells, via allostimulation in the presence of costimulatory blockade with either a combination of anti-B7.1 and anti-B7.2 antibodies or first-generation cytotoxic T-lymphocyte antigen 4-immunoglobulin (CTLA4-Ig), induces alloantigen-specific hyporesponsiveness and expands alloantigen-specific regulatory T cells (Treg). We have successfully used this approach in the clinical setting of haploidentical hematopoietic stem cell transplantation. Recently, the in vivo use of a new second-generation CTLA4-Ig, belatacept, has shown promise in controlling alloresponses after transplantation of both human kidneys and islet cells. We therefore compared the efficiency of first- and second-generation CTLA4-Ig in alloanergizing human peripheral blood mononuclear cells (PBMCs) and investigated whether ex vivo alloanergization with belatacept could be used to engineer an alloantigen-specific immunoregulatory population of autologous cells suitable for administration to recipients of cellular or solid organ transplant recipients. Alloanergization of HLA-mismatched human PBMCs with belatacept resulted in a greater reduction in subsequent alloresponses than alloanergization with first generation CTLA4-Ig. Moreover, subsequent ex vivo re-exposure of alloanergized cells to alloantigen in the absence of belatacept resulted in a significant expansion of Tregs with enhanced alloantigen-specific suppressive function. Alloanergized PBMCs retained functional Epstein-Barr virus (EBV)-specific T-cell responses, and expanded Tregs did not suppress EBV-specific proliferation of autologous cells. These results suggest that ex vivo alloanergization with belatacept provides a platform to engineer populations of recipient Treg with specificity for donor alloantigens but without nonspecific suppressive capacity. The potential advantages of such cells for solid organ transplantation include ( 1 ) reduction of the need for nonspecific immunosuppression, ( 2 ) retention of pathogen-specific immunity, and ( 3 ) control of graft rejection, if used as an intervention. |
| first_indexed | 2024-04-13T15:15:53Z |
| format | Article |
| id | doaj.art-9917ab872c68469eb03db47457f8b329 |
| institution | Directory Open Access Journal |
| issn | 0963-6897 1555-3892 |
| language | English |
| last_indexed | 2024-04-13T15:15:53Z |
| publishDate | 2012-09-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Cell Transplantation |
| spelling | doaj.art-9917ab872c68469eb03db47457f8b3292022-12-22T02:41:53ZengSAGE PublishingCell Transplantation0963-68971555-38922012-09-012110.3727/096368912X637479Ex Vivo Alloanergization with Belatacept: A Strategy to Selectively Modulate Alloresponses after TransplantationJeff K. Davies0Christine M. Barbon1Annie Voskertchian2Lee M. Nadler3Eva C. Guinan4Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, UKDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USABrigham and Women's Hospital, Boston, MA, USADepartments of Radiation Oncology and Pediatrics, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USAEx vivo alloanergization of human immune cells, via allostimulation in the presence of costimulatory blockade with either a combination of anti-B7.1 and anti-B7.2 antibodies or first-generation cytotoxic T-lymphocyte antigen 4-immunoglobulin (CTLA4-Ig), induces alloantigen-specific hyporesponsiveness and expands alloantigen-specific regulatory T cells (Treg). We have successfully used this approach in the clinical setting of haploidentical hematopoietic stem cell transplantation. Recently, the in vivo use of a new second-generation CTLA4-Ig, belatacept, has shown promise in controlling alloresponses after transplantation of both human kidneys and islet cells. We therefore compared the efficiency of first- and second-generation CTLA4-Ig in alloanergizing human peripheral blood mononuclear cells (PBMCs) and investigated whether ex vivo alloanergization with belatacept could be used to engineer an alloantigen-specific immunoregulatory population of autologous cells suitable for administration to recipients of cellular or solid organ transplant recipients. Alloanergization of HLA-mismatched human PBMCs with belatacept resulted in a greater reduction in subsequent alloresponses than alloanergization with first generation CTLA4-Ig. Moreover, subsequent ex vivo re-exposure of alloanergized cells to alloantigen in the absence of belatacept resulted in a significant expansion of Tregs with enhanced alloantigen-specific suppressive function. Alloanergized PBMCs retained functional Epstein-Barr virus (EBV)-specific T-cell responses, and expanded Tregs did not suppress EBV-specific proliferation of autologous cells. These results suggest that ex vivo alloanergization with belatacept provides a platform to engineer populations of recipient Treg with specificity for donor alloantigens but without nonspecific suppressive capacity. The potential advantages of such cells for solid organ transplantation include ( 1 ) reduction of the need for nonspecific immunosuppression, ( 2 ) retention of pathogen-specific immunity, and ( 3 ) control of graft rejection, if used as an intervention.https://doi.org/10.3727/096368912X637479 |
| spellingShingle | Jeff K. Davies Christine M. Barbon Annie Voskertchian Lee M. Nadler Eva C. Guinan Ex Vivo Alloanergization with Belatacept: A Strategy to Selectively Modulate Alloresponses after Transplantation Cell Transplantation |
| title | Ex Vivo Alloanergization with Belatacept: A Strategy to Selectively Modulate Alloresponses after Transplantation |
| title_full | Ex Vivo Alloanergization with Belatacept: A Strategy to Selectively Modulate Alloresponses after Transplantation |
| title_fullStr | Ex Vivo Alloanergization with Belatacept: A Strategy to Selectively Modulate Alloresponses after Transplantation |
| title_full_unstemmed | Ex Vivo Alloanergization with Belatacept: A Strategy to Selectively Modulate Alloresponses after Transplantation |
| title_short | Ex Vivo Alloanergization with Belatacept: A Strategy to Selectively Modulate Alloresponses after Transplantation |
| title_sort | ex vivo alloanergization with belatacept a strategy to selectively modulate alloresponses after transplantation |
| url | https://doi.org/10.3727/096368912X637479 |
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