Renal allograft rejection, lymphocyte infiltration, and de novo donor-specific antibodies in a novel model of non-adherence to immunosuppressive therapy
Abstract Background Non-adherence has been associated with reduced graft survival. The aim of this study was to investigate the immunological mechanisms underlying chronic renal allograft rejection using a model of non-adherence to immunosuppressive therapy. We used a MHC (major histocompatibility c...
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| Language: | English |
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BMC
2017-12-01
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| Series: | BMC Immunology |
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| Online Access: | http://link.springer.com/article/10.1186/s12865-017-0236-6 |
| _version_ | 1828793188976951296 |
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| author | Louisa Kühne Bettina Jung Helen Poth Antonia Schuster Simone Wurm Petra Ruemmele Bernhard Banas Tobias Bergler |
| author_facet | Louisa Kühne Bettina Jung Helen Poth Antonia Schuster Simone Wurm Petra Ruemmele Bernhard Banas Tobias Bergler |
| author_sort | Louisa Kühne |
| collection | DOAJ |
| description | Abstract Background Non-adherence has been associated with reduced graft survival. The aim of this study was to investigate the immunological mechanisms underlying chronic renal allograft rejection using a model of non-adherence to immunosuppressive therapy. We used a MHC (major histocompatibility complex) -mismatched rat model of renal transplantation (Brown Norway to Lewis), in which rats received daily oral cyclosporine A. In analogy to non-adherence to therapy, one group received cyclosporine A on alternating days only. Rejection was histologically graded according to the Banff classification. We quantified fibrosis by trichrome staining and intra-graft infiltration of T cells, B cells, and monocytes/macrophages by immunohistochemistry. The distribution of B lymphocytes was assessed using immunofluorescence microscopy. Intra-graft chemokine, chemokine receptor, BAFF (B cell activating factor belonging to the TNF family), and immunoglobulin G transcription levels were analysed by RT-PCR. Finally, we evaluated donor-specific antibodies (DSA) and complement-dependent cytotoxicity using flow cytometry. Results After 28 days, cellular rejection occurred during non-adherence in 5/6 animals, mixed with humoral rejection in 3/6 animals. After non-adherence, the number of T lymphocytes were elevated compared to daily immunosuppression. Monocyte numbers declined over time. Accordingly, lymphocyte chemokine transcription was significantly increased in the graft, as was the transcription of BAFF, BAFF receptor, and Immunoglobulin G. Donor specific antibodies were elevated in non-adherence, but did not induce complement-dependent cytotoxicity. Conclusion Cellular and humoral rejection, lymphocyte infiltration, and de novo DSA are induced in this model of non-adherence. |
| first_indexed | 2024-12-12T03:23:02Z |
| format | Article |
| id | doaj.art-aa5e1048859641d39a46708aa7409694 |
| institution | Directory Open Access Journal |
| issn | 1471-2172 |
| language | English |
| last_indexed | 2024-12-12T03:23:02Z |
| publishDate | 2017-12-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Immunology |
| spelling | doaj.art-aa5e1048859641d39a46708aa74096942022-12-22T00:40:08ZengBMCBMC Immunology1471-21722017-12-0118111410.1186/s12865-017-0236-6Renal allograft rejection, lymphocyte infiltration, and de novo donor-specific antibodies in a novel model of non-adherence to immunosuppressive therapyLouisa Kühne0Bettina Jung1Helen Poth2Antonia Schuster3Simone Wurm4Petra Ruemmele5Bernhard Banas6Tobias Bergler7Department of Nephrology, University Hospital RegensburgDepartment of Nephrology, University Hospital RegensburgDepartment of Nephrology, University Hospital RegensburgDepartment of Nephrology, University Hospital RegensburgDepartment of Nephrology, University Hospital RegensburgDepartment of Pathology, University Hospital ErlangenDepartment of Nephrology, University Hospital RegensburgDepartment of Nephrology, University Hospital RegensburgAbstract Background Non-adherence has been associated with reduced graft survival. The aim of this study was to investigate the immunological mechanisms underlying chronic renal allograft rejection using a model of non-adherence to immunosuppressive therapy. We used a MHC (major histocompatibility complex) -mismatched rat model of renal transplantation (Brown Norway to Lewis), in which rats received daily oral cyclosporine A. In analogy to non-adherence to therapy, one group received cyclosporine A on alternating days only. Rejection was histologically graded according to the Banff classification. We quantified fibrosis by trichrome staining and intra-graft infiltration of T cells, B cells, and monocytes/macrophages by immunohistochemistry. The distribution of B lymphocytes was assessed using immunofluorescence microscopy. Intra-graft chemokine, chemokine receptor, BAFF (B cell activating factor belonging to the TNF family), and immunoglobulin G transcription levels were analysed by RT-PCR. Finally, we evaluated donor-specific antibodies (DSA) and complement-dependent cytotoxicity using flow cytometry. Results After 28 days, cellular rejection occurred during non-adherence in 5/6 animals, mixed with humoral rejection in 3/6 animals. After non-adherence, the number of T lymphocytes were elevated compared to daily immunosuppression. Monocyte numbers declined over time. Accordingly, lymphocyte chemokine transcription was significantly increased in the graft, as was the transcription of BAFF, BAFF receptor, and Immunoglobulin G. Donor specific antibodies were elevated in non-adherence, but did not induce complement-dependent cytotoxicity. Conclusion Cellular and humoral rejection, lymphocyte infiltration, and de novo DSA are induced in this model of non-adherence.http://link.springer.com/article/10.1186/s12865-017-0236-6Donor specific antibodiesHumoral rejectionRenal transplantationNon-adherenceLeukocyte infiltrationBAFF |
| spellingShingle | Louisa Kühne Bettina Jung Helen Poth Antonia Schuster Simone Wurm Petra Ruemmele Bernhard Banas Tobias Bergler Renal allograft rejection, lymphocyte infiltration, and de novo donor-specific antibodies in a novel model of non-adherence to immunosuppressive therapy BMC Immunology Donor specific antibodies Humoral rejection Renal transplantation Non-adherence Leukocyte infiltration BAFF |
| title | Renal allograft rejection, lymphocyte infiltration, and de novo donor-specific antibodies in a novel model of non-adherence to immunosuppressive therapy |
| title_full | Renal allograft rejection, lymphocyte infiltration, and de novo donor-specific antibodies in a novel model of non-adherence to immunosuppressive therapy |
| title_fullStr | Renal allograft rejection, lymphocyte infiltration, and de novo donor-specific antibodies in a novel model of non-adherence to immunosuppressive therapy |
| title_full_unstemmed | Renal allograft rejection, lymphocyte infiltration, and de novo donor-specific antibodies in a novel model of non-adherence to immunosuppressive therapy |
| title_short | Renal allograft rejection, lymphocyte infiltration, and de novo donor-specific antibodies in a novel model of non-adherence to immunosuppressive therapy |
| title_sort | renal allograft rejection lymphocyte infiltration and de novo donor specific antibodies in a novel model of non adherence to immunosuppressive therapy |
| topic | Donor specific antibodies Humoral rejection Renal transplantation Non-adherence Leukocyte infiltration BAFF |
| url | http://link.springer.com/article/10.1186/s12865-017-0236-6 |
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