IL‐6 receptor blockade for allograft dysfunction after lung transplantation in a patient with COPA syndrome
Abstract Objective COPA syndrome is a genetic disorder of retrograde cis‐Golgi vesicle transport that leads to upregulation of pro‐inflammatory cytokines (mainly IL‐1β and IL‐6) and the development of interstitial lung disease (ILD). The impact of COPA syndrome on post‐lung transplant (LTx) outcome...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2021-01-01
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| Series: | Clinical & Translational Immunology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/cti2.1243 |
| _version_ | 1828890198660874240 |
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| author | Peter Riddell Sajad Moshkelgosha Liran Levy Nina Chang Prodipto Pal Kieran Halloran Phil Halloran Michael Parkes Lianne G Singer Shaf Keshavjee Tereza Martinu Stephen C Juvet |
| author_facet | Peter Riddell Sajad Moshkelgosha Liran Levy Nina Chang Prodipto Pal Kieran Halloran Phil Halloran Michael Parkes Lianne G Singer Shaf Keshavjee Tereza Martinu Stephen C Juvet |
| author_sort | Peter Riddell |
| collection | DOAJ |
| description | Abstract Objective COPA syndrome is a genetic disorder of retrograde cis‐Golgi vesicle transport that leads to upregulation of pro‐inflammatory cytokines (mainly IL‐1β and IL‐6) and the development of interstitial lung disease (ILD). The impact of COPA syndrome on post‐lung transplant (LTx) outcome is unknown but potentially detrimental. In this case report, we describe progressive allograft dysfunction following LTx for COPA‐ILD. Following the failure of standard immunosuppressive approaches, detailed cytokine analysis was performed with the intention of personalising therapy. Methods Multiplexed cytokine analysis was performed on serum and bronchoalveolar lavage (BAL) fluid obtained pre‐ and post‐LTx. Peripheral blood mononuclear cells (PMBCs) obtained pre‐ and post‐LTx were stimulated with PMA, LPS and anti‐CD3/CD28 antibodies. Post‐LTx endobronchial biopsies underwent microarray‐based gene expression analysis. Results were compared to non‐COPA LTx recipients and non‐LTx healthy controls. Results Multiplexed cytokine analysis showed rising type I/II IFNs, and IL‐6 in BAL post‐LTx that decreased following treatment of acute rejection but rebounded with further clinical deterioration. In vitro stimulation of PMBCs suggested that myeloid cells were driving deterioration, through IL‐6 signalling pathways. Tocilizumab (IL‐6 receptor antibody) administration for 3 months (4 mg kg−1, monthly) effectively suppressed IL‐6 levels in BAL. Mucosal gene expression profile following tocilizumab suggested greater similarity to normal. Conclusion Clinical effectiveness of IL‐6 receptor blockade was not observed. However, we identified IL‐6 upregulation associated with graft injury, effective IL‐6 suppression with tocilizumab and evidence of beneficial effect on molecular transcripts. This mechanistic analysis suggests a role for IL‐6 blockade in post‐LTx care that should be investigated further. |
| first_indexed | 2024-12-13T12:54:35Z |
| format | Article |
| id | doaj.art-e005dc5d1f4a44e780b7404579ab436e |
| institution | Directory Open Access Journal |
| issn | 2050-0068 |
| language | English |
| last_indexed | 2024-12-13T12:54:35Z |
| publishDate | 2021-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical & Translational Immunology |
| spelling | doaj.art-e005dc5d1f4a44e780b7404579ab436e2022-12-21T23:45:13ZengWileyClinical & Translational Immunology2050-00682021-01-01102n/an/a10.1002/cti2.1243IL‐6 receptor blockade for allograft dysfunction after lung transplantation in a patient with COPA syndromePeter Riddell0Sajad Moshkelgosha1Liran Levy2Nina Chang3Prodipto Pal4Kieran Halloran5Phil Halloran6Michael Parkes7Lianne G Singer8Shaf Keshavjee9Tereza Martinu10Stephen C Juvet11Toronto Lung Transplant Program Toronto General Hospital Toronto ON CanadaLatner Thoracic Research Labs Toronto General Hospital Research Institute Toronto ON CanadaToronto Lung Transplant Program Toronto General Hospital Toronto ON CanadaDepartment of Pathology Toronto General Hospital Toronto ON CanadaDepartment of Pathology Toronto General Hospital Toronto ON CanadaDepartment of Medicine University of Alberta Edmonton AB CanadaDepartment of Medicine University of Alberta Edmonton AB CanadaTranscriptome Sciences Inc.University of Alberta Edmonton AB CanadaToronto Lung Transplant Program Toronto General Hospital Toronto ON CanadaToronto Lung Transplant Program Toronto General Hospital Toronto ON CanadaToronto Lung Transplant Program Toronto General Hospital Toronto ON CanadaToronto Lung Transplant Program Toronto General Hospital Toronto ON CanadaAbstract Objective COPA syndrome is a genetic disorder of retrograde cis‐Golgi vesicle transport that leads to upregulation of pro‐inflammatory cytokines (mainly IL‐1β and IL‐6) and the development of interstitial lung disease (ILD). The impact of COPA syndrome on post‐lung transplant (LTx) outcome is unknown but potentially detrimental. In this case report, we describe progressive allograft dysfunction following LTx for COPA‐ILD. Following the failure of standard immunosuppressive approaches, detailed cytokine analysis was performed with the intention of personalising therapy. Methods Multiplexed cytokine analysis was performed on serum and bronchoalveolar lavage (BAL) fluid obtained pre‐ and post‐LTx. Peripheral blood mononuclear cells (PMBCs) obtained pre‐ and post‐LTx were stimulated with PMA, LPS and anti‐CD3/CD28 antibodies. Post‐LTx endobronchial biopsies underwent microarray‐based gene expression analysis. Results were compared to non‐COPA LTx recipients and non‐LTx healthy controls. Results Multiplexed cytokine analysis showed rising type I/II IFNs, and IL‐6 in BAL post‐LTx that decreased following treatment of acute rejection but rebounded with further clinical deterioration. In vitro stimulation of PMBCs suggested that myeloid cells were driving deterioration, through IL‐6 signalling pathways. Tocilizumab (IL‐6 receptor antibody) administration for 3 months (4 mg kg−1, monthly) effectively suppressed IL‐6 levels in BAL. Mucosal gene expression profile following tocilizumab suggested greater similarity to normal. Conclusion Clinical effectiveness of IL‐6 receptor blockade was not observed. However, we identified IL‐6 upregulation associated with graft injury, effective IL‐6 suppression with tocilizumab and evidence of beneficial effect on molecular transcripts. This mechanistic analysis suggests a role for IL‐6 blockade in post‐LTx care that should be investigated further.https://doi.org/10.1002/cti2.1243COPA syndromeIL‐6lung transplantationtocilizumab |
| spellingShingle | Peter Riddell Sajad Moshkelgosha Liran Levy Nina Chang Prodipto Pal Kieran Halloran Phil Halloran Michael Parkes Lianne G Singer Shaf Keshavjee Tereza Martinu Stephen C Juvet IL‐6 receptor blockade for allograft dysfunction after lung transplantation in a patient with COPA syndrome Clinical & Translational Immunology COPA syndrome IL‐6 lung transplantation tocilizumab |
| title | IL‐6 receptor blockade for allograft dysfunction after lung transplantation in a patient with COPA syndrome |
| title_full | IL‐6 receptor blockade for allograft dysfunction after lung transplantation in a patient with COPA syndrome |
| title_fullStr | IL‐6 receptor blockade for allograft dysfunction after lung transplantation in a patient with COPA syndrome |
| title_full_unstemmed | IL‐6 receptor blockade for allograft dysfunction after lung transplantation in a patient with COPA syndrome |
| title_short | IL‐6 receptor blockade for allograft dysfunction after lung transplantation in a patient with COPA syndrome |
| title_sort | il 6 receptor blockade for allograft dysfunction after lung transplantation in a patient with copa syndrome |
| topic | COPA syndrome IL‐6 lung transplantation tocilizumab |
| url | https://doi.org/10.1002/cti2.1243 |
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