IL-6 receptor blockade for allograft dysfunction after lung transplantation in a patient with COPA syndrome

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

doi:10.1002/cti2.1243

IL-6 receptor blockade for allograft dysfunction after lung transplantation in a patient with COPA syndrome

Clin Transl Immunology. 2021 Jan 28;10(2):e1243. doi: 10.1002/cti2.1243. eCollection 2021.

Authors

Peter Riddell¹, Sajad Moshkelgosha², Liran Levy¹, Nina Chang³, Prodipto Pal³, Kieran Halloran⁴, Phil Halloran⁴, Michael Parkes⁵, Lianne G Singer¹, Shaf Keshavjee^{1

2}, Tereza Martinu^{1

2}, Stephen C Juvet^{1

2}

Affiliations

¹ Toronto Lung Transplant Program Toronto General Hospital Toronto ON Canada.
² Latner Thoracic Research Labs Toronto General Hospital Research Institute Toronto ON Canada.
³ Department of Pathology Toronto General Hospital Toronto ON Canada.
⁴ Department of Medicine University of Alberta Edmonton AB Canada.
⁵ Transcriptome Sciences Inc. University of Alberta Edmonton AB Canada.

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.

Keywords: COPA syndrome; IL‐6; lung transplantation; tocilizumab.

Publication types

Case Reports