Augmented CD47 expression impairs alloreactive T-cell clearance after allo-HCT
Abstract
Abstract Graft-versus-host disease (GVHD) ensues as the most common nonrelapse complication after allogeneic hematopoietic cell transplantation (allo-HCT). A pivotal goal in GVHD management revolves around quelling inflammation. Phagocytic clearance of inflammatory cells contributes substantially to termination of inflammatory processes. Nevertheless, the precise functions of phagocytosis in GVHD remain largely unclear. In this study, we identified the “do not eat me” signal CD47 as a promising target for therapeutic interventions aimed at eradicating alloreactive T cells subsequent to allo-HCT. Analysis of global data sets revealed a remarkable upregulation of CD47 expression on T cells residing in the ileum of patients with inflamed intestine. Building on this finding, we examined CD47 levels in the gastrointestinal tract (GIT) after allo-HCT. Our work not only confirmed upregulated CD47 expression in the GIT of GVHD patients but also identified CD47 on T cells in the ileum of GVHD mice after allo-HCT. Additionally, we found that activated donor T cells suppress antibody-dependent cellular phagocytosis (ADCP) via CD47 signaling in vitro. Application of anti-CD47 antibodies significantly invigorated the impaired ADCP of activated T cells. Administering anti-CD47 antibodies to mice elevated phagocytosis of T cells in the GIT, induced immunosuppressive responses, and improved survival. Finally, transplantation of CD47-deficient donor T cells significantly improved clinical GVHD score with improved survival after allo-HCT. Collectively, our findings illuminate CD47 upregulation as a pivotal mechanism in patients with GVHD, leading to impaired phagocytic clearance of alloreactive T cells. This study proposes that anti-CD47 treatment could rectify the compromised phagocytosis of alloreactive T cells, thereby aiding in the resolution of inflammation after allo-HCT.
Article Details
Authors (22)
Cindy Flamann
1Department of Internal Medicine 5, Hematology and Oncology, University Hospital Erlangen, Erlangen, Germany
Haroon Shaikh
University Hospital Würzburg
Carina Matos
1Clinic and Polyclinic for Internal Medicine III, University Hospital Regensburg, Regensburg, Germany
Marina Kreutz
Hla Ali
4Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
Michael A. G. Kern
2Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany
Maike Büttner-Herold
Benedikt Jacobs
1Department of Internal Medicine 5, Hematology and Oncology, University Hospital Erlangen, Erlangen, Germany
Simon Völkl
Friedrich-Alexander-University Erlangen–Nuremberg, Erlangen, Germany
Christopher Lischer
1University Hospital Erlangen, Department of Medicine 5 – Haematology and Oncology, Erlangen, Germany
Christian Kellner
6Division of Transfusion Medicine, Cell Therapeutics and Hemostaseology, Ludwig Maximilian University Hospital, Ludwig Maximilian University Munich, Munich, Germany
Johannes Berges
1University Hospital Erlangen, Department of Medicine 5 – Haematology and Oncology, Erlangen, Germany
Katrin Bitterer
1University Hospital Erlangen, Department of Medicine 5 – Haematology and Oncology, Erlangen, Germany
Domenica Saul
1Department of Internal Medicine 5, Hematology and Oncology, University Hospital Erlangen, Erlangen, Germany
Manisha Goel
Cornelia S. Link-Rachner
7Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
Alma Zernecke
4Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
Daniela Weber
Dimitrios Mougiakakos
Andreas Mackensen
Friedrich-Alexander-Universität Erlangen–Nürnberg, Erlangen, Germany
Andreas Beilhack
2Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany
Heiko Bruns
1Department of Internal Medicine 5, Hematology and Oncology, University Hospital Erlangen, Erlangen, Germany