Lrg1 as a therapeutic target in Graft-versus-Host Disease
Final Report Abstract
The objective of this project was to study the endothelium and specifically the role of leucine-rich alpha-2-glycoprotein 1 (Lrg1) in graft-versus-host disease (GVHD) and other inflammatory diseases. Animal disease models have been criticized for lack of resembling human illnesses, hampering transfer of knowledge from preclinical research to clinical medicine. During the current project, we established and murine chronic GVHD models, which resemble the clinical situation more closely as compared to previously existing models. Prior to the project the mechanisms were largely unknown how the endothelium contributes to the biology of acute GVHD and chronic GVHD. In chronic GVHD models as well as in patient we discovered a new mechanism of disease termed ‘endothelial to mesenchymal transition’, which can be therapeutically used. We were able to demonstrate that the endothelium can be used as a therapeutic target in steroid-refractory acute GVHD. Our results demonstrate that metabolic changes in the lipid oxidation pathways occur during acute GVHD and can be used therapeutically. In prospective studies, we successfully tested an endothelium-based biomarker panel (endothelial activation and stress index, EASIX). We found elevated LRG1 serum levels in patients with cytokine release syndrome (CRS) after chimeric antigen receptor (CAR) T-cell therapy as well as in patients with acute GVHD after allogeneic stem cell transplantation. In pre-clinical models of aGVHD, we found vasculature-associated LRG1 upregulation as well as LRG1 pathway gene upregulation. The genetic deletion of LRG1 in alloHSCT donors and in alloHSCT recipients led to reduced clinical and histologic aGVHD. In line with this, LRG1 deletion led to clinically and histologically reduced disease severity in experimental inflammatory models of colitis (DSS colitis) and paw edema. LRG1 deletion reduced inflammation-related vascular leakiness, endothelial cell proliferation and migration. The current data support the hypothesis that LRG1 is able to initiate vascular permeability during inflammation. LRG1 is an attractive therapeutic target in cancer immunotherapy because of its role in dysfunctional tumor vessels as well as in immunotherapy-related inflammation. In summary, we successfully studied the mechanisms of endothelial pathology and LRG1-mediated vascular dysfunction during GVHD and other inflammatory diseases. In addition, results from the DFG- funded project provide improved animal models for studying chronic GVHD.
Publications
-
Endothelial damage and dysfunction in acute graft-versus-host disease. Haematologica, 106(8), 2147-2160.
Steffen, Cordes; Zeinab, Mokhtari; Maria, Bartosova; Sarah, Mertlitz; Katarina, Riesner; Yu, Shi; Jörg, Mengwasser; Martina, Kalupa; Aleixandria, McGeary; Johanna, Schleifenbaum; Jens, Schrezenmeier; Lars, Bullinger; Maribel, Diaz-Ricart; Marta, Palomo; Enric, Carrreras; Gernot, Beutel; Claus, Peter Schmitt; Andreas, Beilhack & Olaf, Penack
-
Novel pre-clinical mouse models for chronic Graft-versus-Host Disease. Frontiers in Immunology, 13.
Verlaat, Lydia; Riesner, Katarina; Kalupa, Martina; Jung, Beate; Mertlitz, Sarah; Schwarz, Constanze; Mengwasser, Jörg; Fricke, Claudine & Penack, Olaf
-
Endothelial Activation and Stress Index (EASIX) to predict mortality after allogeneic stem cell transplantation: a prospective study. Journal for ImmunoTherapy of Cancer, 12(1), e007635.
Penack, Olaf; Luft, Thomas; Peczynski, Christophe; Benner, Axel; Sica, Simona; Arat, Mutlu; Itäla-Remes, Maija; Corral, Lucia López; Schaap, Nicolaas P. M.; Karas, Michal; Raida, Ludek; Schroeder, Thomas; Dreger, Peter; Metafuni, Elisabetta; Ozcelik, Tulay; Sandmaier, Brenda M.; Kordelas, Lambros; Moiseev, Ivan; Schoemans, Hélène ... & Peric, Zinaida
-
Leucine-rich α-2 glycoprotein 1 (LRG1) during inflammatory complications after allogeneic stem cell transplantation and CAR-T cell therapy. Journal for ImmunoTherapy of Cancer, 13(3), e009372.
Mertlitz, Sarah; Riesner, Katarina; Kalupa, Martina; Uhlig, Nora; Cordes, Steffen; Verlaat, Lydia; Jamali, Mina; Li, Ningyu; Mohamed, Hadeer Mohamed Elsayed Rasheed; Bullinger, Lars; Moss, Stephen; Greenwood, John; Jatzlau, Jerome; Knaus, Petra; Vallecillo-Garcia, Pedro & Penack, Olaf
