Effekte der intestinalen Mikrobiota und ihrer Metaboliten auf Immunrekonstitution und Graft-versus-Host Erkrankung bei Patienten nach allogener hämatopoetischer Stammzelltransplantation
Zusammenfassung der Projektergebnisse
Acute graft-versus-host disease (GVHD) remains a major limitation of allogeneic hematopoietic cell transplantation (allo-HCT) despite prophylactic immunosuppression. Not all patients who develop acute GVHD respond to currently available treatment and thus there is a pressing need for novel prophylactic and therapeutic strategies. Using preclinical GVHD models I investigated strategies to modulate alloreactive T cells by targeting selectively T cell receptor (TCR) signaling (Aim 1) or intestinal microbiota (Aim 2) with the major goal is to improve patient outcomes after allo-HCT by preventing GVHD using strategies informed by preclinical studies. Aim 1: I demonstrate that ITK inhibition using the highly selective ITK inhibitor CPI-818 has potential as a novel targeted approach to prevent acute GVHD through the suppression of T cell activation and proliferation. Aim 2: I found that inflammation reduced the abundance of microbiome-encoded bile salt hydrolase gene, leading to decreased levels of unconjugated and secondary BAs (SBAs). Microbiota-dependent BAs counteracted the activation of the farnesoid X receptor (FXR) in vitro, posing that loss of SBAs may increase FXR activity in vivo. In preclinical models, GVHD-related mortality increased with pharmacological activation of FXR but decreased with genetic ablation in donor T cells. Patients developing GVHD after allogeneic hematopoietic cell transplant show similar disturbances in their BA pool with decreased unconjugated BAs and SBAs that we stipulate counteracts FXR activation. Loss of SBAs and increased FXR activation may be an important mechanism to induce inflammation and amplify immune-driven pathologies.
Projektbezogene Publikationen (Auswahl)
-
Update in clinical and mouse microbiota research in allogeneic haematopoietic cell transplantation. Current Opinion in Hematology, 27(6), 360-367.
Lindner, Sarah & Peled, Jonathan U.
-
Fecal microbiota diversity disruption and clinical outcomes after auto-HCT: a multicenter observational study. Blood, 137(11), 1527-1537.
Khan, Niloufer; Lindner, Sarah; Gomes, Antonio L. C.; Devlin, Sean M.; Shah, Gunjan L.; Sung, Anthony D.; Sauter, Craig S.; Landau, Heather J.; Dahi, Parastoo B.; Perales, Miguel-Angel; Chung, David J.; Lesokhin, Alexander M.; Dai, Anqi; Clurman, Annelie; Slingerland, John B.; Slingerland, Ann E.; Brereton, Daniel G.; Giardina, Paul A.; Maloy, Molly ... & Peled, Jonathan U.
-
Highly Selective Irreversible ITK Inhibitor Cpi-818 Reduces Acute Graft-Versus Host Disease. Blood, 138(Supplement 1), 3814-3814.
Lindner, Sarah; Lee, Nicole; Armijo, Gabriel K.; Burgos, da Silva Marina D.; Herrera, Pamela S.; Nguyen, Chi L.; Dwomoh, Emmanuel A.; Ghale, Romina; Smith, Melody; Perales, Miguel-Angel; Markey, Kate A.; Buggy, Joseph J.; Janc, James W. & van, den Brink Marcel
-
Early intestinal microbial features are associated with CD4 T-cell recovery after allogeneic hematopoietic transplant. Blood, 139(18), 2758-2769.
Miltiadous, Oriana; Waters, Nicholas R.; Andrlová, Hana; Dai, Anqi; Nguyen, Chi L.; Burgos, da Silva Marina; Lindner, Sarah; Slingerland, John; Giardina, Paul; Clurman, Annelie; Armijo, Gabriel K.; Gomes, Antonio L. C.; Lakkaraja, Madhavi; Maslak, Peter; Scordo, Michael; Shouval, Roni; Staffas, Anna; O.’Reilly, Richard; Taur, Ying ... & van den Brink Marcel, R. M.
-
Microbial Bile Acid Metabolism Shapes Effector T Cell Responses During Inflammation in Mouse and Human. Accepted CSHL Microbiome 2022 and ASH 2022(Oral presentation).
Sarah Lindner, Oriana Miltiadous, Ruben J. Ramos, Anqi Dai, Anastasia Kousa, Gabriel K. Armijo, Romina Ghale, Chi L. Nguyen, Jenny Paredes Sanchez, Teng Fei, John Frame, Sebastien Monette, Emily Fontana, John Slingerland, Marina Burgos da Silva, Ying Taur, Kate A. Markey, Jonathan U. Peled, Melody Smith ... & Marcel R.M. van den Brink
