title: Pharmacologic blockade of JAK1/JAK2 reduces GvHD and preserves the graft-versus-leukemia effect.
abstract: We have recently reported that interferon gamma receptor deficient (IFNγR-/-) allogeneic donor T cells result in significantly less graft-versus-host disease (GvHD) than wild-type (WT) T cells, while maintaining an anti-leukemia or graft-versus-leukemia (GvL) effect after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We demonstrated that IFNγR signaling regulates alloreactive T cell trafficking to GvHD target organs through expression of the chemokine receptor CXCR3 in alloreactive T cells. Since IFNγR signaling is mediated via JAK1/JAK2, we tested the effect of JAK1/JAK2 inhibition on GvHD. While we demonstrated that pharmacologic blockade of JAK1/JAK2 in WT T cells using the JAK1/JAK2 inhibitor, INCB018424 (Ruxolitinib), resulted in a similar effect to IFNγR-/- T cells both in vitro (reduction of CXCR3 expression in T cells) and in vivo (mitigation of GvHD after allo-HSCT), it remains to be determined if in vivo administration of INCB018424 will result in preservation of GvL while reducing GvHD. Here, we report that INCB018424 reduces GvHD and preserves the beneficial GvL effect in two different murine MHC-mismatched allo-HSCT models and using two different murine leukemia models (lymphoid leukemia and myeloid leukemia). In addition, prolonged administration of INCB018424 further improves survival after allo-HSCT and is superior to other JAK1/JAK2 inhibitors, such as TG101348 or AZD1480. These data suggest that pharmacologic inhibition of JAK1/JAK2 might be a promising therapeutic approach to achieve the beneficial anti-leukemia effect and overcome HLA-barriers in allo-HSCT. It might also be exploited in other diseases besides GvHD, such as organ transplant rejection, chronic inflammatory diseases and autoimmune diseases.
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Jaebok
authors.initials: J
authors.lastname: Choi
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Cooper
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Bader
authors.initials: B
authors.lastname: Alahmari
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Julie
authors.initials: J
authors.lastname: Ritchey
authors.affiliation: BRIGHT Institute, and Molecular Imaging Center, Mallinckrodt Institute of Radiology, and Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Lynne
authors.initials: L
authors.lastname: Collins
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Matthew
authors.initials: M
authors.lastname: Holt
authors.affiliation: Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: John F
authors.initials: JF
authors.lastname: DiPersio
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D015973:Gene Expression Regulation, Leukemic; D006086:Graft vs Host Disease / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D020544:Graft vs Leukemia Effect / Q000187:drug effects; D018380:Hematopoietic Stem Cell Transplantation; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D007945:Leukemia, Lymphoid / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009570:Nitriles; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation; D000096743:Interferon gamma Receptor; D000096926:Benzenesulfonamides
chemical_list: D053613:Janus Kinase 1; D053614:Janus Kinase 2; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011759:Pyrrolidines; D017471:Receptors, Interferon; D013449:Sulfonamides; D000096743:Interferon gamma Receptor; C545606:AZD 1480; C528327:fedratinib; D000096926:Benzenesulfonamides; C540383:ruxolitinib; C507905:Jak1 protein, mouse; C507926:Jak2 protein, mouse