Journal Article

Pharmacologic Blockade of JAK1/JAK2 Reduces GvHD and Preserves the Graft-Versus-Leukemia Effect

Ritchey, Julie, Cooper, Matthew L., DiPersio, John F., Collins, Lynne, Holt, Matthew, Choi, Jaebok, Alahmari, Bader

2014

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animal models / Animals / Autoimmune diseases / Biological response modifiers / Biology and Life Sciences / Bone marrow / Breast cancer / Cloning / CXCR3 protein / Cytokines / Disease Models, Animal / Gene Expression Regulation, Leukemic / Graft rejection / Graft vs Host Disease - enzymology / Graft vs Host Disease - immunology / Graft vs Host Disease - pathology / Graft vs Host Disease - prevention & control / Graft vs Leukemia Effect - drug effects / Graft-versus-host reaction / Graft-versus-leukemia reaction / Grafting / Hematopoietic Stem Cell Transplantation / Hematopoietic stem cells / Histocompatibility antigen HLA / In vivo methods and tests / Inflammatory diseases / Inhibition / Interferon / Interferon gamma Receptor / Janus kinase / Janus Kinase 1 - antagonists & inhibitors / Janus Kinase 1 - genetics / Janus Kinase 1 - immunology / Janus kinase 2 / Janus Kinase 2 - antagonists & inhibitors / Janus Kinase 2 - genetics / Janus Kinase 2 - immunology / Leukemia / Leukemia, Lymphoid - drug therapy / Leukemia, Lymphoid - enzymology / Leukemia, Lymphoid - immunology / Leukemia, Lymphoid - pathology / Leukemia, Myeloid - drug therapy / Leukemia, Myeloid - enzymology / Leukemia, Myeloid - immunology / Leukemia, Myeloid - pathology / Lymphatic leukemia / Lymphocytes / Lymphocytes T / Lymphoma / Major histocompatibility complex / Medicine / Medicine and Health Sciences / Mice / Mice, Inbred BALB C / Mice, Knockout / Mitigation / Myeloid leukemia / Nitriles / Oncology / Organs / Pathogenesis / Pharmacology / Preservation / Protein Kinase Inhibitors - pharmacology / Pyrazoles - pharmacology / Pyrimidines - pharmacology / Pyrrolidines - pharmacology / Receptors, Interferon - deficiency / Receptors, Interferon - genetics / Receptors, Interferon - immunology / Signal Transduction / Signaling / Stem cell transplantation / Stem cells / Sulfonamides - pharmacology / T cells / T-Lymphocytes - drug effects / T-Lymphocytes - enzymology / T-Lymphocytes - immunology / T-Lymphocytes - pathology / Transplantation / Transplantation, Homologous / Tumors / Whole-Body Irradiation