Molecules (Basel, Switzerland), 2024-04, Vol.29 (8), p.1801
2024
Details
- Autor(en) / Beteiligte
- Titel
- Novel JAK Inhibitors to Reduce Graft-Versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation in a Preclinical Mouse Model
- Ist Teil von
- Molecules (Basel, Switzerland), 2024-04, Vol.29 (8), p.1801
- Ort / Verlag
- Switzerland: MDPI AG
- Erscheinungsjahr
- 2024
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Allogeneic hematopoietic cell transplantation (allo-HCT) is a highly effective, well-established treatment for patients with various hematologic malignancies and non-malignant diseases. The therapeutic benefits of allo-HCT are mediated by alloreactive T cells in donor grafts. However, there is a significant risk of graft-versus-host disease (GvHD), in which the donor T cells recognize recipient cells as foreign and attack healthy organs in addition to malignancies. We previously demonstrated that targeting JAK1/JAK2, mediators of interferon-gamma receptor (IFNGR) and IL-6 receptor signaling, in donor T cells using baricitinib and ruxolitinib results in a significant reduction in GvHD after allo-HCT. Furthermore, we showed that balanced inhibition of JAK1/JAK2 while sparing JAK3 is important for the optimal prevention of GvHD. Thus, we have generated novel JAK1/JAK2 inhibitors, termed WU derivatives, by modifying baricitinib. Our results show that WU derivatives have the potential to mitigate GvHD by upregulating regulatory T cells and immune reconstitution while reducing the frequencies of antigen-presenting cells (APCs) and CD80 expression on these APCs in our preclinical mouse model of allo-HCT. In addition, WU derivatives effectively downregulated CXCR3 and T-bet in primary murine T cells. In summary, we have generated novel JAK inhibitors that could serve as alternatives to baricitinib or ruxolitinib.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1420-3049eISSN: 1420-3049DOI: 10.3390/molecules29081801Titel-ID: cdi_doaj_primary_oai_doaj_org_article_285037f35a544d1d92c4818b095a7e72
- Format
- –
- Schlagworte
- Animals, Antigen-Presenting Cells - drug effects, Antigen-Presenting Cells - immunology, Antigen-Presenting Cells - metabolism, Antigens, Autoimmune diseases, Azetidines - pharmacology, B cells, Biological response modifiers, Carbon, Disease Models, Animal, Disease prevention, FDA approval, Graft versus host disease, Graft vs Host Disease - drug therapy, Graft vs Host Disease - prevention & control, Health aspects, Hematopoietic Stem Cell Transplantation - adverse effects, Hematopoietic stem cells, Interferon, interferon-gamma receptor, Janus Kinase 1 - antagonists & inhibitors, Janus Kinase 1 - metabolism, Janus Kinase 2 - antagonists & inhibitors, Janus Kinase 2 - metabolism, Janus kinase inhibitor, Janus Kinase Inhibitors - pharmacology, Janus kinases, Kinases, Lymphocytes, Medical colleges, Metabolism, Mice, Mice, Inbred C57BL, Nitrogen, Pharmacokinetics, Plasma, Proteins, Psoriasis, Purines - pharmacology, Pyrazoles - pharmacology, Rheumatoid arthritis, Stem cell transplantation, Sulfonamides - pharmacology, T cells, T-Lymphocytes, Regulatory - drug effects, T-Lymphocytes, Regulatory - immunology, Tofacitinib, Transplantation, Transplantation, Homologous