Modeling the Clinical Phenotype of BTK Inhibition in the Mature Murine Immune System
| Autor: | Cheryl Nickerson-Nutter, Dean Messing, Nilufer P. Seth, Sean Keegan, John Douhan, Jason Edmonds, Timothy A. Cook, Stephen E. Benoit, Andrew L. Rankin, Varenka Rodriguez, Sarah Du, Micah J. Benson, Melanie Ruzek, Mark E. Schnute, Kyri Dunussi-Joannopoulos, David von Schack |
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| Rok vydání: | 2014 |
| Předmět: |
Cell Survival
Immunology B-Lymphocyte Subsets Cell generation Biology Mice Immune system immune system diseases Immunity hemic and lymphatic diseases Agammaglobulinaemia Tyrosine Kinase medicine Animals Humans Immunology and Allergy Bruton's tyrosine kinase Clinical phenotype Protein Kinase Inhibitors B cell Mice Knockout Models Immunological Protein-Tyrosine Kinases Immunity Humoral Cell biology B-1 cell medicine.anatomical_structure Immunoglobulin M Mice Inbred CBA biology.protein Immunologic Memory Tyrosine kinase |
| Zdroj: | The Journal of Immunology. 193:185-197 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.1302570 |
| Popis: | Inhibitors of Bruton’s tyrosine kinase (BTK) possess much promise for the treatment of oncologic and autoimmune indications. However, our current knowledge of the role of BTK in immune competence has been gathered in the context of genetic inactivation of btk in both mice and man. Using the novel BTK inhibitor PF-303, we model the clinical phenotype of BTK inhibition by systematically examining the impact of PF-303 on the mature immune system in mice. We implicate BTK in tonic BCR signaling, demonstrate dependence of the T3 B cell subset and IgM surface expression on BTK activity, and find that B1 cells survive and function independently of BTK. Although BTK inhibition does not impact humoral memory survival, Ag-driven clonal expansion of memory B cells and Ab-secreting cell generation are inhibited. These data define the role of BTK in the mature immune system and mechanistically predict the clinical phenotype of chronic BTK inhibition. |
| Databáze: | OpenAIRE |
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