Modeling the Clinical Phenotype of BTK Inhibition in the Mature Murine Immune System

被引：25

作者：

Benson, Micah J. ^{[1
]}

Rodriguez, Varenka ^{[1
]}

von Schack, David ^{[2
]}

Keegan, Sean ^{[1
]}

Cook, Tim A. ^{[1
]}

Edmonds, Jason ^{[1
]}

Benoit, Stephen ^{[1
]}

Seth, Nilufer ^{[1
]}

Du, Sarah ^{[2
]}

Messing, Dean ^{[3
]}

Nickerson-Nutter, Cheryl L. ^{[1
]}

Dunussi-Joannopoulos, Kyri ^{[1
]}

Rankin, Andrew L. ^{[1
]}

Ruzek, Melanie ^{[1
]}

Schnute, Mark E. ^{[4
]}

Douhan, John, III ^{[1
]}

机构：

[1] Pfizer Inc, Biotherapeut Immunosci, Cambridge, MA 02140 USA

[2] Pfizer Inc, Biotherapeut Clin Res & Dev, Cambridge, MA 02140 USA

[3] Pfizer Inc, Biotherapeut Pharmacokinet Dynam & Metab, Cambridge, MA 02140 USA

[4] Pfizer Inc, Biotherapeut Med Chem, Cambridge, MA 02140 USA

来源：

JOURNAL OF IMMUNOLOGY | 2014年 / 193卷 / 01期

关键词：

BRUTONS TYROSINE KINASE; X-LINKED AGAMMAGLOBULINEMIA; B-CELL DEVELOPMENT; CHRONIC LYMPHOCYTIC-LEUKEMIA; IN-VIVO; TARGETING BTK; XID MICE; GENETIC-CONTROL; SIGNALS; RECEPTOR;

D O I：

10.4049/jimmunol.1302570

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

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.

引用

页码：185 / 197

页数：13

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