Regulatory B cells (tBREGS) and their use
Inventors
Arya, Bira • Olkhanud, Purevdorj B. • Bodogai, Monica
Assignees
US Department of Health and Human Services
Publication Number
US-9228171-B2
Publication Date
2016-01-05
Expiration Date
2031-02-04
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Abstract
Regulatory B cells (tBreg) are disclosed herein. These regulatory B cells express CD25 (CD25+) a pan B cell marker such as B220 (B220+), and also express CD19 (CD19+). These regulatory B cells suppress resting and activated T cells in cell contact-dependent manner. Methods for generating these regulatory B cells are also disclosed herein, as are methods for using these regulatory B cells to produce regulatory T cells (Treg). In some embodiments, methods for treating an immune-mediated disorder, such as an autoimmune disease, transplant rejection, graft-versus-host disease or inflammation, are disclosed. These methods include increasing regulatory B cell number or activity and/or by administering autologous regulatory B cells. Methods for treating cancer are also disclosed herein. These methods include decreasing regulatory B cell activity and/or number.
Core Innovation
Regulatory B cells (tBreg) are disclosed which express CD25 (CD25+), CD19 (CD19+), and a pan B cell marker such as B220 (B220+). These regulatory B cells suppress resting and activated T cells in a cell contact-dependent manner and can induce regulatory T cells (Tregs) from CD8+ and/or CD4+ T cells. Methods for generating these regulatory B cells in vitro by treating B cells with conditioned media from tumor cells are also disclosed.
The disclosed regulatory B cells can express additional markers including CD40, CD69, CD80, CD86, BAFF-R, CCR6, CXCR5, MHC class I and II molecules, TSLPR, Fas, FasL, PD-1, phosphorylated STAT3, and lack expression of CD5 and/or CD27. The tBregs are characterized by being poorly proliferative and by suppressing T cells via contact, though in some embodiments they also may suppress in a contact-independent manner. They contribute to cancer escape by promoting Treg-dependent metastasis.
The problem being solved is that while cancer escapes immune responses using suppressive cells such as myeloid-derived suppressive cells and regulatory T cells, the role of other regulatory immune cells, specifically regulatory B cells, was previously unknown. There remains a need to identify other regulatory immune cells and use these cells to treat immune-mediated disorders, and also to inhibit regulatory immune cells that block immune therapy, such as for cancer. The regulatory B cells described herein fill that gap by providing a novel population of regulatory B cells that mediate immune suppression and that can be modulated for therapeutic purposes.
Claims Coverage
The patent contains one independent claim directed to an isolated population of regulatory B cells and covers features of the cells and their functions.
Distinctive marker expression profile of regulatory B cells
The B cells are characterized as CD25HighCD19+ CD81highCD23loIgDhigh IgMInt/Low, lacking CD5 expression and proliferating poorly in vitro.
Contact-dependent T cell suppression by the regulatory B cells
The regulatory B cells suppress T cells through a cell contact-dependent mechanism.
Expression of additional surface markers
The regulatory B cells express CD21 and one or more of CD40, CD69, CD80, CD86, BAFF-R, CCR6, CXCR5 and MHC class I and II molecules, as well as TSLPR, Fas, FasL and programmed death (PD)-1, while lacking CD27 expression.
Expression of phosphorylated STAT3
The regulatory B cells express phosphorylated STAT3, indicating activation of specific signaling pathways.
Induction of FoxP3+ regulatory T cells
The regulatory B cells induce generation of FoxP3+ regulatory T cells (Tregs) from CD8+ and CD4+ T cells.
Promotion of Treg-dependent metastasis in T cell deficient hosts
When introduced into a T cell deficient host, the B cells promote regulatory T cell-dependent metastasis.
Pharmaceutical compositions comprising the regulatory B cells
Compositions include the isolated regulatory B cells in tissue culture medium or buffered saline, optionally combined with a chemotherapeutic agent or anti-inflammatory agent.
The claims cover isolated regulatory B cells defined by distinctive surface marker expression and functional properties including T cell suppression and Treg induction, as well as pharmaceutical compositions containing these cells. The main inventive features focus on the phenotype and immunoregulatory functions of these cells and their use in modulating immune responses and cancer metastasis.
Stated Advantages
Regulatory B cells efficiently suppress resting and activated T cells through contact-dependent mechanisms.
They induce generation of FoxP3+ regulatory T cells from non-regulatory T cells, promoting immune regulation.
tBregs support regulatory T cell-dependent cancer metastasis, indicating their role in cancer immune escape.
The regulatory B cells can be generated from normal B cells using tumor conditioned media, indicating a method to produce these cells in vitro.
Therapeutic manipulation of tBreg number or activity can treat immune-mediated disorders or cancer by increasing or decreasing their presence, respectively.
Documented Applications
Generating regulatory B cells in vitro by contacting B cells with tumor-conditioned media.
Treating immune-mediated disorders such as autoimmune diseases, transplant rejection, graft-versus-host disease, and inflammation by increasing regulatory B cell number or activity or administering autologous regulatory B cells.
Treating cancer by decreasing regulatory B cell activity or number, for example using antibodies against CD25 or CD19.
Monitoring efficacy of therapy by measuring regulatory B cell presence and activity in biological samples from subjects undergoing immunostimulatory, immunosuppressive, or chemotherapeutic treatments.
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