Methods and compositions for modulating peripheral immune function
Inventors
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-9655927-B2
Publication Date
2017-05-23
Expiration Date
Abstract
Disclosed herein are cell preparations useful for modulating various peripheral immune functions, methods for making said cell preparations, and methods for their use.
Core Innovation
The invention provides immunomodulatory cell preparations obtained from marrow adherent stromal cells derived from mesenchymal stem cells (MSCs) by contacting the cell culture with a polynucleotide encoding a Notch intracellular domain (NICD), wherein the polynucleotide does not encode a full-length Notch protein. Cells comprising the polynucleotide are selected, and the selected cells are further cultured in the absence of selection for the polynucleotide, to obtain the immunomodulatory cells described as SB623.
SB623 is characterized by an unexpected senescent/non-proliferating subpopulation, including evidence of senescence markers such as increased p16Ink4A and beta-galactosidase staining, while maintaining strong immunosuppression. SB623 reduces helper T-cell activation and proliferation, shown by decreased CD69 and HLA-DR and reduced CFSE dilution, compared with parental MSCs.
The SB623 preparations promote regulatory T-cells, including increased CD4+CD25+ and FoxP3-positive cells and increased IL-10, and shift the T-cell cytokine profile away from IFN-gamma toward IL-10. SB623 also inhibits monocyte-to-dendritic cell differentiation and dendritic maturation, shown by increased CD14 and reduced CD1a and by reduced dendritic maturation marker expression such as reduced CD86, with stronger inhibition than parental MSCs.
Claims Coverage
Independent claim clm-00001 covers a method that administers an effective amount of NICD-polynucleotide-positive marrow adherent stromal cell preparations to inhibit a peripheral inflammatory response in a subject, with the inhibition mediated by six specified immunological mechanisms. The primary inventive features are directed to the specific NICD polynucleotide design, the selection step followed by further culturing without selection, and the defined mediating effects on T-cells, regulatory T-cells, monocytes, dendritic differentiation, dendritic maturation, and cytokine profile shifts.
Marrow adherent stromal cells contacted with a non-full-length NICD-encoding polynucleotide
Providing a culture of marrow adherent stromal cells; contacting the cell culture with a polynucleotide comprising sequences encoding a Notch intracellular domain (NICD) wherein the polynucleotide does not encode a full-length Notch protein.
Selection of NICD-polynucleotide-positive cells followed by further culturing without selection
Selecting cells that comprise the polynucleotide; further culturing the selected cells in the absence of selection for the polynucleotide.
Administration to inhibit a peripheral inflammatory response
Administering to the subject an effective amount of cells obtained by the contacted, selected, and further-cultured process, wherein inhibition of the peripheral inflammatory response is mediated by inhibition of helper T-cell proliferation; expansion of a regulatory T-cell population; inhibition of differentiation of a monocyte to a dendritic cell; inhibition of dendritic cell maturation; alteration of the cytokine profile of a T-cell or a monocyte from pro-inflammatory to anti-inflammatory; and reduced production of IL-10 by a T-cell or a monocyte.
Across the independent claim coverage, the method is grounded in administering an effective amount of marrow adherent stromal cells processed using a non-full-length NICD-encoding polynucleotide with selection followed by culturing without further selection. The claim ties the resulting immunomodulatory effect to specified mediators including helper T-cell proliferation inhibition, regulatory T-cell expansion, suppression of monocyte-to-dendritic differentiation and dendritic maturation, cytokine profile alteration toward anti-inflammatory signaling, and reduced IL-10 production by a T-cell or a monocyte.
Stated Advantages
Unexpectedly strong immunosuppression while exhibiting a senescent/non-proliferating subpopulation.
Inhibition of helper T-cell activation and proliferation, including reduced CD69 and HLA-DR and reduced CFSE dilution.
Expansion of regulatory T-cells characterized by increased CD4+CD25+ and FoxP3, and an IL-10 shift.
Alteration of T-cell cytokine profile from IFN-gamma toward IL-10.
Inhibition of monocyte-to-dendritic cell differentiation and dendritic maturation, including reduced CD1a and reduced CD86, with stronger inhibition than parental MSCs.
Documented Applications
Inhibition of peripheral inflammatory responses in a subject.
Treatment context associated with graft-versus-host disease (GVHD).
Treatment context associated with graft rejection.
Treatment context associated with autoimmune disorders including rheumatoid arthritis, multiple sclerosis, and lupus.
Interested in licensing this patent?