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-10543234-B2
Publication Date
2020-01-28
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 relates to immunosuppressing a peripheral immune response in a subject by administering an effective amount of cells derived from a culture of marrow adherent stromal cells. The cells are contacted with a polynucleotide encoding a Notch intracellular domain (NICD), where the polynucleotide does not encode a full-length Notch protein, and cells that comprise the polynucleotide are selected and further cultured in the absence of selection for the polynucleotide.
The resulting NICD-modified marrow adherent stromal/mesenchymal stem cell preparations suppress peripheral immune responses through one or more specified immunological effects. These effects include suppressing proliferation and activation of naive CD4+ T-cells, stimulating production of regulatory T-cells (Tregs), increasing production of IL-10 by T-cells, decreasing production of IFN-gamma by T-cells, and increasing production of IL-17 by T-cells under IL-23 stimulation.
The invention further describes additional peripheral immune modulation beyond T-cells, including inhibiting monocyte differentiation into dendritic cells, inhibiting dendritic cell maturation, and increasing production of IL-10 by monocytes. The preparations are described as stronger than parental MSCs and as shifting cytokine output from IFN-gamma-dominant toward IL-10-dominant.
Claims Coverage
The independent claim contains an overall scheme for administering NICD (non-full-length Notch)-modified marrow adherent stromal cells to suppress a peripheral immune response, and it specifies multiple biological mechanisms affecting T-cells, Tregs, cytokines, and monocyte/dendritic cell differentiation and maturation. Dependent claims further narrow the etiology of the peripheral immune response to specific causes and enumerate autoimmune disorders.
Administering NICD-modified marrow adherent stromal cells for peripheral immune suppression
A method for suppressing a peripheral immune response in a subject by administering an effective amount of cells obtained by providing a culture of marrow adherent stromal cells, contacting the cell culture with a polynucleotide encoding NICD that does not encode a full-length Notch protein, selecting cells that comprise the polynucleotide, and further culturing the selected cells in the absence of selection for the polynucleotide.
Suppressing peripheral immune response via specified T-cell, Treg, and cytokine effects
The cells suppress the peripheral immune response by one or more of suppressing proliferation of naive CD4+ T-cells, suppressing activation of naive CD4+ T-cells, stimulating production of regulatory T-cells (Tregs), increasing production of IL-10 by T-cells, decreasing production of IFN-gamma by T-cells, and increasing production of IL-17 by T-cells.
Suppressing peripheral immune response via monocyte and dendritic cell differentiation and maturation effects
The cells suppress the peripheral immune response by one or more of inhibiting the differentiation of monocytes into dendritic cells, inhibiting maturation of dendritic cells, and increasing production of IL-10 by monocytes.
Etiology restriction to rheumatoid arthritis
The method is configured such that the peripheral immune response is caused by rheumatoid arthritis.
Etiology restriction to graft-versus-host disease (GVHD)
The method is further characterized in that the peripheral immune response is caused by graft-versus-host disease (GVHD).
Etiology restriction to graft rejection
The method is further characterized in that the peripheral immune response is caused by graft rejection.
Etiology restriction to autoimmune disorder
The method is further defined such that the peripheral immune response is caused by an autoimmune disorder.
Enumerated autoimmune disorders
The autoimmune disorder is selected from multiple sclerosis, ulcerative colitis, chronic obstructive pulmonary disease (COPD), asthma, lupus, and Type I diabetes.
Across the independent claim, the core inventive concept is administering NICD (non-full-length Notch)-modified marrow adherent stromal cells that suppress peripheral immune responses through specified effects on naive CD4+ T-cell proliferation and activation, regulatory T-cell generation, IL-10/IFN-gamma/IL-17-related outputs, and inhibition of monocyte-to-dendritic differentiation and dendritic maturation. Dependent claims restrict the peripheral immune response etiology to rheumatoid arthritis, GVHD, graft rejection, autoimmune disorders, and enumerate specific autoimmune disorders.
Stated Advantages
Suppresses peripheral immune responses in a subject.
Suppresses proliferation and activation of naive CD4+ T-cells.
Stimulates production of regulatory T-cells (Tregs).
Increases IL-10 production by T-cells and by monocytes.
Decreases IFN-gamma production by T-cells.
Increases IL-17 production by T-cells.
Inhibits monocyte differentiation into dendritic cells.
Inhibits dendritic cell maturation.
Documented Applications
Treating conditions involving peripheral immune response such as graft-versus-host disease (GVHD).
Treating conditions involving peripheral immune response such as graft rejection.
Treating autoimmune disorders, including multiple sclerosis, ulcerative colitis, chronic obstructive pulmonary disease (COPD), asthma, lupus, and Type I diabetes.
Treating rheumatoid arthritis.
Suppressing peripheral immune response in a subject.
Interested in licensing this patent?