Immunoengineered pluripotent cells
AssigneeThe Regents of the University of California
InventorsSonja Schrepfer, Tobias Deuse
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Abstract
The invention provides pluripotent cells that are used therapeutically for regenerating tissues but avoid rejection by subjects that receive them. In particular, the invention provides hypo-immunogenic pluripotent cells that avoid host immune rejection. The cells lack major immune antigens that trigger immune responses and are engineered to avoid phagocytic endocytosis. The invention further provides universally acceptable “off-the-shelf” pluripotent cells and derivatives thereof for generating or regenerating specific tissues and organs.
Claims88
A method of generating a hypo-immunogenic pluripotent stem cell comprising:
- a. eliminating the activity of both alleles of a B2M gene in an induced pluripotent stem cell (iPSC);
- b. eliminating the activity of both alleles of a CIITA gene in said iPSC;
- and
- c. increasing the expression of CD47 in said iPSC.
A Human hypo-immunogenic pluripotent (hHIP) stem cell comprising:
- a. one or more alterations that inactivate both alleles of an endogeneous B2M gene;
- b. one or more alterations that inactivate both alleles of an endogenous CIITA gene;
- and
- c. an alteration causing an increased expression of a CD47 gene in said hHIP stem cell;
- wherein said hHIP stem cell elicits a first Natural Killer (NK) cell response that is lower than a second NK cell response elicited by an induced Pluripotent Stem Cell (iPSC) that comprises said B2M and CIITA alterations but does not comprise said increased CD47 gene expression, and wherein said first and second NK cell responses are measured by determining the IFN-γ levels from NK cells incubated with either of said hHIP or iPSC in vitro.
A Human hypo-immunogenic pluripotent (hHIP) stem cell comprising:
- a. one or more alterations that inactivate both alleles of an endogeneous B2M gene;
- b. one or more alterations that inactivate both alleles of an endogenous CIITA gene;
- and
- c. one or more alterations causing an increased expression of a CD47 gene in said hHIP stem cell;
- wherein said hHIP stem cell elicits a first T cell response in a humanized mouse strain that is lower than a second T cell response in said humanized mouse strain elicited by an iPSC, and wherein said first and second T cell responses are measured by determining the IFN-γ levels from said humanized mice in an Elispot assay.
A hypoimmunogenic pluripotent cell, comprising:
- a. an endogenous Major Histocompatibility Antigen Class I (HLA-I) function that is reduced when compared to a parent pluripotent cell;
- b. an endogenous Major Histocompatibility Antigen Class II (HLA-II) function that is reduced when compared to said parent pluripotent cell;
- and
- c. a reduced susceptibility to NK cell killing when compared to said parent pluripotent cell;
- wherein said hypoimmunogenic pluripotent cell is less susceptible to rejection when transplanted into a subject as a result of said reduced HLA-I function, said reduced HLA-II function, and reduced susceptibility to NK cell killing.
A method for producing a hypoimmunogenic pluripotent cell, comprising
- a. reducing an endogenous Major Histocompatibility Antigen Class I (HLA-I) function in a pluripotent cell;
- b. reducing an endogenous Major Histocompatibility Antigen Class II (HLA-II) function in a pluripotent cell;
- and
- c. increasing the expression of a protein that reduces the susceptibility of said pluripotent cell to NK cell killing.
ß-2 microglobulin 50, wherein said ß-2 microglobulin protein has at least a 90% sequence identity to SEQ ID NO:1.
ß-2 microglobulin 51, wherein said ß-2 microglobulin protein has the sequence of SEQ ID NO:1.
Dependencies are inferred from the claim text.