Method for treating disease using foxp3+cd4+ t cells

Abstract

This document relates to methods and materials for treating a mammal having an autoimmune disease. For example, materials and methods for producing a T cell comprising a FOXP3 polypeptide and one or more transcription factors are provided herein. Methods and materials for treating a mammal having an autoimmune disease comprising administering to a mammal having an autoimmune disease an effective amount of a T cell are also provided herein.

1 - 143 . (canceled) 
     
     
         144 . A method of producing a T cell having a Treg phenotype, the method comprising:
 (a) introducing into a T cell a first nucleic acid sequence encoding a FOXP3 polypeptide and a second nucleic acid sequence encoding one or more transcription factor(s), and   optionally (b) culturing the T cell in growth media under conditions sufficient to expand the T cell.   
     
     
         145 . The method of  claim 144 , wherein the one or more transcriptions factor(s), when present in a mammalian cell, elicit a Treg phenotype in the mammalian cell as compared to when the one or more transcription factor(s) is/are not present in the mammalian cell. 
     
     
         146 . The method of  claim 145 , wherein the one or more transcription factor(s) are selected from the group consisting of: BLIMIP1, EOS, ROR-gt, FOXO1, GATA1, HELIOS, ID2, ID3, IRF4, LEF1, SATB1, GATA3, NFATc2, RUNX1, BC111b, FOXP1, FOXP4, BACH2, STAT3, and XBP1. 
     
     
         147 . The method of  claim 144 , wherein the step (a) comprises introducing a nucleic acid construct into the T cell, wherein the nucleic acid construct comprises the first nucleic acid and the second nucleic acid. 
     
     
         148 . The method of  claim 147 , wherein the nucleic acid construct further comprises a promoter operably linked to the first nucleic acid sequence, and wherein the first nucleic acid sequence is positioned 5′ relative to the second nucleic acid sequence in the nucleic acid construct. 
     
     
         149 . The method of  claim 147 , wherein the nucleic acid construct further comprises a promoter operably linked to the second nucleic acid sequence, and wherein the second nucleic acid sequence is positioned 5′ relative to the first nucleic acid sequence in the nucleic acid construct. 
     
     
         150 . The method of  claim 147 , wherein the nucleic acid construct further comprises an additional nucleic acid sequence between the second nucleic acid sequence and the first nucleic acid sequence, wherein the additional nucleic acid sequence operably links the first nucleic acid sequence to the second nucleic acid sequence. 
     
     
         151 . The method of  claim 150 , wherein the additional nucleic acid sequence encodes (i) an internal ribosome entry site (IRES) sequence or a self-cleaving amino acid, and/or (ii) a promoter or an enhancer. 
     
     
         152 . The method of  claim 144 , wherein step (a) further comprises introducing a third nucleic acid sequence encoding a therapeutic gene product into the T cell, wherein the therapeutic gene product is an antigen-binding antibody fragment or antibody that is capable of binding to an IL-6 polypeptide, an IL-6R polypeptide, an IFN alpha receptor, or a TGF beta receptor polypeptide. 
     
     
         153 . The method of  claim 147 , wherein the nucleic acid construct further comprises a third nucleic acid sequence encoding a therapeutic gene product, wherein the therapeutic gene product is an antigen-binding antibody fragment or antibody that is capable of binding to an IL-6 polypeptide, an IL-6R polypeptide, an IFN alpha receptor, or a TGF beta receptor polypeptide. 
     
     
         154 . The method of  claim 153 , wherein the third nucleic acid sequence is positioned 5′ relative to the first nucleic acid sequence and the second nucleic acid sequence in the nucleic acid construct, wherein the third nucleic acid sequence is operably linked a promoter. 
     
     
         155 . The method of  claim 153 , wherein the third nucleic acid sequence is positioned 3′ relative to the first and second nucleic acid sequences in the nucleic acid construct, wherein the third nucleic acid sequence is operably linked to the first nucleic acid sequence and/or the second nucleic acid sequence. 
     
     
         156 . The method of  claim 144 , wherein step (a) further comprises introducing a fourth nucleic acid sequence encoding a binding agent into the T cell, wherein the binding agent is an antibody, antigen-binding fragment, or a chimeric antigen receptor. 
     
     
         157 . The method of  claim 153 , wherein the nucleic acid construct further comprises a fourth nucleic acid sequence encoding a binding agent, wherein the binding agent is an antibody, antigen-binding fragment, or a chimeric antigen receptor. 
     
     
         158 . The method of  claim 156 , wherein the antigen-binding fragment is a Fab, a F(ab′)2 fragment, a scFv, a scAb, a dAb, a single domain heavy chain antibody, or a single domain light chain antibody that is capable of binding to an antigen on an autoimmune cell. 
     
     
         159 . The method of  claim 156 , wherein the antigen-binding fragment is a Fab, a F(ab′)2 fragment, a scFv, a scAb, a dAb, a single domain heavy chain antibody, or a single domain light chain antibody that is capable of binding to a cell adhesion molecule, wherein the cell adhesion molecule is ICAM-1, VCAM-1, or MADCAM-1. 
     
     
         160 . The method of  claim 156 , wherein the binding agent is a chimeric antigen receptor, wherein the chimeric antigen receptor comprises an extracellular domain, a transmembrane domain, and an intracellular domain, wherein:
 the extracellular domain comprises an antibody or antigen-binding fragment that is capable of binding to an antigen on an autoimmune cell or a cell adhesion molecule; and   the intracellular domain comprises a cytoplasmic signaling domain and one or more co-stimulatory domain(s).   
     
     
         161 . The method of  claim 160 , wherein the antigen-binding fragment is an scFv, wherein the scFv is capable of binding to a cell adhesion molecule selected from the group consisting of: ICAM-1, VCAM-1, and MADCAM-1. 
     
     
         162 . The method of  claim 160 , wherein the cytoplasmic signaling domain is a CD3 zeta domain and the one or more co-stimulatory domain(s) comprise(s) at least one of a cytoplasmic signaling domain from a CD48 polypeptide, a 4-1BB polypeptide, an ICOS polypeptide, a X-40 polypeptide, and a CD27 polypeptide. 
     
     
         163 . The method of  claim 157 , wherein:
 the fourth nucleic acid sequence is positioned 5′ relative to the first nucleic acid sequence and the second nucleic acid sequence in the nucleic acid construct, wherein the fourth nucleic acid sequence is operably linked to a promoter; or   the fourth nucleic acid sequence is positioned 3′ relative to the first nucleic acid sequence and the second nucleic acid sequence in the nucleic acid construct, wherein the fourth nucleic acid sequence is operably linked to the first nucleic acid sequence and/or the second nucleic acid sequence.   
     
     
         164 . The method of  claim 147 , wherein the nucleic acid construct comprises a viral vector selected from the group consisting of: a lentiviral vector, a retroviral vector, an adenoviral vector, and an adeno-associated viral (AAV) vector. 
     
     
         165 . The method of  claim 144 , wherein the T cell is a CD4+ T cell or a CD4+/CD45RA+ T cell. 
     
     
         166 . The method of  claim 144 , wherein the method further comprises:
 obtaining the T cell from a patient.   
     
     
         167 . A vector comprising a first nucleic acid sequence encoding a FOXP3 polypeptide and a second nucleic acid sequence encoding a one or more transcription factors. 
     
     
         168 . The vector of  claim 167 , wherein the one or more transcription factors, when present in a mammalian cell, elicit a T reg phenotype in the mammalian cell as compared to when the one or more transcription factor(s) is/are not present in the mammalian cell and wherein the one or more transcription factor(s) is/are selected from the group consisting of: BLIMIP1, EOS, ROR-gt, FOXO1, GATA1, HELIOS, ID2, ID3, IRF4, LEF1, SATB1, GATA3, NFATc2, RUNX1, BC111b, FOXP1, FOXP4, BACH2, STAT3, and XBP1.