Control of immune responses by modulating activity of glycosyltransferases

Abstract

The invention provides methods for inhibiting immune responses by inhibiting the biosynthesis of the sialyl galactosides that are involved in immune responses. In particular, B lymphocyte-mediated immune responses are mediated by interfering with synthesis of α2,6 sialylgalactosides, while T lymphocyte-mediated immune responses are inhibited by blocking synthesis of α2,3 sialylgalactosides. The inhibition is accomplished by, for example, inhibiting the activity of a glycosyltransferase involved in synthesis of the respective sialyl galactoside.

What is claimed is:  
     
         1 . A method of inhibiting an immune response in a mammal, the method comprising administering to the mammal a therapeutically effective amount of an agent which reduces amounts of a sialylated oligosaccharide present on cells in the mammal, wherein the sialylated oligosaccharide comprises a formula selected from the group consisting of Siaα2-6Gal- and Siaα2,3Gal-.  
     
     
         2 . The method according to  claim 1 , wherein the sialylated oligosaccharide comprises a formula selected from the group consisting of Siaα2-6Galβ1-4GlcNAc and Siaα2,3Galβ1-3GalNAc.  
     
     
         3 . The method according to  claim 1 , wherein the mammal is a human.  
     
     
         4 . The method according to  claim 1 , wherein the cells are lymphoid cells.  
     
     
         5 . The method according to  claim 1 , wherein the immune response is a B lymphocyte-mediated immune response and the sialylated oligosaccharide comprises a formula Siaα2-6Gal-.  
     
     
         6 . The method according to  claim 1 , wherein the immune response is a T lymphocyte-mediated immune response and the sialylated oligosaccharide comprises a formula Siaα2,3 Gal-.  
     
     
         7 . The method according to  claim 6 , wherein the T lymphocytes are CD8 +  T lymphocytes.  
     
     
         8 . The method according to  claim 1 , wherein the agent inhibits expression of a gene encoding a glycosyltransferase involved in synthesis of the sialylated oligosaccharide.  
     
     
         9 . The method according to  claim 8 , wherein the glycosyltransferase is a sialyltransferase.  
     
     
         10 . The method of  claim 9 , wherein the sialyltransferase is selected from the group consisting of an ST6Gal sialyltransferase and an ST3Gal I sialyltransferase.  
     
     
         11 . The method according to  claim 8 , wherein the agent is an antisense nucleic acid which specifically hybridizes to a nucleic acid that encodes the glycosyltransferase.  
     
     
         12 . The method according to  claim 8 , wherein the agent inhibits the ability of a transactivating factor to increase expression of a gene that encodes the glycosyltransferase.  
     
     
         13 . The method according to  claim 12 , wherein the transactivating factor is selected from the group consisting of tumor necrosis factor-alpha, interleukin-1, a glucocorticoids, retinoic acid, and a liver transcription factor.  
     
     
         14 . The method according to  claim 11 , wherein the nucleic acid that encodes the glycosyltransferase is an mRNA or an mRNA precursor.  
     
     
         15 . The method according to  claim 1 , wherein the agent inhibits enzymatic activity of a glycosyltransferase polypeptide.  
     
     
         16 . The method according to  claim 15 , wherein the glycosyltransferase is a sialyltransferase.  
     
     
         17 . The method according to  claim 16 , wherein the sialyltransferase is selected from the group consisting of an ST6Gal sialyltransferase and an ST3Gal I sialyltransferase.  
     
     
         18 . The method according to  claim 15 , wherein the agent comprises an analog of a sialic acid precursor.  
     
     
         19 . The method according to  claim 15 , wherein the agent comprises an analog of a donor substrate, or an analog of an acceptor substrate, for the glycosyltransferase.  
     
     
         20 . The method according to  claim 19 , wherein the agent comprises an analog of a sugar nucleotide.  
     
     
         21 . The method according to  claim 1 , wherein the agent comprises a sialidase which cleaves sialic acid from an the sialylated oligosaccharide.  
     
     
         22 . The method according to  claim 1 , wherein the agent comprises a glycosyltransferase which converts an acceptor substrate for a sialyltransferase to an oligosaccharide which is not a sialyltransferase acceptor substrate.  
     
     
         23 . The method according to  claim 22 , wherein the glycosyltransferase is a fucosyltransferase.  
     
     
         24 . A method of detecting immunodeficiency in a mammal, the method comprising contacting a sample from the mammal with a detection agent which specifically binds to a sialylated oligosaccharide that comprises a formula selected from the group consisting of Siaα2-6Gal- and Siaα2,3Gal-, wherein a substantial reduction of binding of the detection agent to the sample is indicative of immunodeficiency.  
     
     
         25 . The method according to  claim 24 , wherein the detection agent specifically binds to a Sia6LacNAc trisaccharide.  
     
     
         26 . The method according to  claim 25 , wherein the immunodeficiency is characterized by a deficiency in B lymphocyte activation.  
     
     
         27 . The method according to  claim 25 , wherein the lectin is  Sambucus nigra  bark agglutinin.  
     
     
         28 . The method according to  claim 24 , wherein the detection agent specifically binds to an oligosaccharide that comprises a formula Siaα2,3Galβ1-3GalNAc.  
     
     
         29 . The method according to  claim 28 , wherein the immunodeficiency is characterized by a reduction in T lymphocyte population.  
     
     
         30 . The method according to  claim 24 , wherein the detection agent is an antibody.  
     
     
         31 . The method according to  claim 24 , wherein the detection agent is a lectin.  
     
     
         32 . The method according to  claim 24 , wherein the detection agent is a CD22 moiety.  
     
     
         33 . A method of detecting immunodeficiency in a mammal, the method comprising detecting ST6Gal or ST3Gal I sialyltransferase activity in a sample obtained from the mammal, wherein a substantial absence of ST6Gal or ST3Gal I sialyltransferase activity is indicative of immunodeficiency.  
     
     
         34 . A mammalian cell having a genome which comprises an inactivating mutation in a gene that encodes a sialyltransferase.  
     
     
         35 . The mammalian cell of  claim 34 , wherein the mutation is selected from a group consisting of a deletion, a nonsense mutation, an insertion, and a missense mutation.  
     
     
         36 . The mammalian cell of  claim 34 , wherein the mutation is present in a coding region or a regulatory region of a gene that encodes a sialyltransferase.  
     
     
         37 . A chimeric non-human mammal which comprises cells having a genome which comprises an inactivating mutation in a gene that encodes a sialyltansferase.  
     
     
         38 . The chimeric mammal of  claim 37 , wherein the sialyltransferase is selected from the group consisting of an ST3Gal I and an ST6 Gal sialyltransferase.  
     
     
         39 . The chimeric mammal of  claim 37 , wherein the mammal is a mouse.  
     
     
         40 . The chimeric mammal of  claim 37 , wherein the mammal is transgenic.