Methods of stimulating phagocytosis

Abstract

The present invention relates, in general, to methods of stimulating phagocytosis and thereby combating infection and/or modulating immune complex disease, in particular, to methods of modulating the number and type of Fc receptors present on cells that normally possess such receptors, including monocytes and macrophages, as well as on cells that normally do not possess Fc receptors, such as fibroblasts, and to compounds and compositions suitable for use in such methods.

What is claimed is:  
     
         1 . A method of increasing the phagocytic potential of cells present in a mammal comprising introducing into said cells a DNA molecule coding for an Fc receptor under conditions such that said DNA molecule is expressed and said Fc receptor thereby produced and the phagocytic potential of said cells thereby increased.  
     
     
         2 . A method according to  claim 1  wherein said cells are phagocytic prior to introduction of said DNA molecule.  
     
     
         3 . The method according to  claim 1  wherein said cells are macrophages.  
     
     
         4 . The method according to  claim 1  wherein said cells are monocytes.  
     
     
         5 . The method according to  claim 1  wherein said cells are non-phagocytic prior to introduction of said DNA molecule.  
     
     
         6 . The method according to  claim 5  wherein said cells are fibroblasts.  
     
     
         7 . The method according to  claim 5  wherein said cells are T cells or B cells.  
     
     
         8 . The method according to  claim 1  wherein said cells are lung cells.  
     
     
         9 . The method according to  claim 1  wherein said DNA molecule is present as an insert in a viral vector.  
     
     
         10 . The method according to  claim 1  wherein said DNA molecule is present in a liposome.  
     
     
         11 . The method according to  claim 1  wherein said DNA molecule is present in a bacterium.  
     
     
         12 . The method according to  claim 1  further comprising contacting said cells with an effective amount of a drug that increases the phagocytic potential of said cells.  
     
     
         13 . The method according to  claim 12  wherein said drug is γ-interferon, an estrogen or estrogen analog, M-CSF or GM-CSF.  
     
     
         14 . A method of increasing the phagocytic potential of cells of a mammal comprising: 
 i) removing cells from said mammal,    ii) introducing into said cells a DNA molecule encoding an Fc receptor, and    iii) reintroducing said cells into said mammal under conditions such that said DNA molecule is expressed and said Fc receptor thereby produced and the phagocytic potential of said cells thereby increased.    
     
     
         15 . The method according to  claim 14  wherein said cells are T cells or B cells.  
     
     
         16 . The method according to  claim 14  further comprising contacting said cells with an effective amount of a drug that increases the phagocytic potential of said cells.  
     
     
         17 . The method according to  claim 16  wherein said drug is γ-interferon, an estrogen or estrogen analog, M-CSF or GM-CSF.  
     
     
         18 . A liposome comprising a DNA molecule encoding an Fc receptor.  
     
     
         19 . A bacterium comprising a DNA molecule encoding an Fc receptor.  
     
     
         20 . A T cell comprising an exogenous DNA sequence encoding an Fc receptor.  
     
     
         21 . A B cell comprising an exogenous DNA sequence encoding an Fc receptor.  
     
     
         22 . A DNA construct encoding an Fc receptor comprising domains, or functional portions thereof, from at least two of FcγRI, FcγRII, the α chain of FcγRIII and the γ chain of FcγRIII, wherein said domains, or portions thereof, are such that said Fc receptor renders phagocytic a cell comprising same.  
     
     
         23 . The DNA construct according to  claim 22  wherein said construct encodes the extracellular domain of the α chain of FcRγIIIA, the transmembrane domain of the γ chain of FcγRIIIA or FcγRI and the cytoplasmic domain of the γ chain of FcγRIIIA.  
     
     
         24 . The DNA construct according to  claim 22  wherein said construct comprises, in a cytoplasmic domain encoding portion thereof, at least two sequences encoding Y-X2-L, wherein X2 represents any two amino acids.  
     
     
         25 . The DNA construct according to  claim 24  wherein X2 represents the amino acids of a Y-X2-L sequence of the cytoplasmic domain of FcγRIIA or the γ chain of FcγRIII.  
     
     
         26 . A cell comprising the construct according to  claim 22 .  
     
     
         27 . An Fc receptor comprising domains, or functional portions thereof, from at least two of FcγRI, FcγRII, the α chain of FcγRIII and the γ chain of FcγRIII, wherein said domains, or portions thereof, are such that said Fc receptor renders phagocytic a cell comprising same.  
     
     
         28 . The receptor according to  claim 27  wherein said receptor comprises, in a cytoplasmic domain thereof, at least two copies of the sequence Y-X2-L, wherein X2 represents any two amino acids.  
     
     
         29 . The receptor according to  claim 28  wherein X2 represents the amino acids of a Y-X2-L sequence of the cytoplasmic domain of FcγRIIA or the γ chain of FcγRIII.  
     
     
         30 . An Fc receptor comprising, in a cytoplasmic domain thereof, at least one copy of the sequence Y-X2-L in excess of the corresponding naturally occurring cytoplasmic domain, wherein X2 represents any two amino acids.  
     
     
         31 . The Fc receptor according to  claim 30  wherein X2 represents the amino acids of a Y-X2-L sequence of the cytoplasmic domain of FcγRIIA or the γ chain of FcγRIII.  
     
     
         32 . A DNA sequence encoding the Fc receptor according to  claim 30 .  
     
     
         33 . An Fc receptor comprising, in a cytoplasmic domain thereof, at least one repeat of a Y-X2-L sequence, wherein X2 represents any two amino acids.  
     
     
         34 . The Fc receptor according to  claim 33  wherein X2 represents the amino acids of a Y-X2-L sequence of the cytoplasmic domain of FcγRIIA or the γ chain of FcγRIII.  
     
     
         35 . An Fc receptor comprising, in a cytoplasmic domain thereof, one or more repeats of an FcγRIIA or γ chain FcγRIIIA or FcεRI cytoplasmic domain or portion thereof.  
     
     
         36 . The receptor according to  claim 35  wherein said portion includes Y-X2-L, wherein X2 represents the amino acids of a Y-X2-L sequence of the cytoplasmic domain of FcγRIIA or the γ chain of FcγRIII or of FcεRI.  
     
     
         37 . A method of treating an infection comprising administering to a mammal in need of such treatment a DNA molecule encoding an Fc receptor, 
 wherein said administration is effected under conditions such that said DNA molecule is expressed in the cells of said mammal, said Fc receptor is produced, and the phagocytic potential of said cells thereby increased, and    wherein said cells phagocytose particles causing said infection.    
     
     
         38 . The method according to  claim 37  wherein said infection is present in the lungs of said mammal and said cells are lung cells.  
     
     
         39 . The method according to  claim 37  wherein said cells are liver cells.  
     
     
         40 . The method according to  claim 37  wherein said cells are spleen cells.  
     
     
         41 . The method according to  claim 37  wherein said cells are T cells or B cells.  
     
     
         42 . The method according to  claim 37  further comprising administering to said mammal a drug that increases the phagocytic potential of said cells.  
     
     
         43 . The method according to  claim 42  wherein said drug is γ-interferon, an estrogen or estrogen analog, M-CSF or GM-CSF.  
     
     
         44 . A method of stimulating the phagocytic potential of a cell comprising introducing into said cell a construct comprising a nucleotide sequence encoding the Syk gene under conditions such that said Syk gene is expressed and phosphorylation of Fcγ receptors in said cell is effected.  
     
     
         45 . The method according to  claim 44  wherein the phagocytic potential of said cell derives from a naturally occurring Fcγ receptor.  
     
     
         46 . The method according to  claim 44  further comprising introducing into said cell a construct comprising a sequence encoding an Fcγ receptor.