Dendritic cell inhibitory proteins from ticks

Abstract

The present invention provides a dendritic cell modulatory protein which modulates, and preferably inhibits, the differentiation and/or maturation of mammalian dendritic cells. The invention also provides proteins comprising conserved motifs found in such proteins as well as pharmaceutical compositions comprising the dendritic cell modulatory protein and homologues and active fragments thereof, antibodies thereto and methods of treatment which utilise such proteins, homologues, fragments and anti-bodies.

1 - 52 . (canceled) 
     
     
         53 . A composition of matter selected from the group consisting of:
 (I) a dendritic cell (DC) modulatory protein, wherein said protein modulates mammalian DC differentiation and maturation and comprises:   (i) the amino acid sequence of any one of (a) SEQ ID NOs: 2, 25 or 28 (RaA); (b) SEQ ID NOs: 4, 26 or 29 (RaB); or (c) SEQ ID NOs: 6, 24 or 27 (Rsl);   (ii) a homologue of a protein as defined in (i) having at least 40% identity thereto; or   (iii) an active fragment of a protein as defined in (i) above or of a homologue as defined in (ii) above;   (II) a nucleic acid molecule which comprises a nucleic acid sequence encoding a DC modulatory protein of (I), or which hybridises under high stringency hybridisation conditions to a nucleic acid molecule encoding a DC modulatory protein of (I);   (III) a vector comprising a nucleic acid molecule of (II);   (IV) a host cell comprising the vector of (III) or a nucleic acid molecule of (II);   (V) an antibody which binds to the DC modulatory protein of (I);   (VI) a modulated DC produced by a method comprising contacting a DC with a composition of matter of (I), (II), (III), (IV) or (V); or   (VII) a pharmaceutical composition comprising the DC modulatory protein of (I), the nucleic acid of (II), the vector of (III), the host cell of (IV), the antibody of (V) or the DC of claim (VI) and a pharmaceutically acceptable carrier.   
     
     
         54 . The composition of matter of claim  53 (I) wherein the DC modulatory protein comprises the amino acid sequence of any one of SEQ ID NOs 2, 4 or 6. 
     
     
         55 . The composition of matter 53(I) wherein:
 (a) the protein has at least 47% identity to the amino acid sequence of SEQ ID NO: 2;   (b) the protein has at least 53% identity to the amino acid sequence of SEQ ID NO: 4;   (c) the protein has at least 81% identity to the amino acid sequence of SEQ ID NO: 6; or   (d) the protein does not have the amino acid sequence of any one of SEQ ID NOs: 8, 10, 12, 14 or 16.   
     
     
         56 . The composition of matter of  claim 53  (I), wherein said protein is glycosylated at one or more positions, optionally wherein said protein comprises the glycosylation site containing sequence C-(X) 2 -W-(X) 12-16 -N-Z-(S/T)-(X) 3-5 -C, and wherein X is any amino acid and Z is any amino acid except proline. 
     
     
         57 . The composition of matter of  claim 56 , wherein:
 (a) said protein comprises the glycosylation site containing sequence C-(X) 2 -W-(X) 12-16 -N-Z-(S/T)-(F/Y)-(X) 2-4 -C, and wherein X is any amino acid and Z is any amino acid except proline;   (b) said protein comprises the glycosylation site containing sequence C-(X) 2 -W-(X) 7-11 -(I/L)-P-(X) 3 -N-Z-(S/T)-(X) 3-5 -C, and wherein X is any amino acid and Z is any amino acid except proline;   (c) said protein comprises the glycosylation site sequence C-(X) 2 -W-(X) 7-11 -(I/L)-P-(X) 3 -N-Z-(S/T)-(F/Y)-(X) 2-4 -C, and wherein X is any amino acid and Z is any amino acid except proline; or   (d) said protein comprises the cysteine distribution pattern and glycosylation site sequence C-(X) 82-91 -C-(X) 2 -W-(X) 12-16 -N-Z-(S/T)-(X) 4 -C-(X) 10-12 -C, and wherein X is any amino acid and Z is any amino acid except proline.   
     
     
         58 . The composition of matter of claim  53 (I), wherein said protein is a lipocalin, optionally wherein said protein comprises the cysteine distribution pattern C-(X) 82-91 -C-(X) 2 -W-(X) 19-23 -C-(X) 10-12 -C, and wherein X is any amino acid. 
     
     
         59 . The composition of matter according to claim  53 (I), wherein said protein comprises the motif CXXW, and wherein X is any amino acid; optionally wherein said protein comprises the motif CXLW, and wherein X is any amino acid, or wherein said protein comprises the motif CSLW or CELW. 
     
     
         60 . The composition of matter of  claim 53  (I), wherein said protein is complexed to a lipid, optionally wherein the lipid is a steroid or a sterol, or cholesterol or a metabolite of cholesterol, such as vitamin D3 or dexamethasone. 
     
     
         61 . The composition of matter of  claim 53  (I), wherein:
 (a) said protein modulates human DC differentiation and maturation; 
 (b) said protein inhibits DC differentiation and maturation; 
 (c) said protein is isolated from a haematophagous arthropod, optionally isolated from a tick, such as a tick selected from the group Ixodes, Bothriocrotoninae, Amblyomminae, Haemaphysalinae, Rhipicephalinae (including Hyalomminae), Nuttalliellidae, Argasinae, Otobinae, Antricolinae, Nothhoaspinae and Ornithodorinae; 
 (d) said protein inhibits T lymphocyte activation; 
 (e) said protein modulates T lymphocyte polarisation; 
 (f) said protein is an immunosuppressant; or 
 (g) said protein binds to a receptor present on the outer membrane of a DC, optionally wherein said protein binds to a C-type lectin receptor. 
 
     
     
         62 . The composition of matter of claim  53 (II) wherein said nucleic acid molecule comprises any one of SEQ ID NOS: 1, 3, or 5. 
     
     
         63 . A method of modulating a DC comprising said contacting said DC with a composition of matter of  claim 53  (I), (II), (III), (IV) or (V). 
     
     
         64 . The composition of matter according to claim  53 (VII), further comprising one or more additional therapeutic agents. 
     
     
         65 . The composition of matter of  claim 64 , wherein the one or more additional therapeutic agents comprises an anti-inflammatory agent, an immunomodulatory agent, an immunosuppressant, a cytokine, a cytokine mimetic, a cytokine binding protein. 
     
     
         66 . The composition of matter of  claim 64 , wherein the one or more therapeutic agents comprises a disease-associated element. 
     
     
         67 . A method of treating an animal suffering from autoimmune disorders, transplant reactions such as transplant rejection, acute and chronic inflammatory diseases, allergies or other immune-related sensitivities such as hypersensitivity, an infectious disease or cancer comprising administering to said animal a composition of matter of  claim 53  (I), (II), (III), (IV), (V), (VI) or (VII) in a pharmaceutically effective amount. 
     
     
         68 . The method of  claim 67 , which is for treating an animal suffering from an infectious disease. 
     
     
         69 . The method of  claim 67 , which is for treating an animal suffering from cancer. 
     
     
         70 . The method of  claim 67  wherein the DC modulatory protein, nucleic acid, vector, host cell, antibody, DC or pharmaceutical composition is administered in combination with a disease-associated element. 
     
     
         71 . The method of  claim 68 , wherein the disease-associated element is selected from: components associated with infectious agents; allergens; non-self components associated with hypersensitivity reactions other than allergy; self components associated with autoimmune disease; transplantation antigens; blood group antigens; and tumour antigens.