USE OF A VARICELLOVIRUS TAP-INHIBITOR FOR THE INDUCTION OF TUMOR-OR VIRUS-SPECIFIC IMMUNITY AGAINST TEIPP
First Claim
1. An in vitro method for producing a cell that induces CD8+ T lymphocytes that selectively recognize cells presenting T cell epitopes associated with impaired peptide processing (TEIPP), the method comprising treating the cell with an effective amount of a varicellovirus TAP-inhibitor, which has the following properties:
- a) is a protein with at least 50% amino acid sequence identity with at least one of SEQ ID NO;
1, SEQ ID NO;
2, SEQ ID NO;
3 and SEQ ID NO;
4 or is a nucleic acid encoding said protein; and
,b) the TAP inhibitor protein reduces by at least 50% TAP-dependent transport of fluorescein-conjugated synthetic peptide CVNKTERAY (SEQ ID NO;
14) into cells of human melanoma MEL-JUSO cell line that stably express the TAP-inhibitor as compared to TAP-dependent transport of the fluorescein-conjugated peptide into human melanoma MEL-JUSO cells that do not express the TAP-inhibitor.
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Accused Products
Abstract
The present invention provides a novel approach to the modulation of the immune response, directing it towards specific antigens, away from antigens against which no response is desired. The invention is based on the use of viral immune evasion proteins, such as UL49.5, which block antigen presentation to CD8+ T cells. The viral immune evasion proteins are used for: 1) the induction of tumor-specific or virus-specific immunity in cases where a conventional immune response is absent due to antigen processing defects; 2) the induction of empty MHC class I molecules at the cell surface that can be loaded with peptides of a desired specificity; 3) the inhibition of unwanted immune responses against transplanted tissues or organs, e.g. against islets of Langerhans in type 1 diabetes or allogeneic stem cells, or against self antigens in the case of autoimmunity.
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Citations
25 Claims
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1. An in vitro method for producing a cell that induces CD8+ T lymphocytes that selectively recognize cells presenting T cell epitopes associated with impaired peptide processing (TEIPP), the method comprising treating the cell with an effective amount of a varicellovirus TAP-inhibitor, which has the following properties:
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a) is a protein with at least 50% amino acid sequence identity with at least one of SEQ ID NO;
1, SEQ ID NO;
2, SEQ ID NO;
3 and SEQ ID NO;
4 or is a nucleic acid encoding said protein; and
,b) the TAP inhibitor protein reduces by at least 50% TAP-dependent transport of fluorescein-conjugated synthetic peptide CVNKTERAY (SEQ ID NO;
14) into cells of human melanoma MEL-JUSO cell line that stably express the TAP-inhibitor as compared to TAP-dependent transport of the fluorescein-conjugated peptide into human melanoma MEL-JUSO cells that do not express the TAP-inhibitor. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 24, 25)
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13. A nucleic acid molecule comprising a nucleotide sequence encoding a varicellovirus TAP-inhibitor protein that:
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(a) has at least 50% amino acid identity with at least one of SEQ ID NO 1, SEQ ID NO;
2, SEQ ID NO;
3 and SEQ ID NO;
4; and
,(b) reduces by at least 50% TAP-dependent transport of fluorescein-conjugated synthetic peptide CVNKTERAY (SEQ ID NO;
14) into cells of human melanoma MEL-JUSO cell line that stably express the TAP-inhibitor as compared to TAP-dependent transport of the fluorescein-conjugated peptide into human melanoma MEL-JUSO cells that do not express the TAP-inhibitor. - View Dependent Claims (14, 16, 17, 18)
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15. (canceled)
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19. (canceled)
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20. A method for modifying a cell to:
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(i) display an empty MHC class I molecules at its surface, or (ii) to reduce surface expression of MHC class I molecules, comprising treating the cell with a varicellovirus TAP-inhibitor protein or a nucleic acid molecule encoding said protein, thereby causing display of said empty MHC class I molecules or reducing said surface expression of MHC class I molecules.
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21. (canceled)
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22. A modified varicellovirus TAP-inhibitor, protein that has the following properties:
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(a) at least 50% amino acid sequence identity with at least one of SEQ ID NO;
1, SEQ ID NO;
2, SEQ ID NO;
3 and SEQ ID NO;
4;(b) reduces by at least 50% TAP-dependent transport of fluorescein-conjugated synthetic peptide CVNKTERAY (SEQ ID NO;
14) into cells of human melanoma MEL-JUSO cell line that stably express the TAP-inhibitor, as compared to TAP-dependent transport of the fluorescein-conjugated peptide into human melanoma MEL-JUSO cells that do not express the TAP-inhibitor; and
,(c) lacks lysine, serine, threonine and cysteine residues in its cytoplasmic tail, or is modified by deletion or replacement of at least one lysine, serine, threonine or cysteine residues in its cytoplasmic tail, wherein replacement is with an amino acid residue other than lysine, serine, threonine and cysteine.
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23. (canceled)
Specification