Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Amino acid sequence disclosed in whole or in part; or...
Reexamination Certificate
2000-04-28
2002-10-22
Gambel, Phillip (Department: 1644)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Amino acid sequence disclosed in whole or in part; or...
C424S184100, C530S300000, C530S325000, C530S326000, C530S327000, C514S002600, C514S013800, C514S014800, C514S866000, C514S885000
Reexamination Certificate
active
06468537
ABSTRACT:
BACKGROUND OF THE INVENTION
Nucleosome-specific T helper cells (Th cells) initiate and sustain the production of pathogenic, anti-nuclear autoantibodies during the onset and progression of systemic lupus erythematosus (SLE) through cognate interaction with autoimmune B cells (Mohan et al., 1993, J. Exp. Med. 177:1367; Desai-Mehta et al., 1995, J. Clin. Invest. 95:53; Kaliyaperumal et al., 1996, J. Exp. Med. 183:2459; Shi et al., 1998, J. Exp. Med. 187:367; Voll et al., 1997, Arthritis Rheum. 40:2162; Kretz-Rommel, et al., 1997, J. Clin. Invest. 99:1888). These SLE-associated Th cells are primarily responsible for driving the pathogenic autoimmune response. Without the help provided by these Th cells, autoimmune B cells are unable to produce the disease-causing (pathogenic) autoantibodies associated with SLE. Some of the critical epitopes (i.e. autoantigenic determinants) to which these Th cells are directed have been localized to the histone proteins of nucleosomes (i.e. DNA-protein complexes in the nuclei of animal cells). For example, in lupus prone mice, SLE-associated autoepitopes have been identified at amino acid positions 10-33 of the H2B histone protein, at amino acid positions 85-102 of the H3 histone protein, and at amino acid positions 16-39 and 71-94 of the H4 histone protein (Kaliyaperumal et al., 1996, J. Exp. Med. 183:2459).
SLE-associated autoimmune B cells recognize and bind autoantigenic determinants in DNA, histones, or other proteins in nucleosomes through surface molecules (i.e. B cell receptors, BCRs) which are antibody (i.e. immunoglobulin or Ig) receptors. Autoantigenic recognition and binding by an autoimmune B cell is followed by endocytosis and processing of the entire nucleosome particle which bears the recognized autoantigen. As illustrated in
FIG. 1
, the processed histone autoepitope (i.e. a histone peptide) is loaded onto a major histocompatibility complex class II molecule (i.e. a MHC class II molecule or I-A
d
molecule) of the B cell, and is presented as a complex on the surface of the B cell in an interaction with an autoimmune Th cell which has receptors specific for nucleosomal histone peptide autoepitopes. Upon receiving this antigen-specific signal (i.e. signal 1) and other co-stimulatory signals (i.e. signal 2) from the B cell, the autoimmune Th cell helps the autoimmune B cell by recruiting intermolecular support and enabling the B cell to survive and differentiate into an autoantibody-producing B cell associated with SLE (Datta and Kaliyaperumal, 1997, Ann. New York Acad. Sci. 815:155; Datta, 2000, Nature Med. 6:259).
Autoimmune T cells of lupus-prone mice are spontaneously primed to SLE-associated autoepitopes early in life before overt autoantibody production or any clinical manifestations of the disease are present (Kaliyaperumal et al., 1996, J. Exp. Med. 183:2459). Moreover, immunization of pre-autoimmune mice with peptides corresponding to SLE-associated nucleosomal autoepitopes precipitates SLE-associated nephritis by triggering autoimmune T helper cells of subtype 1 (i.e. Th 1 cells) which, in turn, initiate anti-nuclear autoantibody production (Kaliyaperumal et al., 1996, J. Exp. Med. 183:2459). The T helper cell subtypes 2 and 0 (i.e., Th2 and Th0 cells, respectively) are also involved in the progression of SLE, as these T helper cell subtypes maintain autoantibody production (Mohan et al., 1993, J. Exp. Med. 177:1367; Nakajima et al., 1997, J. Immunol. 158:1466).
Unlike organ-specific autoimmune diseases in which the autoimmune response targets a restricted set of autoepitoes and is mediated by a single population of T cells, the autoimmune response in SLE involves a complex web of polyclonal T cell and B cell hyperactivity and appears to be directed by multiple susceptibility genes (Datta et al., 1982, J. Immunol. 129:1539; Klinman and Steinberg, 1987, J. Exp. Med. 165:1755; Cohen and Eisenberg, 1991, Ann. Rev. Immunol. 9:243; Chan and Shlomchik, 1998, J. Immunol. 160:51; Jongstra-Bilen, 1997, J. Immunol. 159:5810; Mohan et al., 1995, J. Immunol. 154:1470; Desai-Mehta, 1996, J. Clin. Invest. 97:2063; Koshy et al., 1996, J. Clin. Invest. 98:826; Liossis, et al., 1996, J. Clin. Invest. 98:2549; Wakeland et al., 1997, J. Clin. Immunol. 17:272; Vyse and Kotzin 1996, Opin. Immunol. 8:843; Kono and Theofilopoulos, 1996, J. Autoimmunity 9:437).
Previously, it has not been considered that a brief tolerogenic regimen of nucleosomal peptides could delay the development of SLE-associated nephritis. Moreover, chronic tolerogenic therapy with peptides has not previously been pursued, as it was not foreseen that such therapy might have the effect of prolonging survival and slowing SLE progression. There has long been a need in the art to identify immunololgically specific agents which could significantly affect the therapeutic outcome of SLE by delaying or preventing the onset and progression of the disease and complications thereof. The present invention provides a novel therapeutic approach to satisfying this need.
SUMMARY OF THE INVENTION
The present invention provides a composition comprising an isolated peptide which has an amino acid sequence corresponding to the amino acid sequence of a portion of a nucleosome histone protein and, and which is capable of promoting immunological tolerance in an animal having systemic lupus erythematosus.
The invention includes an isolated peptide which has an amino acid sequence corresponding to the amino acid sequence of a portion of a nucleosome histone protein, wherein the portion of the nucleosome histone protein corresponds to an autoepitope which is associated with systemic lupus erythematosus and which is recognized by one or more of an autoimmune T cell and an autoimmune B cell.
In one embodiment, the isolated peptide can correspond in amino acid sequence to a nucleosome histone protein which is selected from the group consisting of histone 1 (H1), histone 2A (H2A), histone 2B (H2B), histone 3 (H3), and histone 4 (H4).
In multiple embodiments, the isolated peptide comprises not more than 27 contiguous amino acids and has an amino acid sequence selected from the group consisting of SEQ ID NOs: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, and 26.
In other embodiments, the isolated peptide can further comprise a covalently attached moiety selected from the group consisting of a fluorophore, a chromophore, a biotin moiety, a light reactive group, and an enzyme cleavable group.
In one aspect, the invention includes a composition comprising a pharmaceutically acceptable carrier and an isolated peptide which has an amino acid sequence corresponding to the amino acid sequence of a portion of a nucleosome histone protein and, and which is capable of promoting immunological tolerance in an animal having systemic lupus erythematosus.
In another aspect, the invention includes an isolated nucleic acid encoding an isolated peptide which has an amino acid sequence corresponding to the amino acid sequence of a portion of a nucleosome histone protein and, and which is capable of promoting immunological tolerance in an animal having systemic lupus erythematosus. In this aspect, the isolated nucleic acid can comprise a nucleotide sequence selected from the group consisting of SEQ ID NOS.: 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 and 52. Also included in this aspect of the invention is a vector comprising the isolated nucleic acid.
In multiple embodiments the isolated nucleic acid of the invention comprises a nucleotide sequence selected from the group consisting of SEQ ID NOS.: 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 and 52.
The invention also includes a cell comprising an isolated nucleic acid encoding an isolated peptide which has an amino acid sequence corresponding to the amino acid sequence of a portion of a nucleosome histone protein and, and which is capable of promoting immunological tolerance in an animal having systemic lupus erythemato
Datta Syamal K.
Kaliyaperumal Arunan
Gambel Phillip
Morgan & Lewis & Bockius, LLP
Roark Jessica H.
The Board of Trustees of Northwestern University
LandOfFree
Localization of major peptide autoepitopes for nucleosome... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Localization of major peptide autoepitopes for nucleosome..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Localization of major peptide autoepitopes for nucleosome... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2929294