Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1997-09-12
2001-04-10
Schwadron, Ronald B. (Department: 1644)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023100, C435S325000, C435S252300, C435S254110, C435S320100, C514S04400A
Reexamination Certificate
active
06214985
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to nucleic acid and amino acid sequences of a human autoantigen-like protein and to the use of these sequences in the diagnosis, prevention, and treatment of immune disorders.
BACKGROUND OF THE INVENTION
Autoimmune disorders occur when an immune response is directed to endogenous or “self” proteins that are recognized as “foreign” antigens. Immune response consists of the production of antibodies and the activation of T cells that react with these antigens and initiate a series of destructive changes. The tolerance to “self” antigens is induced in early lymphocyte development by the specific clonal deletion of cells which recognize “self” antigens and is supported by cell—cell interactions, cytokine and immunosuppressive factors, and induction of anergy. The breakdown of tolerance to “self” proteins can occur by a variety of mechanisms. T cells can be stimulated by cross-reacting microbial antigens which have features in common with self antigens, as in rheumatic fever and chronic synovial inflammatory processes. Normally sequestered proteins that become exposed to immune surveillance through tissue changes, as in Hashimoto's thyroiditis, will activate a population of cells that were not originally clonally deleted. There is a correlation between specific major histocompatibility loci (MHC) and susceptibility to certain autoimmune disorders, indicating that multiple components may contribute to disease induction.
Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease that results from the destruction of the insulin-secreting beta-cells of the pancreas. Patients with IDDM have insulitis, a lymphocytic infiltration of the islets of Langerhans, islet-specific Th1 lymphocytes, and antibodies directed against components of the islet cells. IDDM in animal models is T cell mediated and requires the participation of both CD8+, class I MHC restricted and CD4+, class II MHC restricted T cells. There is a demonstrated association between MHC class II DR4 polymorphic alleles and disease susceptibility, indicating that the response is antigen driven. Peptide elution studies indicate that these polymorphisms may modify suceptability to IDDM by selectively affecting the nature of the molecules presented to T cells by these class II molecules (Wicker, L. S. et al. (1995) Annu. Rev. Immunol. 13: 179-200; Reich, E. P. et al. (1994) J. Immunol. 152: 2279-2288).
Several beta-cell proteins have been identified as candidate antigens in IDDM. Antibodies to two glutamate acid decarboxylase isoforms, insulin, carboxypeptidase H, ICA 516 and 64 kD integral membrane proteins, hsp65, and several secretory granule protein have been found in the sera of diabetic and prediabetic individuals. Peripheral blood T cells from a majority of persons newly diagnosed with IDDM respond to a variety of insulin-secretory granule antigens. A mouse insulin-secretory granule antigen (imogen 38) has recently been isolated by using an assay based on the proliferative response of a human IDDM T cell clone. Although this isolated antigen is a mitochondrial protein which occurs in various tissues the imogen 38-reactive antibodies are found only in the diseased pancreatic tissue (Roep, B. O. (1996) Diabetes 45: 1147-1156; and Arden, S. A. et al (1996) J. Clin. Invest. 97: 551-561).
The discovery of an autoantigen-like protein and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention and treatment of immune disorders.
SUMMARY OF THE INVENTION
The invention features a substantially purified polypeptide, autoantigen-like protein (AUTOP), having the amino acid sequence shown in SEQ ID NO:1, or fragments thereof.
The invention further provides an isolated and substantially purified polynucleotide sequence encoding the polypeptide comprising the amino acid sequence of SEQ ID NO:1 or fragments thereof and a composition comprising said polynucleotide sequence. The invention also provides a polynucleotide sequence which hybridizes under stringent conditions to the polynucleotide sequence encoding the amino acid sequence SEQ ID NO:1, or fragments of said polynucleotide sequence. The invention further provides a polynucleotide sequence comprising the complement of the polynucleotide sequence encoding the amino acid sequence of SEQ ID NO: 1, or fragments or variants of said polynucleotide sequence.
The invention also provides an isolated and purified sequence comprising SEQ ID NO:2 or variants thereof. In addition, the invention provides a polynucleotide sequence which hybridizes under stringent conditions to the polynucleotide sequence of SEQ ID NO:2. The invention also provides a polynucleotide sequence comprising the complement of SEQ ID NO:2, or fragments or variants thereof.
The present invention further provides an expression vector containing at least a fragment of any of the claimed polynucleotide sequences. In yet another aspect, the expression vector containing the polynucleotide sequence is contained within a host cell.
The invention also provides a method for producing a polypeptide comprising the amino acid sequence of SEQ ID NO: 1 or a fragment thereof, the method comprising the steps of: a) culturing the host cell containing an expression vector containing at least a fragment of the polynucleotide sequence encoding AUTOP under conditions suitable for the expression of the polypeptide; and b) recovering the polypeptide from the host cell culture.
The invention also provides a pharmaceutical composition comprising a substantially purified AUTOP having the amino acid sequence of SEQ ID NO: 1 in conjunction with a suitable pharmaceutical carrier.
The invention also provides a purified antagonist of the polypeptide of SEQ ID NO: 1. In one aspect the invention provides a purified antibody which binds to a polypeptide comprising the amino acid sequence of SEQ ID NO:1.
Still further, the invention provides a purified agonist of the polypeptide of SEQ ID NO:1.
The invention also provides a method for treating or preventing an immune disorder comprising administering to a subject in need of such treatment an effective amount of an antagonist to AUTOP.
The invention also provides a method for detecting a polynucleotide which encodes AUTOP in a biological sample comprising the steps of: a) hybridizing the complement of the polynucleotide sequence which encodes SEQ ID NO: 1 to nucleic acid material of a biological sample, thereby forming a hybridization complex; and b) detecting the hybridization complex, wherein the presence of the complex correlates with the presence of a polynucleotide encoding AUTOP in the biological sample. In one aspect the nucleic acid material of the biological sample is amplified by the polymerase chain reaction prior to hybridization.
REFERENCES:
Wicker, L.S. et al., “Genetic Control of Autoimmune Diabetes in the NOD Mouse”,Annu. Rev. Immunol., 13:179-200 (1995).
Reich, E. et al., “Self Peptides Isolated from MHC Glycoproteins of Non-Obese Diabetic Mice”,J.Immunol., 152:2279-2288 (1994).
Roep, B.O., “T-Cell Responses to Autoantigens in IDDM”,Diabetes, 45:1147-1156 (1996).
Arden, S.D. et al., “Imogen 38: A Novel 38-kD Islet mitochondrial Autoantigen Recognized by T Cells from a Newly Diagnosed Type 1 diabetic Patient”,J. Clin. Invest, 97(2):551-561 (1996). (GI 1272669) (GI 1272668).
Arden, S.D. et al., (GI 1272669) GenBank Sequence Database (Accession Z46966), National Center for Biotechnology Information: National Library of Medicine, Bethesda, Maryland 20849 (GI 1272668), Apr. 17, 1996.
Arden, S.D. et al., (GI 1272668) GenBank Sequence Database (Accession Z46966), National Center for Biotechnology Information: National Library of Medicine, Bethesda, Maryland 20849, (GI 1272669). Apr. 17, 1996.
Hutton, J.C. and B. Roep, (GI 1546900) GenBank Sequence Database (Accession Z68747), National Center for Biotechnology Information: National Library of Medicine, Bethesda, Maryland 20849, Sep. 16, 1996.
Adams, GenBank Seq. Database (Accession Z46966) Apr. 17, 1996.
Corley Neil C.
Lal Preeti
Tang Y. Tom
Incyte Genomics Inc.
Incyte Genomics, Inc.
Schwadron Ronald B.
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