Immunoprotective methods for beta cell neogenesis
First Claim
1. A method of using a pancreatitis associated peptide to facilitate the growth of a pancreatic cell in a mammal in a manner that simultaneously minimizes the immunostimulation of a leukocyte produced by the mammal that immunospecifically recognizes an epitope present on a pancreatitis associated protein having homology to the pancreatitis associated peptide, the method comprising:
- (a) administering to the mammal a pancreatitis associated peptide comprising the amino acid sequence IGLHDPTQGTEPNGE (SEQ ID NO;
3), wherein the pancreatitis associated peptide can facilitate the growth of the pancreatic cell;
wherein (b) the mammal produces a leukocyte that immunospecifically recognizes an epitope present on the homologous pancreatitis associated protein comprising the sequence MLPPMALPSVSWMLLSCLMLLSQVQGEEPQRELPSARIRCPKGSKAYGSHCYALFLSPKSWT DADLACQKRPSGNLVSVLSGAEGSFVSSLVKSIGNSYSYVWIGLHDPTQGTEPNGEGWEWS SSDVMNYFAWERNPSTISSPGHCASLSRSTAFLRWKDYNCNVRLPYVCIFTD (SEQ ID NO;
1), wherein the epitope is not present on the pancreatitis associated peptide of step (a), so that the administration of the pancreatitis associated peptide facilitates the growth of the pancreatic cell but does not immunospecifically stimulate the leukocyte to the same degree as an equivalent amount of the homologous pancreatitis associated protein.
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Abstract
The invention is based on the disclosure provided herein that a biologically active fragment of pancreatitis associated polypeptide can be used to stimulate beta cell growth and at the same avoid and overcome the T-cell mediated autoimmune attack on the pancreas. Typical embodiments of the invention include methods of inhibiting the onset of Type I diabetes in a mammalian subject predisposed to Type I diabetes comprising administering to the subject a therapeutically effective amount of a pancreatitis associated polypeptide comprising the amino acid sequence IGLHDPTQGTEPNGE (SEQ ID NO: 3).
37 Citations
31 Claims
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1. A method of using a pancreatitis associated peptide to facilitate the growth of a pancreatic cell in a mammal in a manner that simultaneously minimizes the immunostimulation of a leukocyte produced by the mammal that immunospecifically recognizes an epitope present on a pancreatitis associated protein having homology to the pancreatitis associated peptide, the method comprising:
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(a) administering to the mammal a pancreatitis associated peptide comprising the amino acid sequence IGLHDPTQGTEPNGE (SEQ ID NO;
3), wherein the pancreatitis associated peptide can facilitate the growth of the pancreatic cell;
wherein(b) the mammal produces a leukocyte that immunospecifically recognizes an epitope present on the homologous pancreatitis associated protein comprising the sequence MLPPMALPSVSWMLLSCLMLLSQVQGEEPQRELPSARIRCPKGSKAYGSHCYALFLSPKSWT DADLACQKRPSGNLVSVLSGAEGSFVSSLVKSIGNSYSYVWIGLHDPTQGTEPNGEGWEWS SSDVMNYFAWERNPSTISSPGHCASLSRSTAFLRWKDYNCNVRLPYVCIFTD (SEQ ID NO;
1), wherein the epitope is not present on the pancreatitis associated peptide of step (a),so that the administration of the pancreatitis associated peptide facilitates the growth of the pancreatic cell but does not immunospecifically stimulate the leukocyte to the same degree as an equivalent amount of the homologous pancreatitis associated protein. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10)
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11. A method of stimulating neogenesis of pancreatic beta cells in an individual having a predisposition to Type I diabetes comprising:
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(a) determining whether the mammalian subject possesses a T lymphocyte that is;
(i) reactive to the 175 amino acid pancreatitis associated polypeptide protein shown in SEQ ID NO;
1; and
(ii) not reactive to the pancreatitis associated polypeptide peptide shown in SEQ ID NO;
3; and
(b) administering to the subject a therapeutically effective amount of a pancreatitis associated peptide comprising the amino acid sequence shown in SEQ ID NO;
3.
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12. A method of inhibiting the expression in a mammalian subject of an epitope present on the 175 amino acid pancreatitis associated polypeptide protein shown in SEQ ID NO:
- 1, wherein the epitope is recognized by an autoimmune T cell in Type I diabetes, the method comprising exposing a pancreatic ductal cell in the subject to an amount of a pancreatitis associated polypeptide peptide comprising the amino acid sequence shown in SEQ ID NO;
3 sufficient to stimulate beta cell neogenesis. - View Dependent Claims (13, 14, 15, 16, 17, 18, 19)
- 1, wherein the epitope is recognized by an autoimmune T cell in Type I diabetes, the method comprising exposing a pancreatic ductal cell in the subject to an amount of a pancreatitis associated polypeptide peptide comprising the amino acid sequence shown in SEQ ID NO;
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20. A method of inhibiting the onset of Type I diabetes in a mammalian subject predisposed to Type I diabetes comprising administering to the subject a therapeutically effective amount of a pancreatitis associated polypeptide peptide comprising the amino acid sequence shown in SEQ ID NO:
- 3, wherein the mammalian subject is selected to have at least one leukocyte that is;
(a) immunospecifically reactive to the 175 amino acid pancreatitis associated polypeptide protein shown in SEQ ID NO;
1; and
(b) not immunospecifically reactive to the pancreatitis associated polypeptide peptide shown in SEQ ID NO;
3. - View Dependent Claims (21, 22, 23, 24)
- 3, wherein the mammalian subject is selected to have at least one leukocyte that is;
- 25. A method of stimulating neogenesis of pancreatic beta cells in an individual having a predisposition to Type I diabetes comprising administering to the subject a pancreatitis associated polypeptide peptide comprising the amino acid sequence shown in SEQ ID NO:
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29. A method of inhibiting the onset of Type I diabetes in a mammalian subject predisposed to Type I diabetes comprising administering to the subject a therapeutically effective amount of a pancreatitis associated polypeptide peptide comprising the amino acid sequence shown in SEQ ID NO:
- 3, wherein the pancreatitis associated polypeptide peptide does not possess an epitope present in the pancreatitis associated polypeptide protein comprising the amino acid sequence shown in SEQ ID NO;
1 that is recognized by autoimmune T-cells in the individual.
- 3, wherein the pancreatitis associated polypeptide peptide does not possess an epitope present in the pancreatitis associated polypeptide protein comprising the amino acid sequence shown in SEQ ID NO;
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30. A composition comprising a pancreatitis associated polypeptide peptide having the amino acid sequence shown in SEQ ID NO:
- 3 and a pharmaceutically acceptable carrier.
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31. A composition comprising a pancreatitis associated polypeptide peptide having the amino acid sequence shown in SEQ ID NO:
- 3, wherein the peptide has an amino acid substitution at I104, G105, L106, H107, D108, P109, T110, Q111, G112, T113, E114, P115, N116, G117 or E118.
Specification