Identification of self and non-self antigens implicated in autoimmune diseases

a technology of autoimmune diseases and antigens, applied in the field of immunology, can solve the problems of not being able to achieve the effect of using such alignments, not being able to provide evidence, and being more difficult to define mhc class ii binding motifs based on sequence alignments

Inactive Publication Date: 2006-07-20
PEPTIMMUNE
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

No success has been reported using such alignments in identifying epitopes from pathogens that could cross react with presumably pathogenic T cell lines from human patients with autoimmune disease (Oldstone, 1990).
No evidence, however, was provided that these peptides could stimulate clones from diabetic mice (or humans).
Due to the size heterogeneity, however, it has proven more difficult to define MHC class II binding motifs based on sequence alignments.
Even this work, however, could not provide a detailed description of the binding pockets of HLA-DR proteins, the particular residues involved in the formation of these pockets of the structural requirements or antigens for MHC binding.

Method used

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  • Identification of self and non-self antigens implicated in autoimmune diseases

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example 1

Identification of Self Epitopes of Pemphigus vulgaris

[0198] As noted above, Pemphigus vulgaris (PV) is, in different ethnic groups, associated either with a DR4 allele (DRB1*0402) or with a rare DQ1 allele (DQB1*05032); only a small fraction of PV patients have neither susceptibility gene (Ahmed et al., 1991; Ahmed et al., 1990; Scharf et al., 1988). The PV associated molecule has a negative charge (Glu) at the critical position β71; the neighboring position (β70) is also negatively charged. The DR4 subtype associated with PV is the only one that carries a negative charge at DRβ71 (a positive charge (Arg) is found at DRβ71 in the RA associated DR4 molecules). Although polymorphic, the P7 pocket residue DRβ67 (Leu / Ile) does not appear to be involved in peptide binding but probably acts as a TCR contact residue (Stern et al., 1994).

[0199] The charge of a polymorphic residue at DRβ71 could therefore account for susceptibility to two different autoimmune syndromes associated with stru...

examples

[0208] The following examples are intended to further illustrate certain embodiments of the invention and are not intended to limit the scope of the invention.

example i

[0209] Preparation of Segment 1 of the Peptide of SEQ ID NO: 1

[0210] Segment 1, Ac-Glu(OtBu)-Pro-Asn(Trt)-His(Trt)-Leu-Asn(Trt)-Ser(tBu)-Lys(Boc)-Ile-Ala-OH, (amino acids 1-10), is prepared by the solid phase peptide synthesis (SPPS) approach using an Fmoc-strategy. SPPS is based on the sequential addition of Fmoc-amino acid derivatives possessing appropriate side chain protection to an insoluble polymeric support. The base labile Fmoc-group is used for N-α-protection. The polymeric support employed in the synthesis of Segment 1 is the superacid labile HMPB resin, which is prepared with Fmoc-Ala coupled to the resin via its carboxy group. After removal of the Fmoc group with piperidine, the next Fmoc-amino acid is added using 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) as coupling reagent. The reaction is monitored by an in-process control trinitrobenzenesulfonic acid test (TNBS). When coupling of the Fmoc-amino acid is complete, excess amino acid ...

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Abstract

The present invention provides isolated peptides relating to the autoimmune disease Pemphigus vulgaris. The peptides relating to Pemphigus vulgaris are self epitopes derived from human pathogens which are implicated in the aetiology and remissions of the disease. Pharmaceutical preparations for tolerizing and / or immunizing individuals are provided as well as methods relating thereto. Methods are provided for identifying other self and non-self epitopes involved in human autoimmune disease and similar pharmaceutical preparations and methods of use for these epitopes are also provided.

Description

FIELD OF THE INVENTION [0001] The present invention relates to the field of immunology and, in particular, to the identification of self and non-self antigens implicated in human autoimmune responses. The invention relates to methods of identifying such self antigens and provides examples of such antigens relating to Pemphigus vulgaris. The invention also relates to the use of such antigens for in vitro assays, animal models, therapeutic agents and vaccines. BACKGROUND OF THE INVENTION [0002] Human autoimmune diseases have a striking genetic association with particular alleles of major histocompatability complex (“MHC”) class I or class II genes. The field was established by the seminal discovery of HLA-B27 linked susceptibility to ankylosing spondylitis, a chronic inflammatory joint disease (Brewerton (et al., 1973; Schlosstein et al., 1973). MHC associated susceptibility has now been documented for a variety of human autoimmune diseases, including insulin dependent diabetes mellit...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395A61K31/70C07K16/42A61K39/00C07K7/08C07K14/47
CPCA61K39/0008C07K14/4713A61P17/00A61P37/06A61K38/10
Inventor RASMUSSEN, JAMESYU, BEI
Owner PEPTIMMUNE
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