Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1997-09-15
2000-05-02
Jones, Dwayne C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 14, 514 15, 514 16, 514 17, 530326, 530327, 530328, 530329, 530330, A61K 3800
Patent
active
060572949
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to peptides which affect T-cells, presumably by action on the T-cell antigen receptor. The present invention further relates to the therapy of various inflammatory and autoimmune disease states involving the use of these peptides. Specifically, the peptides are useful in the treatment of disorders where T-cells are involved or recruited.
T-cells are a subgroup of cells which together with other immune cell types (polymorphonuclear, eosinophils, basophils, mast cells, B-, NK cells), constitute the cellular component of the immune system. Under physiological conditions T-cells function in immune surveillance and in the elimination of foreign antigen(s). However, under pathological conditions there is compelling evidence that T-cells play a major role in the causation and propagation of disease. In these disorders, breakdown of T-cell immunological tolerance, either central or peripheral, is a fundamental process in the causation of autoimmune disease.
Central tolerance involves thymic deletion of self reactive cells (negative selection) and positive selection of T-cells with low affinity for self major histocompatibility complex antigens (MHC). In contrast, there are four, non-mutually exclusive hypotheses that have been proposed to explain peripheral T-cell tolerance which are involved in the prevention of tissue specific autoimmune disease. These include: anergy (loss of co-stimulatory signals, down regulation of receptors critical for T-cell activation), deletion of reactive T-cells, ignorance of the antigen by the immune system and suppression of autoreactive T-cells. Tolerance once induced does not necessarily persist indefinitely. A breakdown in any of these mechanisms may lead to autoimmune disease.
Autoimmune disease and other T-cell mediated disorders are characterised by the recruitment of T-cells to sites of inflammation. T-cells at these sites, coupled with their ability to produce and regulate cytokines and influence B-cell function, orchestrate the immune response and shape the final clinical outcome. An understanding of the process of antigen recognition and subsequent T-cell activation, leading to T-cell proliferation and differentiation, is therefore pivotal to both health and disease. The critical component of antigen recognition on the surface of T-cells is the complex antigen receptor (TCR) which is a multisubunit structure that recognises antigen in the context of MHC-encoded proteins on the surface of antigen-presenting cells. Disturbance in this intricate structure-function relationship of the TCR, integrating antigen recognition with T-cell activation may provide the therapeutic means to deal with inflammation and T-cell mediated disorders.
The TCR is composed of at least seven transmembrane proteins. The disulfide-linked (.alpha..beta.-Ti) heterodimer forms the clonotypic antigen recognition unit, while the invariant chains of CD3, consisting of .epsilon., .gamma., .delta., and .zeta. and .eta. chains, are responsible for coupling the ligand binding to signalling pathways that result in T-cell activation and the elaboration of the cellular immune responses. Despite the gene diversity of the TCR chains, two structural features are common to all known subunits. Firstly, they are transmembrane proteins with a single transmembrane spanning domain--presumably alpha-helical. Secondly, all the TCR chains have the unusual feature of possessing a charged amino acid within the predicted transmembrane domain. The invariant chains have a single negative charge, conserved between the mouse and human, and the variant chains possess one (TCR-.beta.) or two (TCR-.alpha.) positive charges. Listed below in TABLE 1 is the transmembrane sequence of TCR-.alpha. in a number of species showing that phylogenetically this region is highly conserved indicating an important functional role. The substitutions between species are very conservative.
TABLE 1 ______________________________________
Sequence comparison of TCR-.alpha. transmembrane region
SPECIES SEQUENCE
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Delacroix-Muirheid C.
Jones Dwayne C.
Northern Sydney Area Health Service of Pacific Highway
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