Epitope Of Heat Shock Protein Research Articles

Recurrent Aphthous Stomatitis: Towards Evidence-Based Treatment?

Recurrent aphthous stomatitis is one of the most common oral mucosal diseases seen by dental professionals, and yet its aetiology remains unclear, and its management based on less than robust evidence. The literature remains confused because of the lack of clarity in diagnosis and the lack of a standardised ulcer severity scoring system and agreed outcome measures. However, recent literature is encouraging in meeting these aims. There is agreement that recurrent aphthous stomatitis (RAS) is a localized mucosal disease not secondary to systemic disease and therefore distinguishable from over 40 other types of oral ulcers. Disease severity scores have been introduced and outcome measures have become more standardised. RAS appears to be an auto-immune disease directed at epitopes of heat shock proteins whilst most recent work on aetiology has focused on cytokines and genetics. Pro-inflammatory cytokines including TNF-a and IL-6 and IL-17 are raised in RAS and TNF inhibitors can inhibit episodes of ulceration. Many local anti-inflammatory agents will help ulcers heal, and local steroids remain the treatment of choice. Some systemic drugs have evidence-based data indicating efficacy at preventing new ulcers including colchicine, prednisolone, thalidomide, pentoxyfilline and dapsone. The field would benefit from further trials combining local and systemic therapy using defined outcome measures.

DiaPep277 peptide therapy in the context of other immune intervention trials in type 1 diabetes

Introduction: Type 1 diabetes (T1D) is characterized by the autoimmune destruction of pancreatic β-cells. The aim of immune intervention is to arrest this autoimmune attack. DiaPep277, a major T-cell epitope of heat shock protein 60 (hsp60), has been shown to be effective in the modulation of the immune response in recent onset T1D and is the main focus of this review in the context of other ongoing trials using different approaches.Areas covered: The authors performed a literature search of Pubmed listed publications (from the last 10 years) and a website search of the company licensing DiaPep277. DiaPep277 has been investigated in Phase I – III trials in humans. Phase II trials showed a significant preservation of β-cell function in adult T1D patients (but not children) with an absence of adverse effects and not accompanied by lower glycosylated haemoglobin (HbA1c) levels or reduced daily insulin requirement compared with placebo-treated patients.Expert opinion: Administration of DiaPep277 is safe and represents a promising therapeutic strategy in patients with recent-onset T1D. The results of two large Phase III trials will tell us whether this therapy may change our current approach to treating T1D patients at diagnosis.

CD4+ T cell responses to epitopes of self-heat shock protein 70 in patients with juvenile dermatomyositis

Background and objectivesJuvenile dermatomyositis (JDM) is a childhood disease characterised by inflammation in the muscle and the skin. In several human chronic inflammatory diseases CD4 T cell responses to epitopes...

Immunomodulation with heat shock protein DiaPep277 to preserve beta cell function in type 1 diabetes – an update

Importance of the field: Type 1 diabetes is a chronic autoimmune disease in which pancreatic beta cells are selectively destroyed. Ultimately hyperglycemia develops and insulin substitution becomes necessary. Immunomodulation aims at arresting this autoimmune attack. DiaPep277, the major T-cell epitope of heat shock protein 60 (hsp60), has been shown to be effective as a modulator of the immune system in type 1 diabetes and is the focus of this review.Areas covered in this review: A literature search of Pubmed listed publications covering 1990 – 2009 and a website search of the licensing company were performed.What the reader will gain: DiaPep277 has been successfully employed in animal models and has been investigated in Phase I – III studies in humans. A combined analysis of the Phase II trials showed a significant preservation of beta cell function in adults without adverse effects, but HbA1c was not changed. A Phase III clinical trial is ongoing, and a second Phase III trial will start in early 2010. Addressing the underlying autoimmune process is the call of the future in type 1 diabetes.Take home message: Use of Diapep277 is a promising therapeutic strategy currently being tested in Phase III trials.

Disease association of antibodies to human and mycobacterial hsp70 and hsp60 stress proteins.

Structural homology between microbial and human stress proteins has been postulated to be a basis for autoimmunization in chronic inflammatory diseases. Therefore, we estimated by ELISA titration the antibody levels to mycobacterial (M) and human (H) recombinant hsp70 and M-hsp65 heat-shock proteins in sera of patients with Crohn's disease (n = 29), ulcerative colitis (n = 20) and nontuberculous mycobacterial disease of the lungs (n = 20). Antibodies to H-hsp60, separated by two-dimensional gel electrophoresis, were tested in six sera of each group of patients. In Crohn's disease, antibody titres to the M-hsp65 antigen without detectable H-hsp60 binding were significantly elevated in 52% of the patients. In contrast titres to both M-hsp70 and H-hsp70 were demonstrable and correlated, but increased over control values only in four (14%) patients. The antibody pattern in ulcerative colitis was found to be quite different: anti-H-hsp60 binding was demonstrable in most patients, although anti-M-hsp65 titres were not elevated. Furthermore, 25% of patients had significantly elevated titres to M-hsp70, but not to H-hsp70. In non-tuberculous mycobacterial pulmonary disease, about 50% of patients had elevated titres to both hsp65 and hsp71 mycobacterial antigens but not to the corresponding human proteins; patients with Mycobacterium xenopi infection had the highest titres in this group. These results demonstrate the existence of distinct disease-associated patterns in the human antibody response to stress protein antigens. However, these data are not sufficient to imply sensitization with mycobacteria in patients with inflammatory bowel diseases, since certain epitopes of heat-shock proteins are shared by several bacterial genera.

Immune response to heat shock protein of Helicobacter pylori--a candidate as a vaccine component.

. The reactive epitope of heat shock protein 60 (HSP60) of Helicobacter pylori to its monoclonal antibody (H9) was determined, and its synthesized peptide designated pH9 was used for ELISA. The patients with H. pylori infection had significantly lower titers of pH9 antibody than did uninfected patients. In C57BL/6 mice immunized intraperitoneally with the pH9 peptide with Freund's complete adjuvant (FCA), the number of H. pylori organisms colonizing the stomach was significantly lower than that in mice immunized with FCA only. These results suggest that HSP60 of H. pylori is effective in protection against H. pylori infection and might be a good candidate as a vaccine component.

T Cells Recognize an Immunodominant Epitope of Heat Shock Protein 65 in Kawasaki Disease

Kawasaki disease (KD) is an acute systemic vasculitis of infancy and early childhood that is characterized by endothelial cell damage associated with T-cell activation. Lymphocytes infiltrating damaged tissues might be responsible for the disease through secretion of cytokines, such as tumor necrosis factor (TNF)-alpha, that could cause fever, as well as endothelial tissue damage. Debate is growing about the nature of antigen responsible for T-cell activation in KD. Bacillus Calmette Guerin (BCG) and purified protein derivative (PPD) hyperresponsiveness was observed in KD patients and this phenomenon was hypothetically ascribed to cross-reactivity between mycobacterial Heat Shock Protein (HSP) 65 and human homologue HSP63. CD4+ and CD8+ T-cell clones were obtained from peripheral blood of KD patients in acute phase, or control subjects. The clones were tested for reactivity toward HSP65 and derived peptides. Both proliferation and cytokine production were analyzed. A significant fraction of CD4 and CD8 T-cell clones from KD patients recognized an epitope from HSP65, spanning amino acids 65-85. T-cell clones cross-reacted with the corresponding 90-110 peptide sequence of human HSP-63. Cross-reactivity between specific epitopes of mycobacterial and human HSP could play a role in the development of the tissue-damage characteristic of KD.

Nasal administration of arthritis-related T cell epitopes of heat shock protein 60 as a promising way for immunotherapy in chronic arthritis.

Adjuvant Arthritis (AA) can be induced in Lewis rats by immunisation with mycobacterial antigens. The disease can be passively transferred with T cell clone A2b, which recognises the 180-188 amino acid sequence in mycobacterial heat shock protein 60 (hsp60) and which crossreacts with crude cartilage proteoglycans. We succeeded to induce peripheral tolerance to this AA-associated T cell epitope following nasal administration of a peptide containing this epitope (mycobacterial hsp60 176-190). In rats treated nasally with 176-190 and immunised with mycobacterial hsp60, proliferative responses to 176-190 were reduced. AA was inhibited nasally with 176-190 treated rats and not in rats nasally treated with a control mycobacterial hsp60 peptide (211-225). Moreover, nasal 176-190 led to similar arthritis protective effects in a non-microbially induced experimental arthritis (avridine induced arthritis). In a subsequent study we tried to prevent and to treat AA through nasal administration of mycobacterial hsp60 peptide 180-188 and a peptide analogue of 180-188, 180-188(L183->A) (Alanine 183), which has been shown to have an increased MHC-binding affinity for rat RT1 Bl and an increased capacity to inhibit the proliferative A2b response in vitro. We found that nasal administration of 180-188 had a moderate arthritis suppressive effect in AA, whereas its analogue peptide Alanine 183, had a strong suppressive effect. This strong arthritis suppressive effect was only partly due to the higher MHC-binding affinity for rat RT1 Bl. Furthermore, it was possible to passively transfer nasal Alanine 183 induced disease protection. The present findings may in our view offer novel prospects for immunotherapy through nasal administration of (analogue) peptides, with a mimicry relationship with joint specific cartilage proteoglycan epitopes.

A synthetic mycobacterial heat shock peptide prevents adjuvant arthritis but not proteoglycan-induced synovitis in the rat

Intradermal immunization of female Lewis rats with 100 micrograms of a nine-amino acid synthetic peptide corresponding to the arthritic T cell-reactive epitope of mycobacterial heat shock protein, three weeks prior to induction of adjuvant arthritis, produced inhibition of day 16 ankle swelling and histologic score. Intraarticular injection of 10 micrograms of bovine articular cartilage proteoglycan monomer emulsified in heavy mineral oil into normal Lewis rat stifle joints produced several hallmarks of chronic synovitis at day 16. Pre-treatment with nonapeptide did not inhibit proteoglycan-induced synovitis. These results indicate that tolerance to the critical epitope of heat shock protein does not abrogate the ability of proteoglycan to induce synovitis in rats.

Heat shock protein expression in corpora amylacea in the central nervous system: clues to their origin

Small bodies expressing epitopes of the 72 kD heat shock protein (HSP) have been identified in the brain and spinal cord in normal and neurologically abnormal individuals. These bodies resemble the 'pre-corpora amylacea' (pre-CA), thought to be the primary structure in the development of the mature body. Corpora amylacea are laminated hyaline bodies composed of polyglucosans. They are found in larger numbers with increasing age in the brain and spinal cord. Mature, histologically 'classical', corpora amylacea express epitopes of HSP chiefly at the periphery of the corpus, whilst smaller immature 'pre-corpora' stain intensely throughout the entire structure. A heat shock or stress response in neurons and glial cells may be part of the cellular reaction to accumulation of abnormal products.