Heat shock proteins (hsps) are highly conserved proteins that play an important role in various cellular processes. They are highly conserved proteins that are induced by a wide variety of chemical and physiological stimuli. Hsps are expressed both as constitutive proteins that act as molecular chaperones and as inducible stress proteins. Hsp’s were first described and later named due to their production by cells exposed to sudden elevations in termperature. The hsps include proteins of various molecular weights, including 20, 60, 6-68, 70, 90 and 110 kD.
HSPs bind peptides including antigenic peptides generated within cells. They also interact with antigen presenting cells through CD91 and other receptors, eliciting a cascade of events including representation of heat shock protein chaperoned peptides by MHC, translocation of NFkB into the nuclei and maturation of DCs (Srivastava, Annu. Rev. Immuno. 2002, 20, 395-425).
HSP60:
Structure:
Analogs and Equivalents: The bacterial equivalent of HSP60 is HSP65. Synthetic analogs (synthetically created compounds that differ from the natural compound both in structure and function) include peptide p277, also known as DiaPep277. P277 is a synthetic analog of a native 24 amino acid fragment p277 of the 60kDa human HSP60.
Where expressed: HSP60 isby cells exposed to stress or immune activation, and is present in the blood and tissues during inflammation.
Functions: HSP60 serves as a chaperone inside the cell. It is also involved as an autoantigen in type 1 diabetes and arthritis, and appears to down-regulate inflammation in models of these autoimmune diseases. The immune system reacts to hsp60 epitopes that are either cross-reactive between the human and bacterial analogues, or idiosyncratic. In addition to its role as an autoantigen involved in progression of various autoimmune diseases for modulating the development of such diseases, HSP60, via TLR2 may inhibit T cell migration in response to CXCL12 and the expression of its receptor CXCR4.
HSP70:
HSP70 is often induced in cells exposed to stressful stimuli and its role in reducing stress induced damage through its chaperone function is well established. Independent of its chaperone function, it can also directly bind and inhibit JNK and thereby reduce apoptosis induced by a variety of insults. This inhibition involves direct binding of HSP70 to JNK.
Human HSP70 gene has also been propsoed as an an adjuvant for DNA vaccine (J Gene Med 2007, 9, 715-726).
HSP96 (HSPPC-96/gp96/GRP94/endoplasmin): is a protein peptide complex consisting of a 96 kDaheat shock protein (Hsp), gp96, and an array of gp96 associated cellular peptides. Oncophage, a cancer vaccine in late state clinical trials is prepared by recovering and generating a purified fraction of the stress protein gp96 from human tumors which are then packaged and csent to a central processing facility. After proecesing, the pruified protein fraction is transferred back to the clinical for administration back to the same pateint (Gorden, Methods 32 (2004) 63-69).
Activation of Heat Shock Proteins
Hsp synthesis is induced by the activation of the heat shock factor (HSF) 1. In resting cells several chaperones, most importantly Hsp90, were shown to bind to HSF-1 and keep it in an inactive form. During stress, this repressing chaperone becomes occupied by misfolded proteins, which results in the dissociation of the cytoplasmic chaperone/HSF-1 complex. Dissociation of HSF-1 from Hsp90 uncovers the nuclear localization signal of this transcription factor and allows its translocation to the cell nucleus. Hsp90 inhibitors can also cause the transcriptional activation of HSF-1 by disrupting Hsp/HSF-1 complexes. For example, geldanamycin and 17AAG have been shown to activate HSF-1. Thus, the inhibition of Hsp90, paradoxically, leads to an increase in its overall amount as well.
Therapeutic Applications
Treatment of Autoimmune Diseases, generally:
Albani (US 2002/0146759) disclosesusing fragments of a stress protein for treating immune mediated disease in a subject.
Karomon (WO 03/063759) discloses that exposure of antigen presenting cells such as DCs to Hsps such as HSP60 enables these APCs to activate T cells to produce immunomodulatory cytokines which is useful for the prevention or treatment of diseases (chronic inflmmatory diseases, graft rejection, certin autoimmune diseases) involving abnormal Th1 or Th2 levels.
–Treatment of Hepatitis:
Mizzen (WO 02/062959) teaches treating HBV infection with compositions which comprise a stress protein such as a Hsp.
–Treatment of Diabetes:
Cohen (US 6,180,103) teaches a peptide haivng the structure of the p277 sequence of hsp60 in which one or both cystein residues are replaces by valine with the same biological activity as p277 but improved stability and which is particulalry useful for treatment of Type I diabetes. Cohen also teaches that even a two amino acid change can have importance in determining effect on results (p277 (Val6-Val11) was effective but not p277 (Ser6-Ser11).