Experimental immunization with Heat Shock Proteins (HSP) or HSP peptides in models of inflammatory diseases and in humans with type I diabetes or rheumatoid arthritis (RA) have been demonstrated to arrest inflammatory damage by the induction of T cells producing anti-inflammatory cytokines. In experimental models of induced autoimmunity it was shown that regulatory T cells operate by recognising endogenous HSP (over-) expressed by cells under stress at sites of inflammation. From this it can be inferred that HSP expression by tissue cells is an essential factor in HSP induced immunoregulation and also, possibly, for maintaining these HSP specific regulatory T cells at the appropriate level in immune homeostasis.
This would imply that a reduced HSP expression under conditions of cell stress would lead to an impaired immune-regulation resulting from a reduced T cell response to endogenous HSP.
Aging is a well-known cause of the decreasing HSP inducibility in the elderly. Expression of HSP in cells depends of the activity of so-called Heat Shock Factor (HSF). The function of this transcription element in cells gets compromised in older individuals. Therefore, a major factor in the biology of aging is the reduced stress-resistance of cells due to the relatively deficient HSP up-regulation.
A mechanism essential for the presentation of endogenous (cytosolic) HSP peptides in the context of MHCII molecules is autophagy. As regulatory T cells are MHCII restricted, such presentation of self-antigens in MHCII is a prerequisite for T cells to see cell stress up-regulated HSP. Especially so-called chaperone mediated autophagy (CMA) is the primary mechanism for HSP70 epitopes to be loaded onto MHCII molecules. And again, autophagy turns out to become compromised with rising age.
Thus, several factors are jointly responsible for a decreased capacity to up-regulate HSP during aging. And therefore this diminished HSP presentation during aging may contribute to the decreased immuno-regulation in the elderly.
A general aim of our contribution to Tolerage will be to see whether the age related decrease of HSP inducibility can be corrected by the administration of HSP (co-) inducing compounds. For this project we aim to
1) compare immune responsiveness to bacterial and self (mammalian) HSP in young and aged mice (fine epitope mapping, T cell frequencies)
2) study the immuno-regulatory effects of HSP inducing compounds in in vitro and in in vivo systems
3) study the effects of HSP inducing compounds on the development of T regulatory cells (both IL10 producing induced regulatory T cells and natural FoxP3 positive T regs)
4) study the effect of induced HSP up-regulation in experimental arthritis in mice (Proteoglycan induced arthritis in Balb/c mice)
Selected References
Van Eden et al. Heat shock proteins induce T cell regulation of chronic inflammation. Nat.Rev. Imm. 5: 318-330; 2005
Van Eden and Waksmann. Immune regulation of adjuvant arthritis: implications for innovative therapeutic strategies in arthritis. Arthrit. & Rheum. 48: 1788-1797; 2003
Van Eden et al. Stress proteins as inducers and targets of regulatory T cells in arthritis. Int. Rev. Immunol. 24: 181-197; 2005
Guarner et al. Mechanisms of disease: the hygiene hypothesis revisited. Nature Clin. Pract. Gastroenterol. Hepatol. 3: 275-84; 2006
Berlo SE, Guichelaar T, Ten Brink CB, van Kooten PJ, Hauet-Broeren F, Ludanyi K, van Eden W, Broeren CP, Glant TT. Increased arthritis susceptibility in cartilage proteoglycan-specific T cell receptor-transgenic mice. Arthritis Rheum. 54 :2423-33; 2006
Van Eden W. Immuno-regulation of autoimmune diseases. Hum Immunol. 67: 446-53; 2006.