In vivo treatment of mice with heat shock protein, gp96, improves survival of skin grafts with minor and major antigenic disparity

Caught with their PAMPs down? The extracellular signalling actions of molecular chaperones are not due to microbial contaminants

“…Although HSPC4 has been reported to have proinflammatory effects and to induce peptide-specific protective immunity, it has been demonstrated that high-dose HSPC4 does not induce protective anti-tumour immunity (Chandawarkar et al 1999), indeed it can attenuate inflammatory disease and delay skin transplant rejection (Chandawarkar et al 1999(Chandawarkar et al , 2004Kovalchin et al 2006). These anti-inflammatory properties appear to be mediated by the induction and/or activation of immunoregulatory CD4 + T-cell populations (Chandawarkar et al 1999).…”

“…However, there is increasing evidence that molecular chaperones can inhibit the functions of immune cells. Evidence has been presented that Hsp10 (Johnson et al 2005), Hsp27 (Miller-Graziano et al 2008), human Hsp60 (Zanin-Zhorov et al 2003, 2006Cohen-Sfady et al 2005), the endoplasmic reticulum Hsp70 family member, BiP (Corrigall et al 2001(Corrigall et al , 2004 and HSPC4 (Chandawarkar et al 1999(Chandawarkar et al , 2004Kovalchin et al 2006;Slack et al 2007), inhibit monocyte or lymphocyte activation. Indeed, Hsp10 was actually discovered in human blood, as an immunosuppressive factor, 1 year (1977) before the terminology of molecular chaperones was introduced (Morton et al 1977;Noonan et al 1979).…”

Administration of the stress protein gp96 prolongs rat cardiac allograft survival, modifies rejection-associated inflammatory events, and induces a state of peripheral T-cell hyporesponsiveness

“…Furthermore, work has shown that high-dose gp96 purified from normal liver (2 ϫ 100 g subcutaneously) can suppress the onset of diabetes in nonobese diabetic mice and myelin basic protein-or proteolipid protein-induced autoimmune encephalomyelitis (EAE) in SJL mice (Chandawarkar et al 2004), as well as prolong the survival of murine skin allografts exhibiting minor or major histocompatibility differences (Kovalchin et al 2006a).…”

“…Published data indicate that the anti-inflammatory properties of high-dose gp96 are not dependent on the tissue source of the administered gp96 (Chandawarkar et al 2004;Kovalchin et al 2006a) but do appear to involve the induction, activation, and/or recruitment of as yet unidentified immunoregulatory T-cell populations. Evidence for this comes from studies that have demonstrated that the adoptive transfer of CD4 ϩ T cells from animals that have been treated with high-dose gp96 inhibits the induction of tumor immunity by low-dose gp96 and protects against diabetes and EAE (Chandawarkar et al 1999(Chandawarkar et al , 2004.…”

Heat shock proteins are no DAMPs, rather 'DAMPERs'

“…Third, in vitro-cultured dendritic cells have been shown to adopt a tolerizing phenotype, rather than a mature or activated phenotype, in the presence of HSPs 10,11 . Fourth, in experimental models of autoimmunity and of tissue or tumour transplants, immunization with HSPs was shown to lead to the induction of regulatory T cells, which suppressed disease or transplant rejection [12][13][14][15][16][17][18][19] .…”