Autologous Hsp70 Induces Antigen Specific Th1 Immune Responses in a Murine T-Cell Lymphoma

Abstract

Heat Shock protein-70 derived from tumor cells is highly immunogenic and induces specific anti-tumor immune response by directly activating cytotoxic CD8(+) T cells. Additionally, Hsp70 is known to be a strong activator of antigen presenting cells and therefore, up regulates the production of pro-inflammatory cytokines and chemokines. In this study, we have shown the effect of tumor-derived Hsp70 on the induction of delayed type hypersensitivity reaction in a T cell lymphoma bearing mice. The autologous Hsp70 augments contact hypersensitivity and delayed type hypersensitivity responses in mice challenged with allergen in vehicle and antigens respectively. The adoptive transfer of splenocytes derived from Hsp70 immunized mice is able to enhance delayed type hypersensitivity response in antigen challenged normal and DL-bearing host. Furthermore, adoptive transfer of macrophages incubated with autologous Hsp70 also enhances DTH reactivity in mice. The pro-inflammatory cytokines and C-C chemokines are found to be elevated in the DTH footpad extract of antigen challenged normal and DL-bearing mice. Increased production of IFN-gamma and MIP-1alpha+/- suggest that autologous Hsp70 augments the recruitment of antigen specific Th1 cells, which further secretes pro-inflammatory cytokines and C-C chemokines mediating the hypersensitivity reaction upon challenge with antigens.

PKC-Inhibitors Induce Apoptosis by Inhibiting Hsp70-Mediated Protection of Anti-Apoptotic BCL2 Proteins in Dalton’s Lymphoma Cells

“…Heat shock response enhances the synthesis of intracellular heat shock protein (hsp70) that confers a protective effect against a wide range of cellular stresses such as chemotherapy, tumor burden and malignancies [1][2][3][4]19,25] . Therefore, heat shock and concurrent heat shock treatments were applied to induce the expression of intracellular hsp70 in DL cells.…”

“…Additionally, research has shown that hsp70 is a promising molecule in controlling and regulating apoptosis [1,2] . Inhibition/depletion of hsp70 disrupts heterodimerization with anti-apoptotic BCL2 proteins (BCL2/Bcl-xL), leading to the release of cytochrome-c, the activation of caspase-3/6/7 and ultimately apoptosis [1][2][3][4] .…”

“…Malfunctions in apoptosis result, in severe side effects including cancer, myocardial infarction, neurodegenerative disease and ischemic stroke [1] . Activation of the intrinsic apoptotic pathway(s) induces release of cyt-c, activation of effectors caspases-3/6/9, and loss of mitochondrial potential [2] .…”

“…Inhibition/depletion of hsp70 disrupts heterodimerization with anti-apoptotic BCL2 proteins (BCL2/Bcl-xL), leading to the release of cytochrome-c, the activation of caspase-3/6/7 and ultimately apoptosis [1][2][3][4] . However, it was reported that enhanced expression of hsp70 protects anti-apoptotic BCL2 proteins by organizing complex structures with BCL2 and therefore inhibiting over expression of pro-apoptotic BCL2 proteins (Bax, BCl-Xs), resulting in increased cell survival [2] .…”

“…plays an important role in maintaining cellular equilibrium [1][2][3][4][15][16] . Bax/Bcl-Xs and Bak are important regulators of the mitochondrialdependent apoptotic pathway [8,15,17] .…”