The immune response to Mycobacterial 70-kDa heat shock proteins frequently involves autoreactive T cells and is quantitatively disregulated in multiple sclerosis

Salvetti, Marco; Ristori, Giovanni; Buttinelli, Carla; Fiori, P.; Falcone, Marika; Britton, Warwick J.; Adams, Elizabeth M.; Paone, Gregorino; Grasso, Maria Grazia; Pozzilli, Carlo

doi:10.1016/0165-5728(96)00013-6

Cited by 56 publications

(25 citation statements)

References 57 publications

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“…HSPs are not only functional but also structurally highly conserved from prokaryotic to higher eukaryotic organisms. 51 A potential safety concern arises from the existence of T-lymphocytes crossreactive with myobacterial and human HSP70 52 and the demonstration of intestinal inflammation due to the transfer of HSP60-reactive CD8 þ T cells into mice. 53 Although we cannot discount this risk entirely, we believe that in a clinical setting the use of a human gene will reduce the risk of autoimmunity due to crossreactive T-lymphocytes primed by the HSP vaccine.…”

Section: Hsp70-mediated Antigen Targeting For Dna Vaccines H Hauser Ementioning

confidence: 99%

Secretory heat-shock protein as a dendritic cell-targeting molecule: a new strategy to enhance the potency of genetic vaccines

Shen

et al. 2004

Gene Ther

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DNA vaccines are an appealing strategy for inducing cytotoxic T-lymphocyte and antibody responses against tumor cells as well as infectious agents. Dendritic cells (DCs) play a critical role in inducing immune responses, but their potential is not fully utilized in the DNA vaccine setting since they take up only a minor fraction of the injected DNA. Here we describe a novel DNA vaccination strategy based on the targeting of a modified tumor-associated antigen, the human papilloma virus (HPV) type 16 E7 protein, to DCs by a heat-shock protein (HSP) to enhance antigen presentation and immune responses. Specifically, a chimerical HPV-E7 and HSP70 fusion gene preceded with a leader sequence was constructed. When mice were immunized with this construct, the DNA is taken up by various types of cells, which then produce and secrete an HPV-E7-HSP70 fusion protein that is targeted to DCs by the HSP70 portion of the chimerical molecule for antigen presentation. In studies to test the efficacy of this strategy, we demonstrated that DNA vaccination with this secretory HPV-E7-HSP70 construct strongly enhanced an antigen-specific CD8 þ T-cell response as well as a specific B-cell response in mice. Furthermore, this immunization approach not only protected mice against lethal challenge with an HPV E7-expressing tumor line (TC-1), but also showed a therapeutic effect against established tumors. The results of this study indicate that secretory HSPs can be broadly used to target tumorassociated antigens to DCs to enhance antigen-specific immune responses. Gene Therapy (2004) 11, 924-932.

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Section: Hsp70-mediated Antigen Targeting For Dna Vaccines H Hauser Ementioning

confidence: 99%

Secretory heat-shock protein as a dendritic cell-targeting molecule: a new strategy to enhance the potency of genetic vaccines

Shen

et al. 2004

Gene Ther

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“…T cells and antibodies generated against microbial HSP may target self-HSP, either through the recognition of conserved epitopes or via cross-reactivity (molecular mimicry), thus leading to tissue inflammation (111,112). The responses induced by molecular mimicry between bacterial and mammalian Hsp60 and Hsp70 have been implicated in the pathogenesis of some autoimmune and inflammatory diseases, including type-1 diabetes (113), atherosclerosis (114), arthritis (115) and MS (116)(117)(118)(119), and elevated levels of extracellular HSP and anti-self HSP antibodies have been found in patients with these diseases. However, contrary to expectations, in several studies using animal models of arthritis (120,121), diabetes and MS (122,123) as well as in clinical trials (124), preimmunization with bacterial gp96, Hsp60 or Hsp70 abrogated the subsequently induced inflammatory disease.…”

Section: Molecular Mimicrymentioning

confidence: 99%

Heat Shock Protein 70: Roles in Multiple Sclerosis

Mansilla

Montalbán

Espejo

2012

Mol Med

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Heat shock proteins (HSP) have long been considered intracellular chaperones that possess housekeeping and cytoprotective functions. Consequently, HSP overexpression was proposed as a potential therapy for neurodegenerative diseases characterized by the accumulation or aggregation of abnormal proteins. Recently, the discovery that cells release HSP with the capacity to trigger proinflammatory as well as immunoregulatory responses has focused attention on investigating the role of HSP in chronic inflammatory autoimmune diseases such as multiple sclerosis (MS). To date, the most relevant HSP is the inducible Hsp70, which exhibits both cytoprotectant and immunoregulatory functions. Several studies have presented contradictory evidence concerning the involvement of Hsp70 in MS or experimental autoimmune encephalomyelitis (EAE), the MS animal model. In this review, we dissect the functions of Hsp70 and discuss the controversial data concerning the role of Hsp70 in MS and EAE.

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“…Reasons for selecting the peptides are described 1988; Salvetti et al 1996), little is known on potential HSP70 T cell recognition in humans. In this study, we aimed to identify epitopes of HSP70 that are recognized by T cells from healthy individuals.…”

Section: Discussionmentioning

confidence: 99%

T cell recognition of naturally presented epitopes of self-heat shock protein 70

Jong

Koffeman

Meerding

et al. 2014

Cell Stress and Chaperones

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Self-reactive T cells have shown to have a potential role as regulators of the immune system preventing or even suppressing autoimmunity. One of the most abundant proteins that can be eluted from human HLA molecules is heat shock protein 70 (HSP70). The aims of the current study are to identify HSP70 epitopes based on published HLA elution studies and to investigate whether T cells from healthy individuals may respond to such self-epitopes. A literature search and subsequent in silico binding prediction based on theoretical MHC binding motifs resulted in the identification of seven HSP70 epitopes. PBMCs of healthy controls proliferated after incubation with two of the seven peptides (H167 and H290). Furthermore H161, H290, and H443 induced CD69 expression or production of cytokines IFNγ or TNFα in healthy controls. The identification of these naturally presented epitopes and the response they elicit in the normal immune system make them potential candidates to study during inflammatory conditions as well as in autoimmune diseases.

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The immune response to Mycobacterial 70-kDa heat shock proteins frequently involves autoreactive T cells and is quantitatively disregulated in multiple sclerosis

Cited by 56 publications

References 57 publications

Secretory heat-shock protein as a dendritic cell-targeting molecule: a new strategy to enhance the potency of genetic vaccines

Secretory heat-shock protein as a dendritic cell-targeting molecule: a new strategy to enhance the potency of genetic vaccines

Heat Shock Protein 70: Roles in Multiple Sclerosis

T cell recognition of naturally presented epitopes of self-heat shock protein 70

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