Heat shock protein–antigen fusions lose their enhanced immunostimulatory capacity after endotoxin depletion

Marincek, Boris C.; Kühnle, Marie Cristine; Srokowski, Cathy Cecilia; Schild, Hansjörg; Hämmerling, Günter J.; Momburg, Frank

doi:10.1016/j.molimm.2008.07.039

Cited by 23 publications

(17 citation statements)

References 50 publications

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“…It was suggested that in spinal cord injuries, heat shock protein 70 binds to Apaf-1 and inhibits caspase 9 activation, and it also inhibits apoptosis by playing a key role in the regulation of secondary injury mechanisms (11). In addition, heat shock protein 70 displays an effect on the regulation of the inflammatory response, which is one of the secondary injury mechanisms (4,7,8,11,21,22). …”

Section: Sengul G Et Al: Neuroprotective Effect Of Acute Interferon-mentioning

confidence: 99%

Neuroprotective effect of acute interferon-beta 1b treatment after spinal cord injury

Sengul¹,

Çoban²,

Çakır³

et al. 2012

Turkish Neurosurgery

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AIm: The purpose of this trial was to investigate the effect of a well known immunomodulator -interferon beta-on traumatized spinal cord in terms of biochemical and histopathological features. mAterIAl and methOds: Twenty-four rats were used in this trial. The rats were divided into 3 groups. In the first group of rats, spinal cord injury was created by the weight drop method and interferon beta was administered. In the second group, physiological saline was administered. Third group was used as control. Rats were sacrificed 24 hours following trauma. Heat shock protein 70 levels were measured in the spinal cord samples and the samples were examined histopathologically.results: When the rats in the physiological saline and control groups were compared to rats treated with interferon beta 1b, those treated with interferon beta 1b revealed significant increases in the heat shock protein 70 levels in tissues, and histopathological examination revealed decreases in polymorphonuclear leucocyte infiltration, haemorrhage, oedema and necrosis.COnClusIOn: Although, the results of the study indicated that interferon beta might have some healing effects via increasing the cellular heat shock protein 70 on spinal cord injuries, more studies are needed. KeywOrds:Heat shock protein 70, Interferon beta, Spinal cord injury ÖZ AmAÇ: Bu çalışmanın amacı, immunomodülatör olduğu bilinen interferon betanın travmaya uğramış omurilikteki etkisini biyokimyasal ve histopatolojik olarak araştırmaktır. yÖntem ve GereÇler: Bu çalışmada, 24 adet rat kullanıldı. Ratlar rastgele 3 gruba ayrıldı. Birinci gruptaki ratlarda ağırlık düşürme yöntemi ile omurilik travması oluşturularak interferon beta verildi. İkinci gruptaki ratlarda serum fizyolojik verildi. Üçüncü grup kontrol olarak kullanıldı. Denekler travmadan 24 saat sonra sakrifiye edildi. Alınan omurilik örneklerinde ısı şok proteini 70 düzeyleri ölçüldü ve örnekler histopatolojik olarak incelendi.BulGulAr: İnterferon beta 1b ile tedavi edilen ratlarda doku düzeyinde ısı şok proteini 70 düzeyinin serum fizyolojik verilen ratlara ve kontrollere göre belirgin olarak arttığı ve histopatolojik olarak polimorfonüklear lökosit infiltrasyonun, hemorajinin, ödemin ve nekrozun azaldığı gözlendi. sOnuÇ: Çalışmadan elde edilen veriler, interferon betanın travmatik omurilik yaralanmasında hücre seviyesinde ısı şok proteini 70 i artırarak iyileştirici etkisi olabileceğini göstermekle beraber daha ileri çalışmalara ihtiyaç vardır.AnAhtAr sÖZCÜKler: Isı şok proteini 70, İnterferon beta, Omurilik yaralanması

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Section: Sengul G Et Al: Neuroprotective Effect Of Acute Interferon-mentioning

confidence: 99%

Neuroprotective effect of acute interferon-beta 1b treatment after spinal cord injury

Sengul¹,

Çoban²,

Çakır³

et al. 2012

Turkish Neurosurgery

View full text Add to dashboard Cite

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“…45). Several reports, however, have suggested that low endotoxin contamination of recombinant and commercial hsp preparations may be responsible for immunostimulatory activity, as some responses are lost following endotoxin removal (23,24). Currently there is support for both an intrinsic danger activity of hsp, as well as an adjuvant function for enhancing the response to bacterial products (46).…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, hsc70 is a constitutively expressed member of the hsp70 family, which performs housekeeping functions of protein folding/unfolding, clathrin uncoating, and chaperoning of lysosome-targeted proteins (21). Although recombinant human hsp70 and mixtures of highly purified mouse hsp/hsc70 were previously shown to enhance autoantigen-specific CD8 ϩ T cell activation and promote autoimmune diabetes (22), others have attributed the proinflammatory activities of hsp to contaminating endotoxin (23,24). To directly assess the effects of increased release of pre-existing cellular hsc70, in situ, we used the STZ damage-induced diabetes model in mice transgenically engineered to express additional cytosolic hsc70 in pancreatic ␤ cells, and combined this with the rat insulin promoter (RIP) lymphocytic choriomeningitis virus (LCMV) glycoprotein (RIP-LCMV-GP) Ag model to examine autoantigen-specific CD8 ϩ T cell responses.…”

mentioning

confidence: 99%

Transgenic Expression of Hsc70 in Pancreatic Islets Enhances Autoimmune Diabetes in Response to β Cell Damage

Alam

Harken

Knorn

et al. 2009

The Journal of Immunology

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Inflammation following tissue damage promotes lymphocyte recruitment, tissue remodelling, and wound healing while maintaining self tolerance. Endogenous signals associated with tissue damage and cell death have been proposed to initiate and instruct immune responses following injury. Here we have examined the effects of elevated levels of a candidate endogenous danger signal, heat shock cognate protein 70 (Hsc70), on stimulation of inflammation and autoimmunity following cell damage. We find that damage to pancreatic β-cells expressing additional cytosolic Hsc70 leads to an increased incidence of diabetes in a transgenic mouse model. Steady-state levels of activated APC and T cell populations in the draining lymph node were enhanced, which further increased following streptozotocin-induced β-cell death. In addition, pro-inflammatory serum cytokines, and lymphocyte recruitment were increased in Hsc70 transgenic mice. Islet-antigen-specific T cells underwent a greater extent of proliferation in the lymph nodes of mice expressing Hsc70 following β-cell damage, suggesting elevated antigen presentation following release of antigen in the presence of Hsc70. These findings suggest that an elevated content of Hsc70 in cells undergoing necrotic or apoptotic cell death can increase the extent of sterile inflammation and increase the susceptibility to autoimmunity.

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“…102,105,106,118,120,121 Although the immunological properties of Gp96 were documented extensively, the assumption that the specific immunogenic character of HSP preparations originates from peptides that are noncovalently and physiologically associated with the HSP molecule has been questioned. 118,[122][123][124][125][126] The studies of Binder et al were in favor of this assumption. Gp96 was purified from b-galactosidase-transfected mastocytoma cells.…”

Section: Discovery Of Hsps Gp96 and Their Immunological Propertiesmentioning

confidence: 99%

“…128 However, some doubts remain whether the therapeutic immunological effects of Gp96 treatment, such as cytokine stimulation and CTL responses, are due to contamination with lipopolysaccharide or result from the HSPs themselves and/or the chaperoned peptides. 123,125,129,130 In contrast, specific tumor-rejecting CTL responses were induced in mice that had been immunized with Gp96-secreting tumor cells. The efficiency of crosspriming of T cells in such way was enhanced by more than one million-fold compared with unchaperoned antigen alone.…”

Section: Discovery Of Hsps Gp96 and Their Immunological Propertiesmentioning

confidence: 99%

Active‐specific immunotherapy of human cancers with the heat shock protein Gp96—revisited

Randazzo

Terness

Opelz

et al. 2012

Intl Journal of Cancer

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The passive administration of specific antibodies that selectively target tumors is a well-known strategy in cancer treatment. Active immunotherapy using peptide vaccines, in contrast, is expected to induce specific, cytolytic T cells in the patient, which react against tumor antigens and destroy malignant cells. Although several concepts exist, the identification and low immunogenicity of tumor-specific peptides remain a serious problem. Heat shock proteins (HSPs), notably glycoprotein (Gp) 96, are of special interest, because they are able to take molecular peptide-fingerprints of the protein array characteristic for a particular cell. Association of Gp96 with peptides has been shown to be essential for crosspresentation and activation of T cells. Consequently, Gp96-peptide complexes extracted from cancer cells harbor the tumor-specific peptides and are immunogenic, thus offering a tool for active immunization against the tumor. Already, several immunotherapy studies of human cancers have been carried out, showing no severe adverse effects but unfortunately only limited improvement in the clinical outcome. Vitespen, a commercial HSP-peptide complex vaccine based on tumor-derived Gp96, seems to induce an improved overall survival for subsets of early stage melanoma and kidney cancer patients. The limited access to vaccine material derived from the autologous tumor requires the development of alternative protocols. Moreover, counteracting immunosuppressive mechanisms induced by the malignancy might further improve the efficacy of vaccinations. This review critically analyzes the current state of clinical immunotherapy with Gp96, with special attention to Vitespen.Heat shock proteins (HSPs) came to attention of immunologists, because they chaperone peptides and interact with antigen-presenting cells (APCs) in a specific manner. As molecular chaperones, HSPs are essential for maintaining cellular functions by preventing misfolding and aggregation of nascent polypeptides and by facilitating protein folding. This function has been described for every organism. 1In the 1980s, the potential importance of HSPs for tumor therapy emerged, when it was observed that preparations of certain HSPs isolated from cancer cells elicited immunity by capturing the antigenic fingerprint of a specific cancer, so that they could act as a vaccine against subsequent tumor challenge.2 Since then, the immunological properties of HSPs were studied intensively, particularly those of endoplasmic reticulum (ER)-resident HSPs glycoprotein (Gp)96 (Grp94)

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Heat shock protein–antigen fusions lose their enhanced immunostimulatory capacity after endotoxin depletion

Cited by 23 publications

References 50 publications

Neuroprotective effect of acute interferon-beta 1b treatment after spinal cord injury

Neuroprotective effect of acute interferon-beta 1b treatment after spinal cord injury

Transgenic Expression of Hsc70 in Pancreatic Islets Enhances Autoimmune Diabetes in Response to β Cell Damage

Active‐specific immunotherapy of human cancers with the heat shock protein Gp96—revisited

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