Cellular autoreactivity against heat shock protein 60 in renal transplant patients: peripheral and graft-infiltrating responses

Caldas, Cristina; Luna, Expedito; Spadafora-Ferreira, Mônica; Porto, Georgia; Iwai, Leo Kei; Oshiro, Sandra E.; Monteiro, Sandra Maria; Fonseca, J; Lemos, Francisco José Alves; Hammer, Juergen; Ho, Paulo Lee; Kalil, Jorge; Coelho, Verônica

doi:10.1111/j.1365-2249.2006.03195.x

Cited by 22 publications

(32 citation statements)

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“…In addition to their well-known functions as molecular chaperones, HSPs have been shown to act as immunodominant antigens and to playa role in the activation of different cell types, cytokine secretion and cross-presentation of tumour antigens (6)(7)(8). Nonetheless, various HSPs were related to the development of autoimmune diseases (9)(10). It is thought that peptides derived from foreign HSPs (e.g., bacterial HSPs) could induce crossreactivity against the human HSP homolog leading to breakdown of tolerance, thereby triggering autoimmune diseases (II).…”

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confidence: 99%

No Evidence of Pathological Autoimmunity following Mycobacterium Leprae Heat-Shock Protein 65-Dna Vaccination in Mice

et al. 2009

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Heat-shock proteins (HSPs) are currently one of the most promising targets for the development of immunotherapy against tumours and autoimmune disorders. This protein family has the capacity to activate or modulate the function of different immune system cells. They induce the activation of monocytes, macrophages and dendritic cells, and contribute to cross-priming, an important mechanism of presentation of exogenous antigen in the context of MHe class I molecules. These various immunological properties of HSP have encouraged their use in several clinical trials. Nevertheless, an important issue regarding these proteins is whether the high homology among HSPs across different species may trigger the breakdown of immune tolerance and induce autoimmune diseases. We have developed a DNA vaccine codifying the Mycobacterium /eprae Hsp65 (DNAhsp65), which showed to be highly immunogenic and protective against experimental tuberculosis. Here, we address the question of Whether DNAhsp65 immunization could induce pathological autoimmunity in mice. Our results show that DNAhsp65 vaccination induced antibodies that can recognize the human Hsp60 but did not induce harmful effects in 16 different organs analysed by histopathology up to 210 days after vaccination. We also showed that anti-DNA antibodies were not elicited after DNA vaccination. The results are important for the development of both HSP and DNA-based immunomodulatory agents. 1721-727X (2009) Copyright© by DlOLlFE.8.8.s. This publicationand/or article is for individualuse only and may not be further reproducedwithout written permissionfrom the copyrightholder. Unauthorizedreproductionmay result in financial and other penalties 77The dual roles ofheat-shock proteins (HSPs) in the (I). Due to their potential use as immunomodulators in immune system are still a matter of scientific debate a variety of pathological processes, special attention

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confidence: 99%

No Evidence of Pathological Autoimmunity following Mycobacterium Leprae Heat-Shock Protein 65-Dna Vaccination in Mice

et al. 2009

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“…Nevertheless, in the context of human renal transplantation, our group recently has reported IFN␥ and IL-10 production induced by Hsp60 peptides in different time points after human kidney transplantation, with IL-10 production mainly induced by I-intermediate and C-terminal peptides in late periods post-transplantation, when patients presented no rejection (Caldas et al 2006). It is therefore possible that, under certain inflammatory conditions, peptides derived from particular regions of Hsp60 may assume a predominant regulatory activity, though this most likely is to show specie, strain, and interindividual variations.…”

Section: Discussionmentioning

confidence: 99%

“…Human Hsp60 and its intermediate ; Hsp60 amino acid residues 195-391) and C-terminal ([C-Hsp60]; Hsp60 amino acid residues 392-573) fragments were expressed in Escherichia coli BL21 pLysS (DE3) and purified as described previously (Caldas et al 2006). Briefly, transformed cells were grown in 2YT/ampicillin/cloranphenicol medium and induced with isopropyl-thio-2-D galactopyranoside (IPTG).…”

Section: Expression and Purification Of Recombinant Hsp60 And Its Framentioning

confidence: 99%

“…Eleven peptides from different regions of human Hsp60 were designed previously according to human leukocyte antigen (HLA)-DR interaction using a computer algorithm called TEPITOPE, for the T-cell studies we have been carrying out in the human system (Caldas et al 2006). These peptides were synthesized in an automated multiple peptide synthesizer (PSSM8 Shimadzu Co, Tokyo, Japan) using N-␣-fluorenylmehoxycarbonyl (Fmoc) solid-phase strategy (Wellings and Atherton 1997; Table 1).…”

Section: Peptide Synthesismentioning

confidence: 99%

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Diversity of physiological cell reactivity to heat shock protein 60 in different mouse strains

Luna

Postol²,

Caldas³

et al. 2007

Cell Stress Chaper

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Heat shock proteins (Hsp) are families of highly conserved molecules and immunodominant antigens in some infections and in autoimmune diseases. Some reports suggest that different regions of the Hsp60 molecule induce distinct immune responses. However, there are no reports comparing physiological T-cell reactivity to Hsp60 in mice. In this study, we have analyzed T-cell proliferation and cytokine production induced by Hsp60, under physiological conditions, in three mouse strains bearing distinct major histocompatibility complex (MHC) backgrounds. Proliferative response predominantly was found in C57BL/6 mice, mostly induced by N-terminal and intermediate Hsp60 peptides (P Ͻ 0.0001). Interferon-␥ (IFN␥) production was broadly induced by different regions of Hsp60 in all three mouse strains, although response was focused in different peptide groups in each strain. We did not observe an exclusive Th1 or Th2 cytokine profile induced by any particular region of Hsp60. However, we identified a strain hierarchy in IL-10 production induced by Hsp60 peptides from different regions, mostly detected in C3H/HePas, and in BALB/c, but not in C57BL/6 mice. In contrast, IL-4 production only was induced by the intermediate and C-terminal region peptides in both C3H/HePas and BALB/c mice. Our data give original information on physiological cellular reactivity to Hsp60. We also have identified peptides with the capacity to induce the production of anti-inflammatory cytokines, bringing perspectives for their use in immunotherapy of chronic inflammatory diseases and allograft rejection.

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“…Recombinant human Hsp60 for humoral assays was produced in Escherichia coli bacteria in our laboratory and purified by nickel-histidine affinity chromatography, as described. 14 The recombinant human Hsp60 used for cellular assays was purchased from Lionex GmbH (Braunschweig, Germany). …”

Section: Antigensmentioning

confidence: 99%

Immune response to vaccination with DNA-hsp65 in a phase I clinical trial with head and neck cancer patients

et al. 2009

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DNA-hsp65, a DNA vaccine encoding the 65-kDa heat-shock protein of Mycobacterium leprae (Hsp65) is capable of inducing the reduction of established tumors in mouse models. We conducted a phase I clinical trial of DNA-hsp65 in patients with advanced head and neck carcinoma. In this article, we report on the vaccine's potential to induce immune responses to Hsp65 and to its human homologue, Hsp60, in these patients. Twenty-one patients with unresectable squamous cell carcinoma of the head and neck received three doses of 150, 400 or 600 mg naked DNA-hsp65 plasmid by ultrasound-guided intratumoral injection. Vaccination did not increase levels of circulating anti-hsp65 IgG or IgM antibody, or lead to detectable Hsp65-specific cell proliferation or interferon-g (IFN-g) production by blood mononuclear cells. Frequency of antigen-induced IL-10-producing cells increased after vaccination in 4 of 13 patients analyzed. Five patients showed disease stability or regression following immunization; however, we were unable to detect significant differences between these patients and those with disease progression using these parameters. There was also no increase in antibody or IFN-g responses to human Hsp60 in these patients. Our results suggest that although DNA-hsp65 was able to induce some degree of immunostimulation with no evidence of pathological autoimmunity, we were unable to differentiate between patients with different clinical outcomes based on the parameters measured. Future studies should focus on characterizing more reliable correlations between immune response parameters and clinical outcome that may be used as predictors of vaccine success in immunosuppressed individuals.

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Cellular autoreactivity against heat shock protein 60 in renal transplant patients: peripheral and graft-infiltrating responses

Cited by 22 publications

References 50 publications

No Evidence of Pathological Autoimmunity following Mycobacterium Leprae Heat-Shock Protein 65-Dna Vaccination in Mice

No Evidence of Pathological Autoimmunity following Mycobacterium Leprae Heat-Shock Protein 65-Dna Vaccination in Mice

Diversity of physiological cell reactivity to heat shock protein 60 in different mouse strains

Immune response to vaccination with DNA-hsp65 in a phase I clinical trial with head and neck cancer patients

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