Immunomodulation and Protection Induced by DNA-hsp65 Vaccination in an Animal Model of Arthritis

Santos-Junior, R. R.; Sartori, Alexandrina; Franco, Marcelo De; Filho, Orlando G. R.; Coelho-Castelo, Arlete Aparecida Martins; Bonato, Vânia Luiza Deperon; Cabrera, Wafa Hanna Koury; Ibañez, Olga M.; Silva, Célio Lopes

doi:10.1089/hum.2005.16.1338

Cited by 40 publications

(48 citation statements)

References 52 publications

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“…32 In our model, there was an increase in IL6 and IL12 splenic-secreting cells in both AIRmax sublines at 20 days of PIA induction (Figure 4). These results corroborate our previous studies, where AIRmax mice produced higher amounts of these proinflammatory cytokines in both ex vivo 14 and in vitro experiments, 33 as compared to AIRmin mice. T cells play an important role in the pathology of this disease.…”

Section: Discussionsupporting

confidence: 93%

Slc11a1 (formerly NRAMP1) gene modulates both acute inflammatory reactions and pristane-induced arthritis in mice

et al. 2006

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Mice selected for the maximum acute inflammatory reaction (AIRmax) are highly susceptible to pristane-induced arthritis (PIA), whereas mice selected for the minimum response (AIRmin) are resistant. These lines show distinct patterns of leukocyte infiltration and R and S allele frequency disequilibrium of the solute carrier family 11a member 1 (Slc11a1) gene. In order to study the interactions of the Slc11a1 R and S alleles with the inflammation modulating Quantitative Trait Loci (QTL) during PIA development, homozygous AIRmax RR , AIRmax SS , AIRmin RR and AIRmin SS lines were produced by genotype-assisted breedings. These mice received two intraperitoneal injections of 0.5 ml pristane at 60-day intervals, and the subsequent development of arthritis was assessed for 210 days. Cytokine-secreting cell profiles were investigated using enzyme-linked immunospot. Arthritis incidence in AIRmax RR mice reached 29%, whereas PIA incidence in AIRmax SS mice was 70% by day 180. AIRmin RR mice were resistant, whereas 13.3% of AIRmin SS mice became arthritic. The presence of the defective S allele also increased arthritis severity, although acute inflammation was higher in mice bearing the R allele. A predominant Th0/Th2-type response in Slc11a1 SS mice was observed. These results indicate that Slc11a1 is a strong candidate for the QTL modulating acute inflammation and for PIA.

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Section: Discussionsupporting

confidence: 93%

Slc11a1 (formerly NRAMP1) gene modulates both acute inflammatory reactions and pristane-induced arthritis in mice

et al. 2006

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“…Despite the success of DNAhsp65 immunization in different animal models and the lack of major toxicity detected in either the pre-clinical studies or in a phase I clinical trial (18)(19)(20)(21)(22)(23), it has been suggested that this vaccine could cause necrosis in the lungs of vaccinated animals (24)(25)(26). These results have not been observed by other groups and, on the contrary, several subsequent reports have provided increasing evidence in favour of the potential therapeutic use of Hsp65 against tuberculosis (13)(14)16).…”

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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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“…The hsp produced by Mycobacterium leprae (hsp65) has been the focus of our group as a DNA vaccine against several pathologies including TB, 27,28 leishmaniasis, 4 diabetes, 6 arthritis, 5 and cancer. 7 For the first time, we are showing in this work the potential role of DNA-hsp65 as an immune modulator of pathology in a helminth infection, using an egg-induced granuloma model.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic DNA Vaccine Reduces Schistosoma mansoni–Induced Tissue Damage through Cytokine Balance and Decreased Migration of Myofibroblasts

Frantz

Ito

Cavassani

et al. 2011

The American Journal of Pathology

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Helminths are known to elicit a wide range of immunomodulation characterized by dominant Th2-type immune responses. Our group previously showed that a DNA vaccine encoding the mycobacterial 65-kDa heat shock protein (DNA-hsp65) showed immunomodulatory properties. We also showed, using a helminth-tuberculosis (TB) co-infection model, that the DNA-hsp65 vaccine protected mice against TB. We next investigated the mechanistic role of the vaccine during helminth-TB co-infection. Clinically, helminth infection causes type 2 granulomas in the lung. Mice were immunized with DNA-hsp65 while they were submitted to the type 2 granuloma induction protocol by Schistosoma mansoni eggs infusion. In this work we investigated the effects of DNA-hsp65 on the pathology and immune response during the development of type 2 granuloma induced by S. mansoni eggs. Histologic analyses of lung parenchyma showed that the DNA-hsp65 vaccine protected mice against exacerbated fibrosis induced by Schistosoma eggs, and decreased the size of the granulomas. These changes were correlated with a reduction in the number of T cells specific for the egg antigens in the lung and also with modulation of Th2 cytokine expression. Taken Helminth infections are widespread in the tropics, and are known to elicit a wide range of immunomodulation effects characterized by dominant T helper cell (Th) 2-type immune responses, chronic immune activation, as well as up-regulated regulatory T-cell activity. Our group previously showed that a DNA vaccine encoding the mycobacterial 65-kDa heat shock protein (DNA-hsp65), that protected mice and guinea pigs against tuberculosis (TB), 1-3 also showed immunomodulatory properties in other diseases. 4 -7 We also showed that this DNA-hsp65 vaccine protected mice against TB in a helminth-TB co-infection model. 8 These results led us to investigate the mechanistic role of the vaccine during helminth-TB co-infection.One of the clinical manifestations of helminth infection is the presence of type 2 granulomas. The lung is the primary site of organ involvement in a range of granulomatous conditions. 9 The immune response to Schistosoma mansoni eggs in mice results in the development of hepatic, intestinal, and pulmonary granulomas that lead to extensive fibrosis. 10,11 The cellular composition of the granulomas includes eosinophils, alternatively activated (M2) macrophages, lymphocytes, neutrophils, mast cells, and fibroblasts. 12 Further, the recruitment and migration of these cells into the site of inflammation are controlled by cytokines and chemokines. The complex cytokinechemokine regulatory network has been well established, and dictates the profile of local chemokine expression during T-cell-mediated type 2 lung granuloma formation as a result of S. mansoni egg injection. 13,14 To induce granulomas we used a system based on the embolization of S. mansoni eggs to the lungs. This approach leads the release of glycoproteins, referred to as S. mansoni soluble egg antigen (SEA), inducing a strong polarization of

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Immunomodulation and Protection Induced by DNA-hsp65 Vaccination in an Animal Model of Arthritis

Cited by 40 publications

References 52 publications

Slc11a1 (formerly NRAMP1) gene modulates both acute inflammatory reactions and pristane-induced arthritis in mice

Slc11a1 (formerly NRAMP1) gene modulates both acute inflammatory reactions and pristane-induced arthritis in mice

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

Therapeutic DNA Vaccine Reduces Schistosoma mansoni–Induced Tissue Damage through Cytokine Balance and Decreased Migration of Myofibroblasts

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