Immunotherapy with plasmid DNA encoding mycobacterial hsp65 in association with chemotherapy is a more rapid and efficient form of treatment for tuberculosis in mice

Silva, Célio Lopes; Bonato, Vânia Luiza Deperon; Coelho-Castelo, Arlete Aparecida Martins; Souza, Ana Olı́via de; Santos, Sónia A.P.; Lima, Kauana Santos de; Faccioli, Lúcia Helena; Rodrigues, José J.

doi:10.1038/sj.gt.3302418

Cited by 79 publications

(74 citation statements)

References 33 publications

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“…24,25 This vaccine also induced upregulation of MHC class I and class II molecules on macrophages. 26,27 Moreover, different groups have found that mycobacterial hsp65 gene transfer can elicit a profound antitumoral effect. 28,29 The transfection of J774 histiocytic sarcoma cells with the hsp65 gene resulted in reduced tumor development, and immunization with hsp65-transfected sarcoma cells in mice was protective against challenge with unmodified parental tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Phase I trial of DNA-hsp65 immunotherapy for advanced squamous cell carcinoma of the head and neck

et al. 2008

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Considering that mycobacterial heat-shock protein 65 (hsp65) gene transfer can elicit a profound antitumoral effect, this study aimed to establish the safety, maximum-tolerated dose (MTD) and preliminary efficacy of DNA-hsp65 immunotherapy in patients with advanced head and neck squamous cell carcinoma (HNSCC). For this purpose, 21 patients with unresectable and recurrent HNSCC were studied. Each patient received three ultrasound-guided injections at 21-day intervals of: 150, 600 or 400 mg of DNA-hsp65. Toxicity was graded according to CTCAE directions. Tumor volume was measured before and after treatment using computed tomography scan. The evaluation included tumor mass variation, delayed-type hypersensitivity response and spontaneous peripheral blood mononuclear cell proliferation before and after treatment. The MTD was 400 mg per dose. DNAhsp65 immunotherapy was well tolerated with moderate pain, edema and infections as the most frequent adverse effects. None of the patients showed clinical or laboratory alterations compatible with autoimmune reactions. Partial response was observed in 4 out of 14 patients who completed treatment, 2 of which are still alive more than 3 years after the completion of the trial. Therefore, DNA-hsp65 immunotherapy is a feasible and safe approach at the dose of 400 mg per injection in patients with HNSCC refractory to standard treatment. Further studies in a larger number of patients are needed to confirm the efficacy of this novel strategy.

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Section: Introductionmentioning

confidence: 99%

Phase I trial of DNA-hsp65 immunotherapy for advanced squamous cell carcinoma of the head and neck

et al. 2008

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“…In previous work, using a TB model that classically induces a Th1 pattern, mice immunized with DNAhsp65 showed increases of protective cytokines, IFN-␥ and IL-12. 3,32 Interestingly, in this work we showed that besides the strong Th2 polarization induced by S. mansoni eggs, DNA-hsp65 was able to maintain increased levels of IFN-␥ and IL-12 while simultaneously decreasing the release of Th2-related cytokines (Figure 4). This polarization of the immune response induced by DNA treatment could be associated with the size of lung lesions observed (Figure 1), as well as with differential activation of macrophages in the site of granulomas (Figure 3).…”

Section: Discussionmentioning

confidence: 62%

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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“…Prophylactic DNA vaccines expressing various M. tuberculosis antigens, including Ag85A, Ag85B, MTP-64, ESAT-6, 65-kDa heat-shock protein and PstS-3, were found to be effective at limiting the growth of M. tuberculosis in heavily infected mice. [11][12][13][14] After the completion of chemotherapy in mice infected with M. tuberculosis intravenously, vaccination with plasmid DNA expressing 65-kDa heat-shock protein was effective in preventing reactivation. 14 Ag85A DNA vaccine, when simultaneously administered with chemotherapy, could effectively prevent reactivation of aerogenically transmitted M. tuberculosis.…”

Section: Introductionmentioning

confidence: 99%

Efficient tuberculosis treatment in mice using chemotherapy and immunotherapy with the combined DNA vaccine encoding Ag85B, MPT-64 and MPT-83

Cai

2008

Gene Ther

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Although most cases of tuberculosis (TB) can be cured with antibiotics, relapse is common if patients do not continue chemotherapy for at least 6 months. Thus, improved therapeutic strategies are urgently needed. We previously found that the combined DNA vaccine encoding the Mycobacterium tuberculosis proteins Ag85B, MPT-64 and MPT-83 protected mice from TB following H37Rv challenge and considered whether this combined DNA vaccine has a therapeutic effect. In the present work, we demonstrate that boosting the efficiency of the immune system with the combined DNA vaccine may be a valuable adjunct to shorten the duration of antibacterial chemotherapy. Mice treated with the combined DNA vaccine along with isoniazid and pyrazinamide showed significantly higher interferon-g responses to a mixture of the three specific antigens (Po0.001), which were accompanied by a significant reduction in colony-forming unit in H37Rv-infected animals 3-5 months after treatment (Po0.001). These results suggest that the combined DNA vaccine along with conventional TB chemotherapy has strong potential for TB immunotherapy and may provide new alternatives to control the disease.

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Immunotherapy with plasmid DNA encoding mycobacterial hsp65 in association with chemotherapy is a more rapid and efficient form of treatment for tuberculosis in mice

Cited by 79 publications

References 33 publications

Phase I trial of DNA-hsp65 immunotherapy for advanced squamous cell carcinoma of the head and neck

Phase I trial of DNA-hsp65 immunotherapy for advanced squamous cell carcinoma of the head and neck

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

Efficient tuberculosis treatment in mice using chemotherapy and immunotherapy with the combined DNA vaccine encoding Ag85B, MPT-64 and MPT-83

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