Immune regulatory effect of pHSP65 DNA therapy in pulmonary tuberculosis: activation of CD8<sup>+</sup> cells, interferon‐γ recovery and reduction of lung injury

Bonato, Vânia Luiza Deperon; Gonçalves, Edison; Soares, Edson García; Júnior, R. R. Santos; Sartori, Alexandrina; Coelho-Castelo, Arlete Aparecida Martins; Silva, Célio Lopes

doi:10.1111/j.1365-2567.2004.01931.x

Cited by 66 publications

(94 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%

“…However, preclinical data from our group and others using different animal models show no evidence of autoimmune disease when DNA-hsp65 was used for immunization. [24][25][26]30 It is relevant to point that the immunogenicity of tumor-derived HSP-peptide complexes has been shown to be individually tumor specific and not tumor-type specific. This suggests that the relevant immunoprotective peptides are most likely derived from individual tumorspecific antigens rather than from shared tumor antigens.…”

Section: Introductionmentioning

confidence: 99%

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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%

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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“…This seems to indicate that host conditions are of particular importance with respect to the effects of mycobacterial Hsp65 on the immune response. In support of this notion are the observations in mice that vaccination with the same DNA-hsp65 construct can induce both strong Th1 immune responses, 5,6,26,27 and regulatory responses marked by production of IL-10, 28,29 depending on the experimental model employed. Once again, the intratumoral route of immunization used in this study may have contributed toward this effect.…”

Section: Discussionmentioning

confidence: 89%

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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“…The pVAX1hsp65 construction 22 and pVAX1 vector were prepared using the Endo-Free Plasmid Giga kit (Qiagen, Hildenberg, Germany). The endo-free condition of plasmids was determined by the Limulus Amebocyte Lysate test as recommended by European and US Pharmacopoeias, 23 using the QCL 1000 Limulus Amebocyte Lysate test kit (Cambrex, Walkersville, MD).…”

Section: Plasmid Derivationmentioning

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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Immune regulatory effect of pHSP65 DNA therapy in pulmonary tuberculosis: activation of CD8⁺ cells, interferon‐γ recovery and reduction of lung injury

Cited by 66 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

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

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

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Immune regulatory effect of pHSP65 DNA therapy in pulmonary tuberculosis: activation of CD8+ cells, interferon‐γ recovery and reduction of lung injury

Cited by 66 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

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

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

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Immune regulatory effect of pHSP65 DNA therapy in pulmonary tuberculosis: activation of CD8⁺ cells, interferon‐γ recovery and reduction of lung injury