The mycobacterial 65 kD heat-shock protein and autoimmune arthritis

Eden, Willem van; Hogervorst, E. J. M.; Zee, Ruurd van der; Embden, J. D. A. Van; Hensen, E. J.; Cohen, Irun R.

doi:10.1007/bf00271878

Cited by 45 publications

(22 citation statements)

References 24 publications

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“…As a result, the use of this highly conserved heat shock protein, with its attendant autoimmune potential counteracting any potential benefits as an antimicrobial vaccine (26), remains debatable. In this regard, the multiple pockets of necrosis seen in the lungs of the DNA-vaccinated mice in the immunotherapeutic studies are reminiscent of the famous Koch reaction in which Koch found that immunization of mice with a suspension of mycobacterial antigens triggered necrosis in preexisting lesions in the lungs of these animals (11).…”

Section: Discussionmentioning

confidence: 99%

Pulmonary Necrosis Resulting from DNA Vaccination against Tuberculosis

et al. 2003

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The use of DNA constructs encoding mycobacterial proteins is a promising new approach to vaccination against tuberculosis. A DNA vaccine encoding the hsp60 molecule of Mycobacterium leprae has previously been shown to protect against intravenous infection of mice with Mycobacterium tuberculosis in both the prophylactic and immunotherapeutic modes. It is shown here, however, that this vaccine was not effective in a more realistic aerosol infection model or in a model of latent tuberculosis in the lungs. Moreover, when given in an immunotherapeutic model the immunized mice developed classical Koch reactions characterized by multifocal discrete regions of cellular necrosis throughout the lung granulomas. Similar and equally severe reactions were seen in mice given a vaccine with DNA coding for the Ag85 antigen of M. tuberculosis. This previously unanticipated safety problem indicates that DNA vaccines should be used with caution in individuals who may have already been exposed to tuberculosis.Disease caused by Mycobacterium tuberculosis is the leading cause of death from an infectious disease. Currently, it is estimated that over 2 million people die from tuberculosis yearly and that 8 million people contract the disease (5). Individuals who have been exposed to the bacillus but may have controlled it in the form of a latent infection, and who therefore are at risk of reactivation disease, may number in the hundreds of millions (6).There has been a gradual realization that the existing vaccine against tuberculosis, Mycobacterium bovis BCG, loses its effectiveness in individuals as they pass the teenage years (3, 21), and in certain clinical trials its overall effectiveness has been zero (14). As a result there is now a concerted effort to try to identify more effective vaccines against tuberculosis, using well-characterized animal models for initial screening (16).To date, the most effective vaccine used in mouse studies is a DNA vaccine encoding the 65-kDa heat shock protein of Mycobacterium leprae (hsp60/lep). Mice immunized with this DNA vaccine have shown 2-to 3-log reductions in bacterial load after intravenous challenge with virulent M. tuberculosis, and the vaccine is equally protective if given prophylactically, as an immunotherapeutic vaccine, or in a Cornell type model in which bacteria are eliminated by chemotherapy, leaving only bacilli that are in a latent or dormant form (12).In the study presented here the hsp60/lep vaccine was tested using the more realistic pulmonary infection model in the mouse, in which the animal is exposed to a small challenge dose by aerosol exposure. In this model the hsp60/lep DNA vaccine was ineffective in both the prophylactic and Cornell modes. Moreover, this vaccine, as well as the previous described highly protective Ag85/TB DNA vaccine (1, 8, 25), both induced progressively severe pulmonary necrosis in an immunotherapeutic vaccination model, especially when given to a susceptible mouse strain. While this class of DNA vaccines appears to be completely safe in terms of i...

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Section: Discussionmentioning

confidence: 99%

Pulmonary Necrosis Resulting from DNA Vaccination against Tuberculosis

et al. 2003

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“…4 at 4ЊC overnight. The CII was prepared in our laboratory as described above, and the hsp 65 kD was a kind gift from Dr R. van der Zee (University of Utrecht, The Netherlands) [11]. The rat IgG coat was blocked with 1% BSA in PBS for 2 h at room temperature.…”

Section: Quantification Of Antibodies In Serum and In Sfmentioning

confidence: 99%

Characteristics of synovial fluid effusion in collagen-induced arthritis (CIA) in the DA rat; a comparison of histology and antibody reactivities in an experimental chronic arthritis model and rheumatoid arthritis (RA)

Harris

Liljeström

Klareskog

1997

Clinical and Experimental Immunology

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SUMMARYWe have characterized the cellular content and some antibody reactivities in synovial fluid (SF) from DA rats with CIA. Since CIA is widely used as a model for RA, in which many studies concerning immune responses are performed on SF samples, we considered it important to describe the local, disease-causing immune reactions in CIA. At the peak of disease (day 22 after immunization), the major cell population in CIA SF was granulocytes (72%), but macrophages (17 . 9%), plasma cells (2 . 6%) and lymphocytes (7 . 7%) were also present. The CIA synovial membrane (SM) obtained at the same time was mainly infiltrated by monocytes, with granulocytes, lymphocytes and plasma cells also present. Cell populations in blood did not differ between arthritic and normal DA rats. Equally, high anti-collagen type II (CII) and rheumatoid factor (RF) levels could be detected both in SF and in sera. Notably, RF levels were also increased in normal DA rats. Moderate levels of anti-heat shock protein 65 kD (hsp) antibodies were recorded systemically in both normal and diseased animals. In conclusion, the cellular composition in SF and in SM are similar in rat CIA and in RA. The morphological differences between SF and SM that are characteristic for RA could also be demonstrated in CIA. The antibody data indicate systemic production of anti-CII and anti-hsp antibodies as well as RF, but they give no support for local production of these antibodies in the joints, which is the case in RA.

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“…The Mycobacterial antigen recognized by A2b was later found to be the 65 kDa heat shock protein (HSP65), and we succeeded to identify a peptide from the HSP65 sequence bearing the target epitope [12]. Moreover, the HSP65 molecule itself or its peptide epitope could be used as a vaccine to inhibit AA [12,13]. Thus, we found that effective vaccination therapy for autoimmune disease might include target peptides as well as attenuated T cells.…”

Section: Origins Of Peptide Vaccinationmentioning

confidence: 99%

Peptide therapy for Type I diabetes: the immunological homunculus and the rationale for vaccination

2002

Diabetologia

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The autoimmune process that produces Type I (insulin-dependent) diabetes mellitus seems to respond favourably to therapeutic vaccination with a peptide of the 60 kDa heat shock protein. This article is a personal review of the observations and the thinking that gave rise to the idea of therapeutic peptide vaccination. The rationale for vaccination therapy is compared to other approaches aimed at specific immunological treatment for autoimmune disease. [Diabetologia (2002)

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The mycobacterial 65 kD heat-shock protein and autoimmune arthritis

Cited by 45 publications

References 24 publications

Pulmonary Necrosis Resulting from DNA Vaccination against Tuberculosis

Pulmonary Necrosis Resulting from DNA Vaccination against Tuberculosis

Characteristics of synovial fluid effusion in collagen-induced arthritis (CIA) in the DA rat; a comparison of histology and antibody reactivities in an experimental chronic arthritis model and rheumatoid arthritis (RA)

Peptide therapy for Type I diabetes: the immunological homunculus and the rationale for vaccination

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