DNA Vaccination With Hsp70 Protects Against Systemic Lupus Erythematosus in (NZB × NZW)F1 Mice

Abstract

Objective. To address whether a targeted modulation of the abnormal expression of Hsp70 and autoantibodies against this molecule in systemic lupus erythematosus can influence disease.Methods. Lupus-prone (NZB × NZW)F1 mice that had been DNA-vaccinated with plasmids encoding Hsp70 and controls were monitored for lupus disease parameters including anti-double stranded DNA (anti-dsDNA) autoantibodies and cytokines using enzyme-linked immunosorbent assay, and for kidney function and pathology. The phenotypic and numerical changes in relevant immune cells were evaluated by flow cytometry, and cell function was assessed.Results. Mice that had been DNA-vaccinated with Hsp70 displayed marked suppression of anti-dsDNA antibody production, reduced renal disease, and antiinflammatory responses that are associated with a significantly extended survival, compared to controls. These protective effects in Hsp70-vaccinated mice were associated with an induction of tolerogenic immune responses and an expansion of functional Treg cells.Conclusion. DNA vaccination with Hsp70 suppresses murine lupus by inducing tolerogenic immune responses and antiinflammatory immune responses associated with reduced disease manifestations and increased mouse survival.

Interplay between the Chaperone System and Gut Microbiota Dysbiosis in Systemic Lupus Erythematosus Pathogenesis: Is Molecular Mimicry the Missing Link between Those Two Factors?

“…The administration of a DNA vaccine encoding Hsp90 induced tolerogenic immune responses, with a reduction in anti-dsDNA autoantibody production, that limited SLE manifestations (e.g., renal disease) and extended the survival in lupus-prone mice [ 59 ]. Similar outcomes were obtained using a DNA vaccine encoding Hsp70 [ 60 ].…”

Heat Shock Protein 70 as a Double Agent Acting Inside and Outside the Cell: Insights into Autoimmunity

“…Interestingly, (auto)immune response can be modulated by using DNA vaccines that encode specific antigens. It has been found that vaccination of animals with plasmids encoding Hsp70 has suppressed the rodent model of lupus erythematosus or AA [ 88 , 89 ]. This therapy has led to expansion of Treg or shifted T cell response from a proinflammatory Th1 to a regulatory Th2/3 phenotype, respectively [ 88 , 89 ].…”

Therapeutic Implications of Targeting Heat Shock Protein 70 by Immunization or Antibodies in Experimental Skin Inflammation

“…It is assumed that the immunomodulatory effects of Hsp90 inhibition are at least partly mediated by the up-regulation of intracellular Hsp70 (a surrogate marker of Hsp90 blockade) which inhibits the nuclear factor-kB (NF-kB) inflammatory pathway (3). In addition, increased Hsp70 expression achieved independently of Hsp90 inhibition (e.g., by Hsp70 vaccination) has been demonstrated to be associated with down-regulation of inflammatory processes in several preclinical models of autoimmune diseases (4)(5)(6). However, some contradictory results suggested that both intra-and extracellular Hsp70 can exert a dual role in autoimmune diseases (i.e., either promoting or silencing immune responses), depending on its origin (i.e., bacterial or self), site of inflammation, type of disease, and possibly other undefined reasons (4).…”