Keyhole limpet hemocyanin induces the activation and maturation of human dendritic cells through the involvement of mannose receptor

Presicce, Pietro; Taddeo, Adriano; Conti, Antonietta; Villa, Maria Luisa; Bella, Silvia Della

doi:10.1016/j.molimm.2007.07.020

Cited by 49 publications

(47 citation statements)

References 45 publications

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“…3 also shows that death was delayed in mice of the KLH-immunized group C compared with those of the control group A. The clinical benefit effect conferred by KLH vaccination in this study, although at a significantly lower level than that caused by kinoid immunization, might be the consequence of the known effects of KLH on innate immunity (21).…”

Section: Ifn␣ Kinoid Immunobiologicalmentioning

confidence: 51%

IFNα kinoid vaccine-induced neutralizing antibodies prevent clinical manifestations in a lupus flare murine model

Zagury

Buanec

Mathian

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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A major involvement of IFN␣ in the etiopathogenesis of systemic lupus erythematosus has been suggested by clinical observations, including the increase of serum levels of this cytokine in patients with active disease. Supporting this hypothesis, we have shown that expression of IFN␣ from a recombinant adenovirus (IFN␣ Adv) precipitates lupus manifestations in genetically susceptible New Zealand Black (NZB) ؋ New Zealand White (NZW)F 1 mice (NZB/W) but not in BALB/c mice. In the present investigation, we have prepared an IFN␣ immunogen, termed IFN␣ kinoid, which, appropriately adjuvanted, induces transient neutralizing antibodies (Abs) but no cellular immune response to the cytokine and without apparent side effects. Using this preparation, we also showed that, in kinoid-vaccinated NZB/W mice, lupus manifestations, including proteinuria, histological renal lesions, and death triggered by IFN␣ Adv challenge were delayed/prevented as long as an effective threshold of anti-IFN␣ inhibitory capacity was present in the serum.anti-IFN␣ immunization ͉ anti-SLE immune therapy ͉ systemic lupus erythematosous S ystemic lupus erythematosus (SLE) is a frequent and lifethreatening chronic autoimmune disease characterized by a break of tolerance to nuclear components and profound alterations of the immune system (1). Dysregulated activation of many cells of the immune system involving several cytokines has been studied extensively in both human and murine lupus. Recently, type I IFNs (IFN␣ and ␤) have gained considerable interest as candidates in the etiopathogenic process of lupus (2-4). Involvement of IFN␣ in SLE has initially been suggested by clinicians as early as 1979 based on the findings of (i) elevated levels of this cytokine in the serum of SLE patients (5-7); (ii) IFN␣ treatment of cancer or hepatitis C induced in some patients' autoantibodies (autoAbs), including anti-nucleus Abs and anti-native DNA, and more rarely SLE (Ͻ1%) (8, 9); (iii) gene expression characteristic of an IFN␣ signature in blood cells of SLE patients, revealed by microarray assays (10, 11); (iv) animal experiments in which type I IFN receptor deficiency significantly reduced the expression of the lupus hallmarks in lupus-prone mice (12). More recently, we (13) developed an SLE-like murine flare model in which IFN␣5 supplied by recombinant adenovirus-expressing IFN␣5 (IFN␣ Adv) drives the early expression of lupus manifestations, including autoAbs, glomerulonephritis, and death.SLE patients are currently treated with the antimalarial agents chloroquine and hydroxychloroquine, steroids, and/or immunosuppressive drugs (14). More recently, biological therapies targeting immune cells involved in lupus pathogenesis have been developed, such as CD20 monoclonal antibodies (mAbs) (rituximab) that inhibit B cell activation (15). Monoclonal Abs have also been produced to counteract pathogenic effects of cytokines in SLE. Given the key role of IFN␣ in the SLE pathogenesis (3), anti-BDCA2/4 mAbs blocking IFN␣ production by plasmacytoid dendritic cells were p...

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Section: Ifn␣ Kinoid Immunobiologicalmentioning

confidence: 51%

IFNα kinoid vaccine-induced neutralizing antibodies prevent clinical manifestations in a lupus flare murine model

Zagury

Buanec

Mathian

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Hemocyanins present high percentages of mannose residues that have been reported to contribute to their internalization on APCs and directly in the maturation of DCs [24,27,53]. Our data suggest that hemocyanins sugar moieties are not essential for their immunogenicity and nonspecific immunostimulatory effects because periodic acid Schiff (PAS) staining showed that all the oligosaccharide moieties were eliminated from Ox-CCH (data not shown).…”

Section: Discussionmentioning

confidence: 67%

Enhanced structural stability of Concholepas hemocyanin increases its immunogenicity and maintains its non‐specific immunostimulatory effects

et al. 2012

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Hemocyanins, which boost the immune system of mammals, have been used as carrieradjuvants to promote Ab production against haptens and peptides, as immunostimulants during therapy for bladder carcinoma and as a component in therapeutic vaccines for cancer. These biomedical applications have led to growing interest in obtaining hemocyanins with high immunogenicity. Here, we study the immunological properties of a modified oxidized Concholepas concholepas hemocyanin (Ox-CCH) obtained by the oxidation of its carbohydrates using sodium periodate. We assessed the internalization of Ox-CCH into DCs and its immunogenicity and antitumor effects. Transmission electron microscopy showed no changes in Ox-CCH quaternary structure with respect to native CCH, although proteolytic treatment followed by SDS-PAGE analysis demonstrated that Schiff bases were formed. Interestingly, DCs internalized Ox-CCH faster than CCH, mainly through macropinocytosis. During this process, Ox-CCH remained inside endosome-like structures for a longer period. Mouse immunization experiments demonstrated that Ox-CCH is more immunogenic and a better carrier than CCH. Moreover, Ox-CCH showed a significant antitumor effect in the B16F10 melanoma model similar to that produced by CCH, inducing IFN-γ secretion. Together, these data demonstrate that the aldehydes formed by the periodate oxidation of sugar moieties stabilizes the CCH structure, increasing its adjuvant/immunostimulatory carrier effects.

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“…Concerning that DCs play a pivotal role in the generation of antitumor immune response, recently it has been proposed that KLH induce the maturation of DCs through their interaction with lectin-receptors, like mannose receptor [59]. Thus, we think if there are an ancient conserved immunogenic mechanism that is induced by KLH and CCH, it able to enhance Th1 immunity and leads to antitumor activity, the common signal might be in part, in some carbohydrate moieties on a subunit.…”

Section: Discussionmentioning

confidence: 99%

Immunodominant role of CCHA subunit of Concholepas hemocyanin is associated with unique biochemical properties

Becker

Fuentes

Campo

et al. 2009

International Immunopharmacology

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Keyhole limpet hemocyanin induces the activation and maturation of human dendritic cells through the involvement of mannose receptor

Cited by 49 publications

References 45 publications

IFNα kinoid vaccine-induced neutralizing antibodies prevent clinical manifestations in a lupus flare murine model

IFNα kinoid vaccine-induced neutralizing antibodies prevent clinical manifestations in a lupus flare murine model

Enhanced structural stability of Concholepas hemocyanin increases its immunogenicity and maintains its non‐specific immunostimulatory effects

Immunodominant role of CCHA subunit of Concholepas hemocyanin is associated with unique biochemical properties

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