Immunohistological findings in patients with superficial bladder carcinoma after intravesical instillation of keyhole limpet haemocyanin

Jurincic-Winkler, C.; Metz, K.; Beuth, Josef; Engelmann, U.; Klippel, K. F.

doi:10.1111/j.1464-410x.1995.tb00760.x

Cited by 8 publications

(5 citation statements)

References 20 publications

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“…In fact, preimmunization with hemocyanins before tumor inoculation is essential to the success of the immunotherapy in humans [17,18] and mice [30]. Indeed, in patients with urinary bladder cancer under intravesical KLH therapy, a delayed-type hypersensitivity reactions (DTH) occurs [54]. This type of responses is mediated by Th1 lymphocytes secreting IFNγ, a response associated with the generation of cellular immunity [30].…”

Section: Discussionmentioning

confidence: 98%

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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Section: Discussionmentioning

confidence: 98%

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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“…via presentation in MHC‐II), this molecule may also be present in MHC‐I. Consistent with this notion, immunohistological studies of biopsies from SBC patients undergoing immunotherapy with KLH showed a massive infiltration of mononuclear cells and CD4 + lymphocytes and, to a lesser extent, CD8 + lymphocytes and granulocytes [74]. These results can be interpreted, in part, in the context of a cross‐presentation of KLH [26], which has not been comprehensively studied.…”

Section: Discussionmentioning

confidence: 76%

C‐type lectin receptors MR and DC‐SIGN are involved in recognition of hemocyanins, shaping their immunostimulatory effects on human dendritic cells

et al. 2021

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Hemocyanins are used as immunomodulators in clinical applications because they induce a strong Th1‐biased cell‐mediated immunity, which has beneficial effects. They are multiligand glycosylated molecules with abundant and complex mannose‐rich structures. It remains unclear whether these structures influence hemocyanin‐induced immunostimulatory processes in human APCs. We have previously shown that hemocyanin glycans from Concholepas concholepas (CCH), Fissurella latimarginata (FLH), and Megathura crenulata (KLH), participate in their immune recognition and immunogenicity in mice, interacting with murine C‐type lectin receptors (CLRs). Here, we studied the interactions of these hemocyanins with two major mannose‐binding CLRs on monocyte‐derived human DCs: MR (mannose receptor) and DC‐SIGN (DC‐specific ICAM‐3–grabbing nonintegrin). Diverse analyses showed that hemocyanins are internalized by a mannose‐sensitive mechanism. This process was calcium dependent. Moreover, hemocyanins colocalized with MR and DC‐SIGN, and were partly internalized through clathrin‐mediated endocytosis. The hemocyanin‐mediated proinflammatory cytokine response was impaired when using deglycosylated FLH and KLH compared to CCH. We further showed that hemocyanins bind to human MR and DC‐SIGN in a carbohydrate‐dependent manner with affinity constants in the physiological concentration range. Overall, we showed that these three clinically valuable hemocyanins interact with human mannose‐sensitive CLRs, initiating an immune response and promoting a Th1 cell‐driving potential.

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“…Unexpectedly, we found that KLH and FLH induced an upregulation of MHC-I in BMDCs (Figure 3A), suggesting a role of cross-presentation in the processing of hemocyanins and consequential induction of CD8+ T cells related to the antitumor immune response (68). In this context, it is important to remark that immunohistological studies of biopsies from superficial bladder cancer patients who underwent immunotherapy with KLH showed a massive infiltration of mononuclear cells and CD4+ lymphocytes, as well as, to a lesser extent, CD8+ lymphocytes and granulocytes (69). In addition, during immunotherapy with KLH, a CD4+ lymphocyte response with an increase in CD8+ lymphocytes in the lymphatic nodules has been observed (70).…”

Section: Discussionmentioning

confidence: 99%

TLR4, but Neither Dectin-1 nor Dectin-2, Participates in the Mollusk Hemocyanin-Induced Proinflammatory Effects in Antigen-Presenting Cells From Mammals

et al. 2019

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Mollusk hemocyanins have biomedical uses as carriers/adjuvants and nonspecific immunostimulants with beneficial clinical outcomes by triggering the production of proinflammatory cytokines in antigen-presenting cells (APCs) and driving immune responses toward type 1 T helper (Th1) polarization. Significant structural features of hemocyanins as a model antigen are their glycosylation patterns. Indeed, hemocyanins have a multivalent nature as highly mannosylated antigens. We have previously shown that hemocyanins are internalized by APCs through receptor-mediated endocytosis with proteins that contain C-type lectin domains, such as mannose receptor (MR). However, the contribution of other innate immune receptors to the proinflammatory signaling pathway triggered by hemocyanins is unknown. Thus, we studied the roles of Dectin-1, Dectin-2, and Toll-like receptor 4 (TLR4) in the hemocyanin activation of murine APCs, both in dendritic cells (DCs) and macrophages, using hemocyanins from Megathura crenulata ( KLH), Concholepas concholepas (CCH) and Fissurella latimarginata (FLH). The results showed that these hemocyanins bound to chimeric Dectin-1 and Dectin-2 receptors in vitro ; which significantly decreased when the glycoproteins were deglycosylated. However, hemocyanin-induced proinflammatory effects in APCs from Dectin-1 knock-out (KO) and Dectin-2 KO mice were independent of both receptors. Moreover, when wild-type APCs were cultured in the presence of hemocyanins, phosphorylation of Syk kinase was not detected. We further showed that KLH and FLH induced ERK1/2 phosphorylation, a key event involved in the TLR signaling pathway. We confirmed a glycan-dependent binding of hemocyanins to chimeric TLR4 in vitro . Moreover, DCs from mice deficient for MyD88-adapter-like (Mal), a downstream adapter molecule of TLR4, were partially activated by FLH, suggesting a role of the TLR pathway in hemocyanin recognition to activate APCs. The participation of TLR4 was confirmed through a decrease in IL-12p40 and IL-6 secretion induced by FLH when a TLR4 blocking antibody was used; a reduction was also observed in DCs from C3H/HeJ mice, a mouse strain with a nonfunctional mutation for this receptor. Moreover, IL-6 secretion induced by FLH was abolished in macrophages deficient for TLR4. Our data showed the involvement of TLR4 in the hemocyanin-mediated proinflammatory response in APCs, which could cooperate with MR in innate immune recognition of these glycoproteins.

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Immunohistological findings in patients with superficial bladder carcinoma after intravesical instillation of keyhole limpet haemocyanin

Cited by 8 publications

References 20 publications

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

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

C‐type lectin receptors MR and DC‐SIGN are involved in recognition of hemocyanins, shaping their immunostimulatory effects on human dendritic cells

TLR4, but Neither Dectin-1 nor Dectin-2, Participates in the Mollusk Hemocyanin-Induced Proinflammatory Effects in Antigen-Presenting Cells From Mammals

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