Disease-associated dendritic cells respond to disease-specific antigens through the common heat shock protein receptor

Blood ◽  
2003 ◽  
Vol 102 (5) ◽  
pp. 1806-1814 ◽  
Author(s):  
Justin Stebbing ◽  
Brian Gazzard ◽  
Simon Portsmouth ◽  
Frances Gotch ◽  
Louise Kim ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Heat Shock ◽  
Immune Responses ◽  
Cytotoxic T Cells ◽  
Kaposi Sarcoma ◽  
Antigenic Peptides ◽  
Protein Receptor ◽  
Functionally Impaired ◽  
The Common ◽  
Hiv 1

AbstractThe most abundant intracellular proteins, heat shock proteins (HSPs), serve as molecular chaperones for regulatory and maturation pathways. Diverse families of HSPs have been shown to bind antigenic peptides and to play major roles in innate and adaptive immune responses through the common HSP receptor, CD91. HIV-1+ patients with Kaposi sarcoma (KS) were matched for CD4 count and HIV-1 RNA viral load to HIV-1+ patients without Kaposi sarcoma (and negative for Kaposisarcoma–associated herpesvirus). We then investigated the pathways used by tumor lysates, viral lysates, and viral particles in their activation. In particular, we observed immune responses after HSP depletion using antitumor antibiotics and blockade of the common HSP receptor, CD91. Despite the impaired functional capacity of dendritic cells (DCs) derived from patients with KS, DCs retain the ability to prime the adaptive arm of the immune system through the common HSP receptor, leading to phenotypic activation and stimulation of tetramer-positive CD8+ cytotoxic T cells. We also show that interferon-producing plasmacytoid DCs are selectively depleted in KS-positive compared with matched KS-negative HIV-1–infected patients. Functionally impaired DCs can effectively cross-present immune responses through the common HSP receptor. These results have important implications for the etiopathogenesis of KS and for the development and design of any compounds, including vaccines, derived from cellular lysates.

scholarly journals Inhibition of lipid antigen presentation in dendritic cells by HIV-1 Vpu interference with CD1d recycling from endosomal compartments

Blood ◽  
2010 ◽  
Vol 116 (11) ◽  
pp. 1876-1884 ◽  
Author(s):  
Markus Moll ◽  
Sofia K. Andersson ◽  
Anna Smed-Sörensen ◽  
Johan K. Sandberg
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Antigen Presentation ◽  
Nkt Cells ◽  
Cellular Immune Responses ◽  
Antigen Presentation Pathway ◽  
Early Endosomes ◽  
Presentation Pathway ◽  
Cellular Immune ◽  
Hiv 1

AbstractDendritic cells (DCs) play an important role in viral infections both as initiators of immunity and as viral targets. Interaction between DCs and the innate-like CD1d-restricted natural killer T (NKT) cells results in the mutual activation of both cells and the subsequent initiation of cellular immune responses. Here, we show that HIV-1 inhibits the surface expression of CD1d in productively infected DCs and identify this as a novel activity of the HIV-1 vpu gene product. Interestingly, the viral protein U (Vpu) does not enhance constitutive CD1d endocytosis or induce rapid CD1d degradation. Instead, the Vpu protein interacts with CD1d and suppresses its recycling from endosomal compartments to the cell surface by retaining CD1d in early endosomes. This interference with the CD1d antigen presentation pathway strongly inhibits the ability of infected DCs to activate CD1d-restricted NKT cells. Given that the interaction with CD1d-expressing DCs is central to the ability of NKT cells to regulate immunity, these data suggest that interference with the CD1d antigen presentation pathway represents an HIV-1 strategy to evade innate cellular immune responses and imply a role for the innate-like CD1d-restricted NKT cells in the host defense against HIV-1.

A Crucial Cytotoxic Role of Anti-Idiotypic Antibody in Immunotherapy for B-Cell Neoplasms with Tumor Cell-Derived Heat Shock Protein 70.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1642-1642
Author(s):  
Kazuya Sato ◽  
Junko Jimbo ◽  
Naoka Okamura ◽  
Takaaki Hosoki ◽  
Motohiro Shindo ◽  
...  
Keyword(s):  
Heat Shock ◽  
Immune Responses ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Variable Region ◽  
Autologous Tumor ◽  
Antigenic Peptides ◽  
Control Peptide ◽  
Specific Antigens ◽  
Idiotypic Antibody

Abstract Abstract 1642 Poster Board I-668 Background Tumor-derived heat shock proteins (HSPs), which bind to tumor-specific antigenic peptides, can be used for cancer immunotherapy. In this meeting, we previously reported that vaccination with mouse B-cell leukemia/lymphoma cell line, A20, -derived HSP70 (A20-HSP) against A20 cells in mice induces tumor-specific cellular immune responses (Sato et al. Blood 2001;98:1852-1857; Iuchi et al. Int J Hematol 2006;84:449-458) as well as A20-specific humoral immunity through complement dependent cell-cytotoxicities (CDCs) (Sato K et al., 2007, Blood 110:682a, Abstruct#2302). In the B-cell neoplasms, idiotype is known as one of the important tumor specific antigens which induce anti-idiotype cellular and humoral immune responses. A20-secreted monoclonal IgG (A20-Ig) and A20-idiotypic epitope peptide (A20-IP: DYWGQGTEL), which is derived from variable region of the heavy chain of the A20-Ig, are known as the A20-specific antigens (J Immunol. 2002; 168: 3983-91). Further analysis using A20-Ig and A20-IP enables to establish novel HSP70-based therapeutic strategies for B-cell neoplasms. The present study investigated whether immunization with A20-HSP induces anti-idiotypic antibodies, and also evaluated whether the antibodies showed CDCs. Methods A20 and syngeneic Balb/c mice (H-2Kd) were used in this study. HSP70 was purified from either A20 cells or healthy mouse liver tissue. A20-Ig was purified from A20 culture supernatants. After the subcutaneous immunization with A20-HSP, liver-derived HSP70 (control) to the healthy mice, the sera were harvested for the following experiments. To detect anti-A20-IP antibodies, the sera were assayed by ELISA to detect the specific IgG against A20-HSP, or A20-Ig. To confirm that immunization with A20-HSP induces anti-idiotypic antibodies, we analyzed the inhibitory effect (% inhibition) of A20-IP on the A20-HSP-mice sera reactivity against A20-HSP by preincubation of the sera with A20-IP or H-2Kd biding control peptide (mouse influenza hemagglutinin peptide: IYSTVASSL) by ELISA. To confirm that A20-HSP mice sera contains CDC type antibody directed to A20-IP, the CDC activity was determined by the trypan blue uptake of A20 cells after incubation with the complement and A20-HSP mice sera preincubated without or with A20-IP or control peptide. Results The IgG level in the A20-HSP mice against either A20-HSP or A20-Ig was significantly increased in comparison to that in control mice. % inhibition of A20-IP (45.7%) was significantly higher than that of control peptide (1.0%), indicating that almost half of IgG in the A20-HSP mice sera which reacts to A20-HSP recognizes A20-IP. The CDC activity of A20-HSP mice sera against A20 was markedly inhibited by preincubation of the sera with A20-IP but with control peptide. Conclusions: Immunization with A20-HSP70 induces anti-idiotype antibody and the antibody contributes a crucial role in eradication of A20 by CDC activity in mice. These findings enable to establish a novel and advantageous therapeutic strategy against B-cell neoplasms utilizing the anti-idiotypic antibody in HSP-based autologous tumor immunotherapy. Disclosures No relevant conflicts of interest to declare.

Immunotherapy using heat-shock protein preparations of leukemia cells after syngeneic bone marrow transplantation in mice

Blood ◽  
2001 ◽  
Vol 98 (6) ◽  
pp. 1852-1857 ◽  
Author(s):  
Kazuya Sato ◽  
Yoshihiro Torimoto ◽  
Yasuaki Tamura ◽  
Motohiro Shindo ◽  
Hitoshi Shinzaki ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Heat Shock ◽  
T Lymphocytes ◽  
Immune Responses ◽  
Marrow Transplantation ◽  
Leukemia Cell Line ◽  
Leukemia Cells ◽  
Antigenic Peptides ◽  
Cd8 T Lymphocytes

Abstract Heat-shock proteins (HSPs) act as molecular chaperones binding endogenous antigenic peptides and transporting them to major histocompatibility complexes. HSPs chaperone a broad repertoire of endogenous peptides including tumor antigens. For the immunotherapy of tumors, a strategy using HSPs may be more advantageous than other procedures because the identification of each tumor-specific antigen is not necessary. In this study, the efficacy of immunotherapy against minimal residual leukemia cells using HSP preparations was evaluated. HSP70 and GP96 were purified from syngeneic leukemia cell line A20 and immunized into BALB/c mice during the reconstitution period of the immune system after syngeneic bone marrow transplantation. In this procedure, all mice not immunized were dead within 60 days of A20 inoculation, whereas the survival times of HSP-immunized mice were significantly prolonged. In addition, the depletion of either CD4+ or CD8+ T lymphocyte significantly abrogated this efficacy, indicating that both CD4+ and CD8+ T lymphocytes were required for tumor cell rejection. Moreover, the vaccination of HSPs elicited a specific response of potent CD8+ T lymphocytes cytotoxic against A20 in vitro. These observations suggest that immunization of the complex of HSPs and peptides derived from leukemia cells leads to immune responses. These immune responses are sufficient to reject minimal amounts of leukemia cells for relatively immunocompromised mice after syngeneic bone marrow transplantation.

scholarly journals Anti-CD40 Antibody Fused to CD40 Ligand Is a Superagonist Platform for Adjuvant Intrinsic DC-Targeting Vaccines

2022 ◽  
Vol 12 ◽  
Author(s):  
Valentina Ceglia ◽  
Sandra Zurawski ◽  
Monica Montes ◽  
Mitchell Kroll ◽  
Aurélie Bouteau ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
Class I ◽  
Agonist Activity ◽  
Cell Immunity ◽  
Hiv 1

CD40 is a potent activating receptor expressed on antigen-presenting cells (APCs) of the immune system. CD40 regulates many aspects of B and T cell immunity via interaction with CD40L expressed on activated T cells. Targeting antigens to CD40 via agonistic anti-CD40 antibody fusions promotes both humoral and cellular immunity, but current anti-CD40 antibody-antigen vaccine prototypes require co-adjuvant administration for significant in vivo efficacy. This may be a consequence of dulling of anti-CD40 agonist activity via antigen fusion. We previously demonstrated that direct fusion of CD40L to anti-CD40 antibodies confers superagonist properties. Here we show that anti-CD40-CD40L-antigen fusion constructs retain strong agonist activity, particularly for activation of dendritic cells (DCs). Therefore, we tested anti-CD40-CD40L antibody fused to antigens for eliciting immune responses in vitro and in vivo. In PBMC cultures from HIV-1-infected donors, anti-CD40-CD40L fused to HIV-1 antigens preferentially expanded HIV-1-specific CD8+ T cells versus CD4+ T cells compared to analogous anti-CD40-antigen constructs. In normal donors, anti-CD40-CD40L-mediated delivery of Influenza M1 protein elicited M1-specific T cell expansion at lower doses compared to anti-CD40-mediated delivery. Also, on human myeloid-derived dendritic cells, anti-CD40-CD40L-melanoma gp100 peptide induced more sustained Class I antigen presentation compared to anti-CD40-gp100 peptide. In human CD40 transgenic mice, anti-CD40-CD40L-HIV-1 gp140 administered without adjuvant elicited superior antibody responses compared to anti-CD40-gp140 antigen without fused CD40L. In human CD40 mice, compared to the anti-CD40 vehicle, anti-CD40-CD40L delivery of Eα 52-68 peptide elicited proliferating of TCR I-Eα 52-68 CD4+ T cells producing cytokine IFNγ. Also, compared to controls, only anti-CD40-CD40L-Cyclin D1 vaccination of human CD40 mice reduced implanted EO771.LMB breast tumor cell growth. These data demonstrate that human CD40-CD40L antibody fused to antigens maintains highly agonistic activity and generates immune responses distinct from existing low agonist anti-CD40 targeting formats. These advantages were in vitro skewing responses towards CD8+ T cells, increased efficacy at low doses, and longevity of MHC Class I peptide display; and in mouse models, a more robust humoral response, more activated CD4+ T cells, and control of tumor growth. Thus, the anti-CD40-CD40L format offers an alternate DC-targeting platform with unique properties, including intrinsic adjuvant activity.

scholarly journals Polyelectrolyte Capsules-containing HIV-1 p24 and Poly I:C Modulate Dendritic Cells to Stimulate HIV-1-specific Immune Responses

2010 ◽  
Vol 18 (7) ◽  
pp. 1408-1416 ◽  
Author(s):  
Winni De Haes ◽  
Stefaan De Koker ◽  
Charlotte Pollard ◽  
Derek Atkinson ◽  
Erika Vlieghe ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune Responses ◽  
Poly I:C ◽  
Hiv 1

scholarly journals Interleukin-12p70 Expression by Dendritic Cells of HIV-1-Infected Patients Fails to Stimulategag-Specific Immune Responses

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Ellen Van Gulck ◽  
Nathalie Cools ◽  
Derek Atkinson ◽  
Lotte Bracke ◽  
Katleen Vereecken ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
Hiv Replication ◽  
Cell Responses ◽  
Antigen Presenting ◽  
Hiv 1 ◽  
Unique Capability

A variety of immune-based therapies has been developed in order to boost or induce protective CD8+T cell responses in order to control HIV replication. Since dendritic cells (DCs) are professional antigen-presenting cells (APCs) with the unique capability to stimulate naïve T cells into effector T cells, their use for the induction of HIV-specific immune responses has been studied intensively. In the present study we investigated whether modulation of the activation state of DCs electroporated with consensus codon-optimized HxB2gagmRNA enhances their capacity to induce HIVgag-specific T cell responses. To this end, mature DCs were (i) co-electroporated with mRNA encoding interleukin (IL)-12p70 mRNA, or (ii) activated with a cytokine cocktail consisting of R848 and interferon (IFN)-γ. Our results confirm the ability of HxB2gag-expressing DCs to expand functional HIV-specific CD8+T cells. However, although most of the patients had detectablegag-specific CD8+T cell responses, no significant differences in the level of expansion of functional CD8+T cells could be demonstrated when comparing conventional or immune-modulated DCs expressing IL-12p70. This result which goes against expectation may lead to a re-evaluation of the need for IL-12 expression by DCs in order to improve T-cell responses in HIV-1-infected individuals.

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