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.

Stimulation of autologous proliferative and cytotoxic T-cell responses by “leukemic dendritic cells” derived from blast cells in acute myeloid leukemia

Blood ◽  
2001 ◽  
Vol 97 (9) ◽  
pp. 2764-2771 ◽  
Author(s):  
Beth D. Harrison ◽  
Julie A. Adams ◽  
Mark Briggs ◽  
Michelle L. Brereton ◽  
John A. Liu Yin
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Dendritic Cells ◽  
T Cell ◽  
Myeloid Leukemia ◽  
T Cell Responses ◽  
Cell Responses ◽  
Antigen Presenting ◽  
Acute Myeloid ◽  
Stimulation Of

Abstract Effective presentation of tumor antigens is fundamental to strategies aimed at enrolling the immune system in eradication of residual disease after conventional treatments. Myeloid malignancies provide a unique opportunity to derive dendritic cells (DCs), functioning antigen-presenting cells, from the malignant cells themselves. These may then co-express leukemic antigens together with appropriate secondary signals and be used to generate a specific, antileukemic immune response. In this study, blasts from 40 patients with acute myeloid leukemia (AML) were cultured with combinations of granulocyte-macrophage colony-stimulating factor, interleukin 4, and tumor necrosis factor α, and development to DCs was assessed. After culture, cells from 24 samples exhibited morphological and immunophenotypic features of DCs, including expression of major histocompatibility complex class II, CD1a, CD83, and CD86, and were potent stimulators in an allogeneic mixed lymphocyte reaction (MLR). Stimulation of autologous T-cell responses was assessed by the proliferative response of autologous T cells to the leukemic DCs and by demonstration of the induction of specific, autologous, antileukemic cytotoxicity. Of 17 samples, 11 were effective stimulators in the autologous MLR, and low, but consistent, autologous, antileukemic cytotoxicity was induced in 8 of 11 cases (mean, 27%; range, 17%-37%). This study indicates that cells with enhanced antigen-presenting ability can be generated from AML blasts, that these cells can effectively prime autologous cytotoxic T cells in vitro, and that they may be used as potential vaccines in the immunotherapy of AML.

scholarly journals Killer artificial antigen-presenting cells: a novel strategy to delete specific T cells

Blood ◽  
2008 ◽  
Vol 111 (7) ◽  
pp. 3546-3552 ◽  
Author(s):  
Christian Schütz ◽  
Martin Fleck ◽  
Andreas Mackensen ◽  
Alessia Zoso ◽  
Dagmar Halbritter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Fas Ligand ◽  
T Cell Responses ◽  
Antigen Presenting Cells ◽  
Cytotoxic T Cell ◽  
Cell Responses ◽  
Cytotoxic T Cell Responses ◽  
Antigen Presenting

Abstract Several cell-based immunotherapy strategies have been developed to specifically modulate T cell–mediated immune responses. These methods frequently rely on the utilization of tolerogenic cell–based antigen-presenting cells (APCs). However, APCs are highly sensitive to cytotoxic T-cell responses, thus limiting their therapeutic capacity. Here, we describe a novel bead-based approach to modulate T-cell responses in an antigen-specific fashion. We have generated killer artificial APCs (κaAPCs) by coupling an apoptosis-inducing α-Fas (CD95) IgM mAb together with HLA-A2 Ig molecules onto beads. These κaAPCs deplete targeted antigen-specific T cells in a Fas/Fas ligand (FasL)–dependent fashion. T-cell depletion in cocultures is rapidly initiated (30 minutes), dependent on the amount of κaAPCs and independent of activation-induced cell death (AICD). κaAPCs represent a novel technology that can control T cell–mediated immune responses, and therefore has potential for use in treatment of autoimmune diseases and allograft rejection.

scholarly journals HIV-1 Reservoir Dynamics after Vaccination and Antiretroviral Therapy Interruption Are Associated with Dendritic Cell Vaccine-Induced T Cell Responses

2015 ◽  
Vol 89 (18) ◽  
pp. 9189-9199 ◽  
Author(s):  
Cristina Andrés ◽  
Montserrat Plana ◽  
Alberto C. Guardo ◽  
Carmen Alvarez-Fernández ◽  
Nuria Climent ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Therapeutic Vaccine ◽  
T Cell Responses ◽  
Therapeutic Vaccines ◽  
Cell Responses ◽  
Hiv 1

ABSTRACTHIV-1-specific immune responses induced by a dendritic cell (DC)-based therapeutic vaccine might have some effect on the viral reservoir. Patients on combination antiretroviral therapy (cART) were randomized to receive DCs pulsed with autologous HIV-1 (n= 24) (DC-HIV-1) or nonpulsed DCs (n= 12) (DC-control). We measured the levels of total and integrated HIV-1 DNA in CD4 T cells isolated from these patients at 6 time points: before any cART; before the first cART interruption, which was at 56 weeks before the first immunization to isolate virus for pulsing DCs; before and after vaccinations (VAC1 and VAC2); and at weeks 12 and 48 after the second cART interruption. The vaccinations did not influence HIV-1 DNA levels in vaccinated subjects. After the cART interruption at week 12 postvaccination, while total HIV-1 DNA increased significantly in both arms, integrated HIV-1 DNA did not change in vaccinees (mean of 1.8 log10to 1.9 copies/106CD4 T cells,P= 0.22) and did increase in controls (mean of 1.8 log10to 2.1 copies/106CD4 T cells,P= 0.02) (P= 0.03 for the difference between groups). However, this lack of increase of integrated HIV-1 DNA observed in the DC-HIV-1 group was transient, and at week 48 after cART interruption, no differences were observed between the groups. The HIV-1-specific T cell responses at the VAC2 time point were inversely correlated with the total and integrated HIV-1 DNA levels after cART interruption in vaccinees (r[Pearson's correlation coefficient] = −0.69,P= 0.002, andr= −0.82,P< 0.0001, respectively). No correlations were found in controls. HIV-1-specific T cell immune responses elicited by DC therapeutic vaccines drive changes in HIV-1 DNA after vaccination and cART interruption. (This study has been registered at ClinicalTrials.gov under registration no. NCT00402142.)IMPORTANCEThere is an intense interest in developing strategies to target HIV-1 reservoirs as they create barriers to curing the disease. The development of therapeutic vaccines aimed at enhancing immune-mediated clearance of virus-producing cells is of high priority. Few therapeutic vaccine clinical trials have investigated the role of therapeutic vaccines as a strategy to safely eliminate or control viral reservoirs. We recently reported that a dendritic cell-based therapeutic vaccine was able to significantly decrease the viral set point in vaccinated patients, with a concomitant increase in HIV-1-specific T cell responses. The HIV-1-specific T cell immune responses elicited by this therapeutic dendritic cell vaccine drove changes in the viral reservoir after vaccinations and significantly delayed the replenishment of integrated HIV-1 DNA after cART interruption. These data help in understanding how an immunization could shift the virus-host balance and are instrumental for better design of strategies to reach a functional cure of HIV-1 infection.

Induction of Potentially Protective HIV-Specific T-Cell Responses In Vitro by Gag mRNA-Electroporated Dendritic Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1261-1261
Author(s):  
Zwi N. Berneman ◽  
Ellen R. Van Gulck ◽  
Leo Heyndrickx ◽  
Peter Ponsaerts ◽  
Viggo F.I. Van Tendeloo ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cell Count ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
T Cell Responses ◽  
Ifn Gamma ◽  
Cell Responses ◽  
Hiv 1

Abstract Human immunodeficiency virus type 1 (HIV-1) infection is characterized by dysfunction of HIV-1-specific T-lymphocytes. In order to suppress the virus and delay evolution to AIDS, antigen-loaded antigen-presenting cells, including dendritic cells (DC) might be useful to boost and broaden HIV-1-specific T-cell responses. Monocyte-derived DC from 15 untreated (“naive”) and 15 highly active anti-retroviral therapy (HAART)-treated HIV-1-infected patients were electroporated with codon-optimized (“humanized”) mRNA encoding consensus HxB-2 (hHxB-2) Gag protein. These DC were co-cultured for 1 week with autologous peripheral blood leucocytes (PBL). Potential expansion of specific T-cells was measured by comparing ELISPOT responses of PBL before and after co-culture, using a pool of overlapping peptides, spanning the HxB-2 Gag. Expansion of specific PBL after co-culture was noted for T cells producing interferon (IFN)-gamma, interleukin (IL)-2 and perforin (Wilcoxon signed rank test p&lt;0.05, except for IL-2 in naive patients). From all HIV-1-seropositive persons tested, 12 HAART-treated and 12 naive patients match in absolute number of CD4+ T-cells. A comparison of the increase of the response between day 0 and after 1 week of stimulation between those two groups showed that the response was higher in HAART-treated subjects for IFN-gamma and IL-2 but not for perforin in comparison to untreated subjects. Examining purified CD4+ and CD8+ T-cells after co-culture revealed that HxB-2 Gag peptides induced IFN-gamma in both subsets, that IL-2 was only secreted by CD4+ T-cells and that perforin was dominantly secreted by CD8+ T-cells. Remarkably, the perforin response in the treatment-naive persons was negatively correlated with the peripheral blood absolute CD4+ and CD8+ T-cell count (respectively R=0.618, p=0.014; and R=0.529, p=0.043). Furthermore, the nadir absolute CD4+ T-cell count in HAART-treated subjects was positively correlated with the IL-2 response (R=0.521, p=0.046) and negatively correlated with the perforin response (R=0.588, p=0.021). In conclusion, DC from HAART-treated and therapy-naive subjects, electroporated with hHxB-2 gag mRNA have the capacity to induce secondary T-cell responses. In an earlier study (Van Gulck ER et al. Blood2006;107:1818–1827), we already demonstrated ex vivo that CD4+ and CD8+ T-cells from non-treated HIV-1-infected subjects can be directly triggered by DC electroporated with autologous proviral-derived gag mRNA. Taken together, our results open the perspective for a DC immunotherapy for HIV disease.

T Cell Responses in Patients Vaccinated with Telomerase (hTERT)-mRNA Transfected Dendritic Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 373-373
Author(s):  
Else Marit Inderberg Suso ◽  
Anne-Marie Rasmussen ◽  
Steinar Aamdal ◽  
Svein Dueland ◽  
Gustav Gaudernack ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cancer Patients ◽  
Cd8 T Cells ◽  
Stable Disease ◽  
T Cell Responses ◽  
Htert Mrna ◽  
Cell Responses

Abstract Abstract 373 Two cancer patients were vaccinated with dendritic cells (DC) loaded with telomerase (hTERT) mRNA to investigate the safety, tolerability and immunological response to vaccination prior to the start of a new phase I/II clinical trial. Following written informed consent one primary lung adenocarcinoma with metastasis and one patient with a relapsed pancreatic ductal type of adenocarcinoma, were treated with autologus monocyte-derived DC transfected with mRNA encoding hTERT. The patients first received four weekly injections administered intradermally followed by monthly booster injections. Peripheral blood mononuclear cells (PBMC) at each vaccination time point were tested in vitro with transfected DC and a panel of 24 overlapping hTERT peptides. In addition, hTERT-specific CD8+ T cells were monitored by pentamer staining. The treatment was well tolerated with minor side effects. Immune responses against telomerase-transfected DC and some of the overlapping hTERT peptides were detected in both patients. We also detected hTERT-specific CD8+ T cells in both patients by pentamer staining in post-vaccination samples. The lung cancer patients obtained a stable disease that lasted 18 months while the patient with pancreas cancer who started the DC vaccination in July 2007 following palliative chemotherapy, still is in stable disease by continuously boost vaccination. T-cell responses against telomerase epitopes have also been identified in both non-vaccinated cancer patients and cancer patients previously vaccinated with telomerase peptide. Since patients with these findings often show extraordinary clinical courses of their disease we hypothesize that it exists a high degree of immunogenicity and HLA promiscuity for some telomerase epitopes. In this study we have shown that vaccination with hTERT-mRNA transfected DC is safe and able to induce robust immune responses to several telomerase T-cell epitopes both in CD4+ and CD8+ T cells. This opens up the possibility for a broad clinical application of mRNA hTERT DC vaccines. Furthermore, responding T cells identified in these patients are strong candidates for T-cell receptor cloning and the receptors identified can thereafter be transferred into T cells creating the next generation of immuno-gene therapy with retargeted T cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Innate immunity defines the capacity of antiviral T cells to limit persistent infection

2010 ◽  
Vol 207 (6) ◽  
pp. 1333-1343 ◽  
Author(s):  
Daniel M. Andrews ◽  
Marie J. Estcourt ◽  
Christopher E. Andoniou ◽  
Matthew E. Wikstrom ◽  
Andrea Khong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Nk Cells ◽  
Viral Persistence ◽  
T Cell Responses ◽  
Cell Responses ◽  
Adaptive Immune ◽  
Acquired Immune Responses ◽  
Antigen Presenting

Effective immunity requires the coordinated activation of innate and adaptive immune responses. Natural killer (NK) cells are central innate immune effectors, but can also affect the generation of acquired immune responses to viruses and malignancies. How NK cells influence the efficacy of adaptive immunity, however, is poorly understood. Here, we show that NK cells negatively regulate the duration and effectiveness of virus-specific CD4+ and CD8+ T cell responses by limiting exposure of T cells to infected antigen-presenting cells. This impacts the quality of T cell responses and the ability to limit viral persistence. Our studies provide unexpected insights into novel interplays between innate and adaptive immune effectors, and define the critical requirements for efficient control of viral persistence.

scholarly journals Modulation of Vaccine-Induced CD4 T Cell Functional Profiles by Changes in Components of HIV Vaccine Regimens in Humans

2018 ◽  
Vol 92 (23) ◽  
Author(s):  
Franco Pissani ◽  
Bianca Schulte ◽  
Michael A. Eller ◽  
Bruce T. Schultz ◽  
Silvia Ratto-Kim ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Hiv Infection ◽  
Cd4 T Cells ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Hiv 1

ABSTRACT To date, six vaccine strategies have been evaluated in clinical trials for their efficacy at inducing protective immune responses against HIV infection. However, only the ALVAC-HIV/AIDSVAX B/E vaccine (RV144 trial) has demonstrated protection, albeit modestly (31%; P = 0.03). One potential correlate of protection was a low-frequency HIV-specific CD4 T cell population with diverse functionality. Although CD4 T cells, particularly T follicular helper (Tfh) cells, are critical for effective antibody responses, most studies involving HIV vaccines have focused on humoral immunity or CD8 T cell effector responses, and little is known about the functionality and frequency of vaccine-induced CD4 T cells. We therefore assessed responses from several phase I/II clinical trials and compared them to responses to natural HIV-1 infection. We found that all vaccines induced a lower magnitude of HIV-specific CD4 T cell responses than that observed for chronic infection. Responses differed in functionality, with a CD40 ligand (CD40L)-dominated response and more Tfh cells after vaccination, whereas chronic HIV infection provoked tumor necrosis factor alpha (TNF-α)-dominated responses. The vaccine delivery route further impacted CD4 T cells, showing a stronger Th1 polarization after dendritic cell delivery than after intramuscular vaccination. In prime/boost regimens, the choice of prime and boost influenced the functional profile of CD4 T cells to induce more or less polyfunctionality. In summary, vaccine-induced CD4 T cell responses differ remarkably between vaccination strategies, modes of delivery, and boosts and do not resemble those induced by chronic HIV infection. Understanding the functional profiles of CD4 T cells that best facilitate protective antibody responses will be critical if CD4 T cell responses are to be considered a clinical trial go/no-go criterion. IMPORTANCE Only one HIV-1 candidate vaccine strategy has shown protection, albeit marginally (31%), against HIV-1 acquisition, and correlates of protection suggested that a multifunctional CD4 T cell immune response may be important for this protective effect. Therefore, the functional phenotypes of HIV-specific CD4 T cell responses induced by different phase I and phase II clinical trials were assessed to better show how different vaccine strategies influence the phenotype and function of HIV-specific CD4 T cell immune responses. The significance of this research lies in our comprehensive comparison of the compositions of the T cell immune responses to different HIV vaccine modalities. Specifically, our work allows for the evaluation of vaccination strategies in terms of their success at inducing Tfh cell populations.

scholarly journals Immunization with host-type CD8α+ dendritic cells reduces experimental acute GVHD in an IL-10–dependent manner

Blood ◽  
2010 ◽  
Vol 115 (3) ◽  
pp. 724-735 ◽  
Author(s):  
Tomomi Toubai ◽  
Chelsea Malter ◽  
Isao Tawara ◽  
Chen Liu ◽  
Evelyn Nieves ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
Class Ii ◽  
Cell Responses ◽  
Histocompatibility Complex

Abstract Little is known about the role of active immunization in suppressing undesirable immune responses. Because CD8α+ dendritic cells (DCs) suppress certain immune responses, we tested the hypothesis that immunization of donors with host-derived CD8α+ DCs will reduce host-specific donor T-cell responses. BALB/c T cells from the animals that were immunized with B6 CD8α+ DCs demonstrated, in vitro and in vivo, significantly reduced proliferation and secretion of inflammatory cytokines but showed enhanced secretion of interleukin-10 (IL-10). The responses against third-party and model antigens were preserved demonstrating antigen specificity. The in vivo relevance was further demonstrated by the reduction on graft-versus-host disease (GVHD) in both a major histocompatibility complex–mismatched clinically relevant BALB/c → B6 model and major histocompatibility complex–matched, minor-mismatched C3H.SW → B6 model of GVHD. Immunization of the donors that were deficient in IL-10 (IL-10−/−) or with CD8α+ DCs from B6 class II (class II−/−) failed to reduce T-cell responses, demonstrating (1) a critical role for secretion of IL-10 by donor T cells and (2) a direct contact between the T cells and the CD8α+ DCs. Together, these data may represent a novel strategy for reducing GVHD and suggest a broad counterintuitive role for vaccination strategies in mitigating undesirable immune responses in an antigen-specific manner.

Activation of influenza virus–specific CD4+ and CD8+ T cells: a new role for plasmacytoid dendritic cells in adaptive immunity

Blood ◽  
2003 ◽  
Vol 101 (9) ◽  
pp. 3520-3526 ◽  
Author(s):  
Jean-François Fonteneau ◽  
Michel Gilliet ◽  
Marie Larsson ◽  
Ida Dasilva ◽  
Christian Münz ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
Plasmacytoid Dendritic Cells ◽  
Type I ◽  
Cell Responses ◽  
Adaptive Immune

Plasmacytoid dendritic cells (pDCs) contribute to innate antiviral immune responses by producing type I interferons (IFNs) upon exposure to enveloped viruses. However, their role in adaptive immune responses, such as the initiation of antiviral T-cell responses, is not known. In this study, we examined interactions between blood pDCs and influenza virus with special attention to the capacity of pDCs to activate influenza-specific T cells. pDCs were compared with CD11c+ DCs, the most potent antigen-presenting cells (APCs), for their capacity to activate T-cell responses. We found that like CD11c+ DCs, pDCs mature following exposure to influenza virus, express CCR7, and produce proinflammatory chemokines, but differ in that they produce type I IFN and are resistant to the cytopathic effect of the infection. After influenza virus exposure, both DC types exhibited an equivalent efficiency to expand anti–influenza virus cytotoxic T lymphocytes (CTLs) and T helper 1 (TH1) CD4+ T cells. Our results pinpoint a new role of pDCs in the induction of antiviral T-cell responses and suggest that these DCs play a prominent role in the adaptive immune response against viruses.

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