Tumor Vaccination That Enhances Antitumor T-Cell Responses Does Not Inhibit the Growth of Established Tumors Even in Combination With Interleukin-12 Treatment: The Importance of Inducing Intratumoral T-Cell Migration

Abstract The objective of this study was to investigate whether the immunostimulatory properties of human monocyte-derived dendritic cells (DCs) could be enhanced by triggering OX40/OX40L signaling. Since monocyte-derived DCs possess only low-cell surface levels of OX40L in the absence of CD40 signaling, OX40L was expressed by transfection of DCs with the corresponding mRNA. We show that OX40L mRNA transfection effectively enhanced the immunostimulatory function of DCs at multiple levels: OX40L mRNA transfection augmented allogeneic and HLA class II epitope-specific CD4+ T-cell responses, improved the stimulation of antigen-specific cytotoxic T lymphocytes (CTLs) in vitro without interfering with the prostaglandin E2 (PGE2)–mediated migratory function of the DCs, and facilitated interleukin 12 p70 (IL-12p70)–independent T helper type 1 (Th1) polarization of naive CD4+ T-helper cells. Furthermore, vaccination of tumor-bearing mice using OX40L mRNA–cotransfected DCs resulted in significant enhancement of therapeutic antitumor immunity due to in vivo priming of Th1-type T-cell responses. Our data suggest that transfection of DCs with OX40L mRNA may represent a promising strategy that could be applied in clinical immunotherapy protocols, while circumventing the current unavailability of reagents facilitating OX40 ligation.

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Myeloid Dendritic Cells (DCs) of Mice Susceptible to Paracoccidioidomycosis Suppress T Cell Responses whereas Myeloid and Plasmacytoid DCs from Resistant Mice Induce Effector and Regulatory T Cells

Infection and Immunity ◽

10.1128/iai.00736-12 ◽

2013 ◽

Vol 81 (4) ◽

pp. 1064-1077 ◽

Cited By ~ 24

Author(s):

Adriana Pina ◽

Eliseu Frank de Araujo ◽

Maíra Felonato ◽

Flávio V. Loures ◽

Claudia Feriotti ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Regulatory T Cells ◽

T Cell Responses ◽

Effector T Cells ◽

Interleukin 12 ◽

Content Type ◽

Cell Responses ◽

Plasmacytoid Dcs

ABSTRACTThe protective adaptive immune response in paracoccidioidomycosis, a mycosis endemic among humans, is mediated by T cell immunity, whereas impaired T cell responses are associated with severe, progressive disease. The early host response toParacoccidioides brasiliensisinfection is not known since the disease is diagnosed at later phases of infection. Our laboratory established a murine model of infection where susceptible mice reproduce the severe disease, while resistant mice develop a mild infection. This work aimed to characterize the influence of dendritic cells in the innate and adaptive immunity of susceptible and resistant mice. We verified thatP. brasiliensisinfection induced in bone marrow-derived dendritic cells (DCs) of susceptible mice a prevalent proinflammatory myeloid phenotype that secreted high levels of interleukin-12 (IL-12), tumor necrosis factor alpha, and IL-β, whereas in resistant mice, a mixed population of myeloid and plasmacytoid DCs secreting proinflammatory cytokines and expressing elevated levels of secreted and membrane-bound transforming growth factor β was observed. In proliferation assays, the proinflammatory DCs from B10.A mice induced anergy of naïve T cells, whereas the mixed DC subsets from resistant mice induced the concomitant proliferation of effector and regulatory T cells (Tregs). Equivalent results were observed during pulmonary infection. The susceptible mice displayed preferential expansion of proinflammatory myeloid DCs, resulting in impaired proliferation of effector T cells. Conversely, the resistant mice developed myeloid and plasmacytoid DCs that efficiently expanded gamma interferon-, IL-4-, and IL-17-positive effector T cells associated with increased development of Tregs. Our work highlights the deleterious effect of excessive innate proinflammatory reactions and provides new evidence for the importance of immunomodulation during pulmonary paracoccidioidomycosis.

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Cell-surface bound pertussis toxin induces polyclonal T cell responses with high levels of interferon-γ in the absence of interleukin-12

European Journal of Immunology ◽

10.1002/eji.200323675 ◽

2003 ◽

Vol 33 (7) ◽

pp. 1859-1868 ◽

Cited By ~ 22

Author(s):

Ayako Wakatsuki ◽

Persephone Borrow ◽

Kevin Rigley ◽

Peter C. L. Beverley

Keyword(s):

T Cell ◽

Cell Surface ◽

Pertussis Toxin ◽

T Cell Responses ◽

Interferon Γ ◽

Interleukin 12 ◽

Cell Responses

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Contribution of Interleukin-12 p35 (IL-12p35) and IL-12p40 to Protective Immunity and Pathology in Mice Infected with Chlamydia muridarum

Infection and Immunity ◽

10.1128/iai.00161-13 ◽

2013 ◽

Vol 81 (8) ◽

pp. 2962-2971 ◽

Cited By ~ 15

Author(s):

Lili Chen ◽

Lei Lei ◽

Zhou Zhou ◽

Jie He ◽

Sha Xu ◽

...

Keyword(s):

T Cell ◽

Chlamydial Infection ◽

T Cell Responses ◽

Host Responses ◽

Interleukin 12 ◽

Content Type ◽

Chlamydia Muridarum ◽

Cell Responses ◽

Time Courses ◽

Deficient Mice

ABSTRACTThe p35 molecule is unique to interleukin-12 (IL-12), while p40 is shared by both IL-12 and IL-23. IL-12 promotes Th1 T cell responses, while IL-23 promotes Th17 T cell responses. The roles of IL-12p35- and IL-12p40-mediated responses in chlamydial infection were compared in mice following an intravaginal infection withChlamydia muridarum. Mice deficient in either IL-12p35 or p40 both developed similar but prolonged infection time courses, confirming the roles of IL-12-mediated immune responses in clearing primary infection. However, all mice, regardless of genotype, cleared reinfection within 2 weeks, suggesting that an IL-12- or IL-23-independent adaptive immunity is protective against chlamydial infection. All infected mice developed severe oviduct hydrosalpinx despite the increased Th2 responses in IL-12p35- or IL-12p40-deficient mice, suggesting that Th2-dominant responses can contribute toChlamydia-induced inflammatory pathology. Compared to IL-12p35 knockout mice, the IL-12p40-deficient mice exhibited more extensive spreading of chlamydial organisms into kidney tissues, leading to significantly increased incidence of pyelonephritis, which both confirms the role of IL-12 or IL-23-independent host responses inChlamydia-induced pathologies and suggests that in the absence of IL-12/IFN-γ-mediated Th1 immunity, an IL-23-mediated response may play an important role in restricting chlamydial organisms from spreading into distal organs. These observations together provide important information for both understanding chlamydial pathogenesis and developing anti-Chlamydiavaccines.

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Immunization With Melan-A Peptide-Pulsed Peripheral Blood Mononuclear Cells Plus Recombinant Human Interleukin-12 Induces Clinical Activity and T-Cell Responses in Advanced Melanoma

Journal of Clinical Oncology ◽

10.1200/jco.2003.12.144 ◽

2003 ◽

Vol 21 (12) ◽

pp. 2342-2348 ◽

Cited By ~ 119

Author(s):

Amy C. Peterson ◽

Helena Harlin ◽

Thomas F. Gajewski

Keyword(s):

T Cell ◽

Peripheral Blood Mononuclear Cells ◽

Mononuclear Cells ◽

T Cell Responses ◽

Advanced Melanoma ◽

Interleukin 12 ◽

Clinical Activity ◽

Peripheral Blood Mononuclear ◽

Cell Responses ◽

Blood Mononuclear Cells

Purpose: Preclinical studies showed that immunization with peripheral blood mononuclear cells (PBMC) loaded with tumor antigen peptides plus interleukin-12 (IL-12) induced CD8+ T-cell responses and tumor rejection. We recently determined that recombinant human (rh) IL-12 at 30 to 100 ng/kg is effective as a vaccine adjuvant in patients. A phase II study of immunization with Melan-A peptide-pulsed PBMC + rhIL-12 was conducted in 20 patients with advanced melanoma. Patients and Methods: Patients were HLA-A2–positive and had documented Melan-A expression. Immunization was performed every 3 weeks with clinical re-evaluation every three cycles. Immune responses were measured by ELISpot assay before and after treatment and through the first three cycles, and were correlated with clinical outcome. Results: Most patients had received prior therapy and had visceral metastases. Nonetheless, two patients achieved a complete response, five patients achieved a minor or mixed response, and four patients had stable disease. The median survival was 12.25 months for all patients and was not yet reached for those with a normal lactate dehydrogenase. There were no grade 3 or 4 toxicities. Measurement of specific CD8+ T-cell responses by direct ex vivo ELISpot revealed a significant increase in interferon gamma–producing T cells against Melan-A (P = .015) after vaccination, but not against an Epstein-Barr virus control peptide (P = .86). There was a correlation between the magnitude of the increase in Melan-A–specific cells and clinical response (P = .046). Conclusion: This immunization approach may be more straightforward than dendritic cell strategies and seems to have clinical activity that can be correlated to a biologic end point.

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Thalidomide Stimulates T Cell Responses and Interleukin 12 Production in HIV-Infected Patients

AIDS Research and Human Retroviruses ◽

10.1089/088922299310269 ◽

1999 ◽

Vol 15 (13) ◽

pp. 1169-1179 ◽

Cited By ~ 60

Author(s):

Patrick A.J. Haslett ◽

Jeffrey D. Klausner ◽

Sanit Makonkawkeyoon ◽

Andre Moreira ◽

Prasit Metatratip ◽

...

Keyword(s):

T Cell ◽

T Cell Responses ◽

Interleukin 12 ◽

Cell Responses

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Naive Human T Cells Develop into Th1 Effectors after Stimulation with Mycobacterium tuberculosis-Infected Macrophages or Recombinant Ag85 Proteins

Infection and Immunity ◽

10.1128/iai.68.12.6826-6832.2000 ◽

2000 ◽

Vol 68 (12) ◽

pp. 6826-6832 ◽

Cited By ~ 17

Author(s):

Donna M. Russo ◽

Natalia Kozlova ◽

David L. Lakey ◽

Douglas Kernodle

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

T Cell ◽

T Cell Responses ◽

Interleukin 12 ◽

Naive T Cells ◽

Naïve T Cells ◽

Cell Responses ◽

Human T Cell ◽

Human T Cells

ABSTRACT Most studies of human T-cell responses in tuberculosis have focused on persons with either active disease or latent infection. Although this work has been critical in defining T-cell correlates of successful versus failed host containment, little is known about the development of Mycobacterium-specific T-cell responses in uninfected persons. To explore this issue, naive T cells from uninfected donors were sensitized in vitro with avirulent Mycobacterium tuberculosis-infected autologous macrophages. T-cell lines primed in this manner proliferated and produced cytokines after challenge with mycobacterial antigens. Of 11 such lines, 8 were high Th1 responders, 2 were low Th1 responders, and 1 was a Th2 responder. Furthermore, similar patterns and magnitudes of proliferative and cytokine responses were seen when Mycobacterium infection-primed lines were challenged with recombinant antigen 85 (Ag85) proteins. The addition of interleukin 12 (IL-12) during the initial sensitization increased the magnitude of Th1 responses; however, antibody to IL-12 did not eliminate Th1 responses, suggesting that additional factors contributed to the differentiation of these cells. Finally, in the presence of IL-12, recombinant Ag85B was able to prime naive T cells for Th1 responses upon challenge with Mycobacterium-infected macrophages or Ag85B. Therefore, under the appropriate conditions, priming with whole bacteria or a subunit antigen can stimulateMycobacterium-specific Th1 effector cell development. Further definition of the antigens and conditions required to drive naive human T cells to differentiate into Th1 effectors should facilitate the development of an improved tuberculosis vaccine.

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