Induction of an antitumor immunological response by an intratumoral injection of dendritic cells pulsed with genetically engineered Semliki Forest virus to produce interleukin-18 combined with the systemic administration of interleukin-12

2003 ◽  
Vol 99 (4) ◽  
pp. 746-753 ◽  
Author(s):  
Ryuya Yamanaka ◽  
Naoto Tsuchiya ◽  
Naoki Yajima ◽  
Junpei Honma ◽  
Hitoshi Hasegawa ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Brain Tumor ◽  
Protective Immunity ◽  
Antitumor Immunity ◽  
Semliki Forest Virus ◽  
Systemic Administration ◽  
Interleukin 18 ◽  
Content Type ◽  
Fine Print

Object. The aim of this study was to investigate further immunogene treatment of malignant brain tumor to improve its therapeutic efficacy. Methods. Intratumoral dendritic cells pulsed with Semliki Forest virus (SFV)—interleukin-18 (IL-18) and/or systemic IL-12 were injected into mice bearing the B16 brain tumor. To study the immune mechanisms involved in tumor regression, we monitored the growth of implanted B16 brain tumor cells in T cell—depleted mice and IFNγ-neutralized mice. To analyze the protective immunity created by tumor inoculation, B16 cells were injected into the left thighs of mice that had received an inoculation, and tumor growth was monitored. The local delivery of dendritic cells pulsed with IL-18 bound by SFV combined with the systemic administration of IL-12 enhanced the induction of the T helper type 1 response from tumor-specific CD4+ and CD8+ T cells and natural killer cells as well as antitumor immunity. Interferon-γ is partly responsible for this IL-18—mediated antitumor immunity. Furthermore, the protective immunity is mediated mainly by CD8+ T cells. Conclusions. Immunogene therapy that combines the local administration of dendritic cells pulsed with IL-18 bound by SFV and the systemic administration of IL-12 may be an excellent candidate for the development of a new treatment protocol. A self-replicating SFV system may therefore open a novel approach for the treatment of malignant brain tumor.

Administration of interleukin-12 and -18 enhancing the antitumor immunity of genetically modified dendritic cells that had been pulsed with Semliki Forest virus—mediated tumor complementary DNA

2002 ◽  
Vol 97 (5) ◽  
pp. 1184-1190 ◽  
Author(s):  
Ryuya Yamanaka ◽  
Naoki Yajima ◽  
Naoto Tsuchiya ◽  
Junpei Honma ◽  
Ryuichi Tanaka ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Antitumor Immunity ◽  
Semliki Forest Virus ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
Antitumor Effects ◽  
Content Type ◽  
Immunogene Therapy ◽  
Fine Print

Object. Immunogene therapy for malignant gliomas was further investigated in this study to improve its therapeutic efficacy. Methods. Dendritic cells (DCs) were isolated from bone marrow and pulsed with phosphate-buffered saline or Semliki Forest virus (SFV)—mediated 203 glioma complementary (c)DNA with or without systemic administration of interleukin (IL)-12 and IL-18 to treat mice bearing the 203 glioma. To study the immune mechanisms involved in tumor regression, the authors investigated tumor growth of an implanted 203 glioma model in T cell subset—depleted mice and in interferon (IFN) γ—neutralized mice. To examine the protective immunity produced by tumor inoculation, a repeated challenge of 203 glioma cells was given by injecting the cells into the left thighs of surviving mice and the growth of these cells was monitored. The authors demonstrated that the combined administration of SFV-cDNA, IL-12, and IL-18 produced significant antitumor effects against the growth of murine glioma cells in vivo and also can induce specific antitumor immunity. The synergic effects of the combination of SFV-cDNA, IL-12, and IL-18 in vivo were also observed to coincide with markedly augmented IFNγ production. The antitumor effects of this combined therapy are mediated by CD4+ and CD8+ T cells and by NK cells. These results indicate that the use of IL-18 and IL-12 in DC-based immunotherapy for malignant glioma is beneficial. Conclusions. Immunogene therapy combined with DC therapy, IL-12, and IL-18 may be an excellent candidate in the development of a new treatment protocol. The self-replicating SFV system may therefore provide a novel approach for the treatment of malignant gliomas.

Marked enhancement of antitumor immune responses in mouse brain tumor models by genetically modified dendritic cells producing Semliki Forest virus—mediated interleukin-12

2002 ◽  
Vol 97 (3) ◽  
pp. 611-618 ◽  
Author(s):  
Ryuya Yamanaka ◽  
Susan A. Zullo ◽  
Jay Ramsey ◽  
Naoki Yajima ◽  
Naoto Tsuchiya ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Brain Tumor ◽  
Tumor Antigens ◽  
Semliki Forest Virus ◽  
Tumor Regression ◽  
Interleukin 12 ◽  
Content Type ◽  
Retrovirus Vector ◽  
Induced Apoptosis ◽  
Fine Print

Object. The authors evaluated dendritic cell (DC)—based immunotherapy for malignant brain tumor to improve its therapeutic efficacy. Methods. Dendritic cells were isolated from bone marrow and pulsed with phosphate-buffered saline, Semliki Forest virus (SFV)—LacZ, retrovirus vector GCsap—interleukin (IL)-12, and SFV—IL-12, respectively, to treat mice bearing brain tumors of the B16 cell line. The results indicated that therapeutic immunization with DCs pulsed with SFV—IL-12 prolonged the survival of mice with established tumors. Semliki Forest virus induced apoptosis in DCs, which in turn facilitated the uptake of apoptotic cells by other DCs, thus providing a potential mechanism for enhanced immunogenicity. Conclusions. Therapy with DCs that have been pulsed with SFV-mediated IL-12 may be an excellent step in the development of new cancer vaccines. Intratumorally injected DCs that have been transiently transduced with IL-12 do not require pulsing of a source of tumor antigens to induce tumor regression.

Enhancement of antitumor immune response in glioma models in mice by genetically modified dendritic cells pulsed with Semliki Forest virus—mediated complementary DNA

2001 ◽  
Vol 94 (3) ◽  
pp. 474-481 ◽  
Author(s):  
Ryuya Yamanaka ◽  
Susan A. Zullo ◽  
Ryuichi Tanaka ◽  
Michael Blaese ◽  
Kleanthis G. Xanthopoulos
Keyword(s):  
Dendritic Cells ◽  
Cancer Vaccines ◽  
Semliki Forest Virus ◽  
Glioma Cell Line ◽  
Tumor Lysate ◽  
Tumor Challenge ◽  
Content Type ◽  
Induced Apoptosis ◽  
Phosphate Buffered Saline ◽  
Fine Print

Object. The aim of this study was to further investigate dendritic cell (DC)—based immunotherapy for malignant glioma to improve its therapeutic efficacy. Methods. Dendritic cells were isolated from the bone marrow and pulsed with phosphate-buffered saline, tumor RNA, tumor lysate, Semliki Forest virus (SFV)-LacZ, SFV-mediated B16 complementary (c)DNA, or SFV-mediated 203 glioma cDNA, respectively, to treat mice bearing tumors of the 203 glioma cell line. The results indicated that preimmunization with DCs pulsed with the same type of cDNA as in the tumor by a self-replicating RNA vector (that is, SFV) protected mice from tumor challenge, and that therapeutic immunization prolonged the survival of mice with established tumors. The SFV induced apoptosis in DCs and their death facilitated the uptake of apoptotic cells by other DCs, thus providing a potential mechanism for enhanced immunogenicity. Conclusions. Therapy with DCs that have been pulsed with SFV-mediated tumor cDNA may be an excellent procedure for the development of new cancer vaccines.

scholarly journals Nonspecific CD8+ T Cells and Dendritic Cells/Macrophages Participate in Formation of CD8+ T Cell-Mediated Clusters against Malaria Liver-Stage Infection

2018 ◽  
Vol 86 (4) ◽  
pp. e00717-17 ◽  
Author(s):  
Masoud Akbari ◽  
Kazumi Kimura ◽  
Ganchimeg Bayarsaikhan ◽  
Daisuke Kimura ◽  
Mana Miyakoda ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Protective Immunity ◽  
Cluster Formation ◽  
Dependent Manner ◽  
Liver Stage ◽  
Content Type ◽  
Stage Infection

ABSTRACT CD8+ T cells are the major effector cells that protect against malaria liver-stage infection, forming clusters around Plasmodium-infected hepatocytes and eliminating parasites after a prolonged interaction with these hepatocytes. We aimed to investigate the roles of specific and nonspecific CD8+ T cells in cluster formation and protective immunity. To this end, we used Plasmodium berghei ANKA expressing ovalbumin as well as CD8+ T cells from transgenic mice expressing a T cell receptor specific for ovalbumin (OT-I) and CD8+ T cells specific for an unrelated antigen, respectively. While antigen-specific CD8+ T cells were essential for cluster formation, both antigen-specific and nonspecific CD8+ T cells joined the clusters. However, nonspecific CD8+ T cells did not significantly contribute to protective immunity. In the livers of infected mice, specific CD8+ T cells expressed high levels of CD25, compatible with a local, activated effector phenotype. In vivo imaging of the liver revealed that specific CD8+ T cells interact with CD11c+ cells around infected hepatocytes. The depletion of CD11c+ cells virtually eliminated the clusters in the liver, leading to a significant decrease in protection. These experiments reveal an essential role of hepatic CD11c+ dendritic cells and presumably macrophages in the formation of CD8+ T cell clusters around Plasmodium-infected hepatocytes. Once cluster formation is triggered by parasite-specific CD8+ T cells, specific and unrelated activated CD8+ T cells join the clusters in a chemokine- and dendritic cell-dependent manner. Nonspecific CD8+ T cells seem to play a limited role in protective immunity against Plasmodium parasites.

scholarly journals Acquired Protective Immunity in Atlantic Salmon Salmo salar against the Myxozoan Kudoa thyrsites Involves Induction of MHIIβ+ CD83+ Antigen-Presenting Cells

2017 ◽  
Vol 86 (1) ◽  
Author(s):  
Laura M. Braden ◽  
Karina J. Rasmussen ◽  
Sara L. Purcell ◽  
Lauren Ellis ◽  
Amelia Mahony ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
Atlantic Salmon ◽  
Protective Immunity ◽  
Antigen Presenting Cells ◽  
Content Type ◽  
Exposed Fish ◽  
Kudoa Thyrsites ◽  
Antigen Presenting

ABSTRACTThe histozoic myxozoan parasiteKudoa thyrsitescauses postmortem myoliquefaction and is responsible for economic losses to salmon aquaculture in the Pacific Northwest. Despite its importance, little is known about the host-parasite relationship, including the host response to infection. The present work sought to characterize the immune response in Atlantic salmon during infection, recovery, and reexposure toK. thyrsites. After exposure to infective seawater, infected and uninfected smolts were sampled three times over 4,275 degree-days. Histological analysis revealed infection severity decreased over time in exposed fish, while in controls there was no evidence of infection. Following a secondary exposure of all fish, severity of infection in the controls was similar to that measured in exposed fish at the first sampling time but was significantly reduced in reexposed fish, suggesting the acquisition of protective immunity. Using immunohistochemistry, we detected a population of MHIIβ+cells in infected muscle that followed a pattern of abundance concordant with parasite prevalence. Infiltration of these cells into infected myocytes preceded destruction of the plasmodium and dissemination of myxospores. Dual labeling indicated a majority of these cells were CD83+/MHIIβ+. Using reverse transcription-quantitative PCR, we detected significant induction of cellular effectors, including macrophage/dendritic cells (mhii/cd83/mcsf), B cells (igm/igt), and cytotoxic T cells (cd8/nkl), in the musculature of infected fish. These data support a role for cellular effectors such as antigen-presenting cells (monocyte/macrophage and dendritic cells) along with B and T cells in the acquired protective immune response of Atlantic salmon againstK. thyrsites.

Glioblastoma multiforme at the site of metal splinter injury: a coincidence?

1999 ◽  
Vol 91 (6) ◽  
pp. 1041-1044 ◽  
Author(s):  
Michael Sabel ◽  
Jörg Felsberg ◽  
Martina Messing-Jünger ◽  
Eva Neuen-Jacob ◽  
Jürgen Piek
Keyword(s):  
Brain Tumor ◽  
Glioblastoma Multiforme ◽  
Malignant Glioma ◽  
Causal Relationship ◽  
Propionibacterium Acnes ◽  
Glioma Tissue ◽  
Left Frontal Lobe ◽  
Content Type ◽  
Chronic Abscess ◽  
Fine Print

✓ The authors report the case of a man who had suffered a penetrating metal splinter injury to the left frontal lobe at 18 years of age. Thirty-seven years later the patient developed a left-sided frontal tumor at the precise site of the meningocerebral scar and posttraumatic defect. Histological examination confirmed a glioblastoma multiforme adjacent to the dural scar and metal splinters. In addition, a chronic abscess from which Propionibacterium acnes was isolated was found within the glioma tissue. The temporal and local association of metal splinter injury with chronic abscess, scar formation, and malignant glioma is highly suggestive of a causal relationship between trauma and the development of a malignant brain tumor.

Metastases of glioblastoma multiforme to cervical lymph nodes

1973 ◽  
Vol 38 (5) ◽  
pp. 631-634 ◽  
Author(s):  
Sayed El-Gindi ◽  
Mamdouh Salama ◽  
Mokhtar El-Henawy ◽  
Said Farag
Keyword(s):  
Brain Tumor ◽  
Glioblastoma Multiforme ◽  
Lymph Nodes ◽  
Metastatic Lesion ◽  
Cervical Lymph Nodes ◽  
Content Type ◽  
The Brain ◽  
Fine Print

✓ Two cases of occipital glioblastoma multiforme are reported in which a metastatic lesion involving the cervical lymph nodes on the side of the previous craniotomy was verified during life. This suggests to the authors that the brain tumor metastasized via lymphatic channels.

scholarly journals A Live and Inactivated Chlamydia trachomatis Mouse Pneumonitis Strain Induces the Maturation of Dendritic Cells That Are Phenotypically and Immunologically Distinct

2005 ◽  
Vol 73 (3) ◽  
pp. 1568-1577 ◽  
Author(s):  
Jose Rey-Ladino ◽  
Kasra M. Koochesfahani ◽  
Michelle L. Zaharik ◽  
Caixia Shen ◽  
Robert C. Brunham
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Chlamydia Trachomatis ◽  
Mhc Class Ii ◽  
Protective Immunity ◽  
Ex Vivo ◽  
Natural Infection ◽  
Pulsed Dc ◽  
Low Levels ◽  
Dc Maturation

ABSTRACT The intracellular bacterial pathogen Chlamydia trachomatis is a major cause of sexually transmitted disease worldwide. While protective immunity does appear to develop following natural chlamydial infection in humans, early vaccine trials using heat-killed C. trachomatis resulted in limited and transient protection with possible enhanced disease during follow-up. Thus, immunity following natural infection with live chlamydia may differ from immune responses induced by immunization with inactivated chlamydia. To study this differing immunology, we used murine bone marrow-derived dendritic cells (DC) to examine DC maturation and immune effector function induced by live and UV-irradiated C. trachomatis elementary bodies (live EBs and UV-EB, respectively). DC exposed to live EBs acquired a mature DC morphology; expressed high levels of major histocompatibility complex (MHC) class II, CD80, CD86, CD40, and ICAM-1; produced elevated amounts of interleukin-12 and tumor necrosis factor alpha; and were efficiently recognized by Chlamydia-specific CD4+ T cells. In contrast, UV-EB-pulsed DC expressed low levels of CD40 and CD86 but displayed high levels of MHC class II, ICAM-1, and CD80; secreted low levels of proinflammatory cytokines; and exhibited reduced recognition by Chlamydia-specific CD4+ T cells. Adoptive transfer of live EB-pulsed DC was more effective than that of UV-EB-pulsed DC at protecting mice against challenge with live C. trachomatis. The expression of DC maturation markers and immune protection induced by UV-EB could be significantly enhanced by costimulation of DC ex vivo with UV-EB and oligodeoxynucleotides containing cytosine phosphate guanosine; however, the level of protection was significantly less than that achieved by using DC pulsed ex vivo with viable EBs. Thus, exposure of DC to live EBs results in a mature DC phenotype which is able to promote protective immunity, while exposure to UV-EB generates a semimature DC phenotype with less protective potential. This result may explain in part the differences in protective immunity induced by natural infection and immunization with whole inactivated organisms and is relevant to rational chlamydia vaccine design strategies.

Correlation of the relationships of brain—tumor interfaces, magnetic resonance imaging, and angiographic findings to predict cleavage of meningiomas

1999 ◽  
Vol 91 (3) ◽  
pp. 384-390 ◽  
Author(s):  
Faruk İldan ◽  
Metin Tuna ◽  
Alp İskender Göcer ◽  
Bülent Boyar ◽  
Hüseyin Bağdatoğlu ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
Brain Tumor ◽  
Magnetic Resonance ◽  
Mr Imaging ◽  
Vascular Supply ◽  
Peritumoral Edema ◽  
Resonance Imaging ◽  
Content Type ◽  
Angiographic Findings ◽  
Fine Print

Object. The authors examined the relationships of brain—tumor interfaces, specific magnetic resonance (MR) imaging features, and angiographic findings in meningiomas to predict tumor cleavage and difficulty of resection.Methods. Magnetic resonance imaging studies, angiographic data, operative reports, clinical data, and histopathological findings were examined retrospectively in this series, which included 126 patients with intracranial meningiomas who underwent operations in which microsurgical techniques were used. The authors have identified three kinds of brain—tumor interfaces characterized by various difficulties in microsurgical dissection: smooth type, intermediate type, and invasive type. The signal intensity on T1-weighted MR images was very similar regardless of the type of brain—tumor interface (p > 0.1). However, on T2-weighted images the different interfaces seemed to correlate very precisely with the signal intensity and the amount of peritumoral edema (p < 0.01), allowing the prediction of microsurgical effort required during surgery. On angiographic studies, the pial—cortical arterial supply was seen to participate almost equally with the meningeal—dural arterial supply in vascularizing the tumor in 57.9% of patients. Meningiomas demonstrating hypervascularization on angiography, particularly those fed by the pial—cortical arteries, exhibited significantly more severe edema compared with those supplied only from meningeal arteries (p < 0.01). Indeed, a positive correlation was found between the vascular supply from pial—cortical arteries and the type of cleavage (p < 0.05).Conclusions. In this analysis the authors proved that there is a strong correlation between the amount of peritumoral edema, hyperintensity of the tumor on T2-weighted images, cortical penetration, vascular supply from pial—cortical arteries, and cleavage of the meningioma. Therefore, the consequent difficulty of microsurgical dissection can be predicted preoperatively by analyzing MR imaging and angiographic studies.

scholarly journals Protective Immunity against Experimental Pulmonary Cryptococcosis in T Cell-Depleted Mice

2011 ◽  
Vol 18 (5) ◽  
pp. 717-723 ◽  
Author(s):  
Karen L. Wozniak ◽  
Mattie L. Young ◽  
Floyd L. Wormley
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protective Immunity ◽  
Effector Memory ◽  
Cell Phenotype ◽  
Cell Mediated Immunity ◽  
Wild Type ◽  
Pulmonary Cryptococcosis ◽  
Content Type ◽  
Immunocompetent Mice

ABSTRACTIndividuals with defects in T cell-mediated immunity (CMI) are highly susceptible to infection withCryptococcus neoformans. The purpose of these studies was to determine if protection against experimental pulmonary cryptococcosis can be generated in T cell-deficient hosts. BALB/c mice were depleted of CD4+and/or CD8+T cells or given an isotype control antibody prior to vaccination with aC. neoformansstrain, designated H99γ, previously shown to induce protection againstC. neoformansinfection in immunocompetent mice. Mice depleted of CD4+or CD8+T cells, but not both subsets, survived an acute pulmonary infection withC. neoformansstrain H99γ and a subsequent second challenge with wild-typeC. neoformansstrain H99. We observed a significant increase in the percentage of CD4+and CD8+T cells expressing the activation marker CD69 in the lungs of mice immunized withC. neoformansstrain H99γ prior to a secondary challenge with wild-type cryptococci. CD4+T cells within the lungs of immunized mice also appeared to acquire a predominantly activated effector memory cell phenotype (CD69+CD44+CCR7−CD45RB−CD62L−) following a second pulmonary challenge with wild-typeC. neoformans, compared to CD4+T cells from naïve mice. Lastly, immunization of immunocompetent mice withC. neoformansstrain H99γ prior to depletion of CD4+and/or CD8+T cells resulted in significant protection against a second challenge with wild-typeC. neoformans. Our studies demonstrate that protective immunity against pulmonary cryptococcosis can be generated in immunosuppressed hosts, thus supporting the development of cryptococcal vaccines.

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