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  • The American Association of Immunologists  (8)
  • 1
    Online Resource
    Online Resource
    Induction of Antitumor Immune Response by Homeostatic Proliferation and CD28 Signaling
    The American Association of Immunologists ; 2008
    In:  The Journal of Immunology Vol. 180, No. 7 ( 2008-04-01), p. 4596-4605
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 180, No. 7 ( 2008-04-01), p. 4596-4605
    Abstract: Inducing lymphopenia before adoptive cell transfer can improve the antitumor effect of donor immune cells. It was recently reported that lymphopenic conditions can initiate the differentiation of naive T cells into effector cells. Although T cells require a specific “strong” signal via TCR as well as costimulatory signals during Ag-driven differentiation, there has been little evidence to suggest any requirement for costimulatory signaling for the differentiation of naive T cells in a lymphopenic host. In this study, we demonstrate that naive CD8+ T cells are indispensable for induction of antitumor effect, and, in addition to Ag-driven differentiation, CD28 signaling is essential for the differentiation of naive CD8+ T cells into functional effector CTLs during homeostatic proliferation (HP). The systemic administration of IL-2 did not restore the antitumor effect induced by HP in the absence of CD28 signaling. These results suggest that homeostatic cytokines enable CD8+ T cells to expand and survive, and that TCR and the CD28 signal initiate the differentiation of effector functions. A deeper understanding of the mechanisms underlying enhanced induction of the antitumor immune response with accompanying HP may allow us to more precisely induce enhanced immunity with costimulation signaling and the administration of common γ-chain cytokines.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.180.7.4596
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2008
    detail.hit.zdb_id: 1475085-5
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  • 2
    Online Resource
    Online Resource
    Systemic Administration of IL-23 Induces Potent Antitumor Immunity Primarily Mediated through Th1-Type Response in Association with the Endogenously Expressed IL-12
    The American Association of Immunologists ; 2007
    In:  The Journal of Immunology Vol. 178, No. 12 ( 2007-06-15), p. 7571-7580
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 178, No. 12 ( 2007-06-15), p. 7571-7580
    Abstract: IL-23, a cytokine, which is composed of the p40 subunit shared with IL-12 and the IL-23-specific p19 subunit, has been shown to preferentially act on Th1 effector/memory CD4+ T cells and to induce their proliferation and IFN-γ production. The IL-23 is also reported to act on Th17-CD4+ T cells, which are involved in inducing tissue injury. In this study, we examined the antitumor effects associated with systemic administration of IL-23 and their mechanisms in mouse tumor system. Systemic administration of high-dose IL-23 was achieved using in vivo electroporation of IL-23 plasmid DNA into the pretibial muscles of C57BL/6 mice. The IL-23 treatment was associated with significant suppression of the growth of pre-existing MCA205 fibrosarcoma and prolongation of the survival of treated mice without significant toxicity when compared with those of the mice treated with EGFP. Although the therapeutic outcomes were similar to those with the IL-12 treatment, the IL-23 treatment induced characteristic immune responses distinctive to those of IL-12 treatment. The IL-23 administration even at the therapeutic levels did not induce detectable IFN-γ concentration in the serum. In vivo depletion of CD4+ T cells, CD8+ T cells, or NK cells significantly inhibited the antitumor effects of IL-23. Furthermore, the CD4+ T cells in the lymph nodes in the IL-23-treated mice showed significant IFN-γ and IL-17 response upon anti-CD3 mAb stimulation in vitro. These results and the ones in the IFN-γ or IL-12 gene knockout mice suggest that potent antitumor effects of IL-23 treatment could be achieved when the Th1-type response is fully promoted in the presence of endogenously expressed IL-12.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.178.12.7571
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2007
    detail.hit.zdb_id: 1475085-5
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  • 3
    Online Resource
    Online Resource
    Differential Antitumor Effects of Administration of Recombinant IL-18 or Recombinant IL-12 Are Mediated Primarily by Fas-Fas Ligand- and Perforin-Induced Tumor Apoptosis, Respectively
    The American Association of Immunologists ; 1999
    In:  The Journal of Immunology Vol. 163, No. 2 ( 1999-07-15), p. 583-589
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 163, No. 2 ( 1999-07-15), p. 583-589
    Abstract: Systemic administration of rIL-18 protein to mice significantly suppresses the growth of murine tumor cell lines. The antitumor effect of IL-18 appears to be primarily mediated by asialo GM1+ cells. Since IL-18 enhances Fas ligand (FasL) expression on NK cell lines, the IL-18 antitumor effects could be mediated by FasL-induced cross-linking of Fas and subsequent tumor apoptosis. To address this question, rIL-18 or rIL-12 was administered to animals bearing the CL8-1 melanoma inoculated intradermally into wild type (wt), lymphoproliferation gene (lpr) (Fas deficient), or generalized lymphoproliferative disease gene (gld) (FasL deficient) mice. Although rIL-12 treatment retained significant antitumor effects in gld and lpr mice, those of rIL-18 administration were completely abrogated in gld but not lpr or wt mice. In vitro cytotoxicity was significantly enhanced against NK-sensitive YAC-1 cells and CL8-1 cells by rIL-18 administration to wt mice, but not to gld mice. Furthermore, rIL-18 administration augmented the cytotoxicity of liver lymphocytes harvested from perforin-deficient mice, whereas rIL-12 administration did not. Consistent with the role of this pathway, rIL-18 administration also up-regulates the expression of FasL mRNA in splenocytes. Lysis of CL8-1 cells induced by anti-Fas agonistic Ab was enhanced about 1.4-fold by IFN-γ, a cytokine that is induced by IL-18 in vitro and in vivo. We conclude that the antitumor effect of IL-18 is exerted predominantly through a Fas-dependent pathway. The perforin pathway, however, appears to be the predominant cytolytic pathway mediating IL-12 antitumor effects.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.163.2.583
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 1999
    detail.hit.zdb_id: 1475085-5
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  • 4
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    Online Resource
    Mammalian and Viral IL-10 Enhance C-C Chemokine Receptor 5 but Down-Regulate C-C Chemokine Receptor 7 Expression by Myeloid Dendritic Cells: Impact on Chemotactic Responses and In Vivo Homing Ability
    The American Association of Immunologists ; 2001
    In:  The Journal of Immunology Vol. 166, No. 12 ( 2001-06-15), p. 7136-7143
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 166, No. 12 ( 2001-06-15), p. 7136-7143
    Abstract: The immunosuppressive and anti-inflammatory cytokine IL-10 inhibits the phenotypic and functional maturation of dendritic cells (DC) and has been reported to confer tolerogenic properties on these important professional APC. Here, we exposed murine bone marrow-derived myeloid DC to either mouse (m) or viral (v) IL-10 early during their in vitro generation in response to GM-CSF and IL-4. Both mIL-10 and vIL-10 down-regulated the expression of CCR7 mRNA determined by RT-PCR, while mIL-10 up-regulated the expression of CCR5 transcripts. These changes in CCR7 and CCR5 expression were associated with inhibition and augmentation, respectively, of DC chemotaxis toward their respective agonists, macrophage inflammatory proteins 3β and 1α, while in vivo homing of DC from peripheral s.c. sites to secondary lymphoid tissue of syngeneic or allogeneic recipients was significantly impaired. Anti-mIL-10R mAb reversed the effects of mIL-10 on CCR expression and restored DC homing ability. Retroviral transduction of mIL-10- and vIL-10-treated DC to overexpress transgenic CCR7 partially restored the cells’ lymphoid tissue homing ability in allogeneic recipients. However, CCR7 gene transfer did not reinstate the capacity of IL-10-treated DC to prime host naive T cells for ex vivo proliferative responses or Th1 cytokine (IFN-γ) production in response to rechallenge with (donor) alloantigen. These findings suggest that in addition to their capacity to subvert DC maturation/function and confer tolerogenic potential on these cells, mIL-10 and vIL-10 regulate DC migratory responses via modulation of CCR expression.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.166.12.7136
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2001
    detail.hit.zdb_id: 1475085-5
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  • 5
    Online Resource
    Online Resource
    Complement Activation Plays a Key Role in Antibody-Induced Infusion Toxicity in Monkeys and Rats
    The American Association of Immunologists ; 2008
    In:  The Journal of Immunology Vol. 180, No. 4 ( 2008-02-15), p. 2294-2298
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 180, No. 4 ( 2008-02-15), p. 2294-2298
    Abstract: Infusion reactions are a major side effect of the administration of therapeutic Abs and are the result of a complex immune reaction. In this study, we report that substitutions of Fc amino acids in the anti-HLA-DR Ab HD8 reduce its ability to induce infusion reactions in rats and monkeys. We first showed that i.v. administration of IgG1- and IgG2-subclass HD8 Abs induces severe infusion reactions in monkeys. These Abs express strong complement-dependent cytotoxicity (CDC), and in vivo depletion of complement in rats by pretreatment with cobra venom factor abrogated the lethal infusion reactions generated by HD8-IgG1. Thus, the infusion reactions appear to be largely driven by the complement system. To reduce the CDC function of HD8-IgG1, its Fc region was modified by two amino acid substitutions at Pro331Ser and Lys322Ala. The modified Ab was incapable of expressing CDC in vitro and did not induce severe infusion reactions in rats and monkeys, even at extremely high doses. The modified Ab retained its Ab-dependent cellular cytotoxicity function as well as its antitumor activity in a tumor-bearing mouse model. In summary, complement appears to drive infusion reactions, and modifications that eliminate the CDC activity of an Ab also reduce its ability to induce infusion reactions.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.180.4.2294
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2008
    detail.hit.zdb_id: 1475085-5
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  • 6
    Online Resource
    Online Resource
    IFN-γ-Inducing Factor/IL-18 Administration Mediates IFN-γ- and IL-12-Independent Antitumor Effects
    The American Association of Immunologists ; 1998
    In:  The Journal of Immunology Vol. 160, No. 4 ( 1998-02-15), p. 1742-1749
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 160, No. 4 ( 1998-02-15), p. 1742-1749
    Abstract: We evaluated the mechanism of the antitumor effects of mouse rIFN-γ-inducing factor/IL-18 protein on the growth of mouse tumor cell lines in vivo. Mice received IL-18 before or after challenge with CL8-1, a mouse melanoma cell line. Both regimens significantly suppressed tumor growth and reduced the number of mice with growth of tumor from 60% (3/5) to 20% (1/5). Furthermore, IL-18 administered before and after tumor inoculation completely abrogated the establishment of CL8-1 in all animals. IL-18 administration also significantly suppressed the growth of MCA205, a sarcoma cell line, even when treatment was delayed to 7 days following tumor inoculation. Although IL-18/IL-12 combination therapy had the most significant and immediate antitumor effects, many mice so treated succumbed with markedly elevated serum IFN-γ levels. The antitumor effects of IL-18 were abrogated almost completely when NK cells were eliminated using anti-asialo GM1 Ab administration, but only marginally impaired in IFN-γ or IL-12 gene-disrupted mice. Immunohistochemical staining revealed that the number of the CD8+ T cells, but not CD4+ T cells, found at the tumor site was reduced in animals treated with IL-18. These results indicate that IL-18 has potent antitumor effects mediated by CD4+ T cells and NK cells, but in IFN-γ- and IL-12-independent pathways.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.160.4.1742
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 1998
    detail.hit.zdb_id: 1475085-5
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  • 7
    Online Resource
    Online Resource
    Viral IL-10-Induced Immunosuppression Requires Th2 Cytokines and Impairs APC Function Within the Allograft
    The American Association of Immunologists ; 2001
    In:  The Journal of Immunology Vol. 166, No. 4 ( 2001-02-15), p. 2385-2393
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 166, No. 4 ( 2001-02-15), p. 2385-2393
    Abstract: Previous reports demonstrated that retroviral mediated gene transfer of viral IL-10 (vIL-10) prolongs allograft survival by decreasing donor-specific cytotoxic T lymphocyte precursor (CTLp) and IL-2-secreting helper T lymphocyte precursor (HTLp) frequency within graft-infiltrating cells (GIC). This report now shows that vIL-10 efficacy is dependent on CD4+ T cells, suggesting that immunosuppression may involve a switch from a Th1 to a Th2 alloresponse. In support of this, anti-IL-4 or anti-murine IL-10 (anti-mIL-10) mAbs, but not anti-IFN-γ mAb, administered at the time of vIL-10 gene transfer prevents enhanced graft survival. Because Th switching involves APC function, GIC were examined for their ability to present alloantigen. GIC from vIL-10-treated grafts were shown to be mostly of recipient (CBA) origin, yet were unable to elicit alloproliferative responses from donor type (C57BL/6) or third party (BALB/c) responders. The inability of vIL-10-treated GIC to stimulate the MLR was not due to the generation of negative regulatory cells or the production of immunosuppressive cytokines such as IL-4, mIL-10, or TGFβ. Using fractionated GIC subpopulations, the number of recipient type cells in the allografts was modestly reduced by vIL-10 gene transfer, while maintaining both APC phenotype and alloantigen presenting function. Conversely, after vIL-10 gene transfer, donor type GIC were unable to participate in direct alloantigen presentation. Therefore, local immunosuppression induced by vIL-10 gene transfer is CD4 T cell and IL-4 and mIL-10 dependent, and impairs direct alloantigen presentation through an alteration of donor type APC function.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.166.4.2385
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2001
    detail.hit.zdb_id: 1475085-5
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  • 8
    Online Resource
    Online Resource
    Systemic Administration of IL-18 Promotes Diabetes Development in Young Nonobese Diabetic Mice
    The American Association of Immunologists ; 2003
    In:  The Journal of Immunology Vol. 171, No. 11 ( 2003-12-01), p. 5865-5875
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 171, No. 11 ( 2003-12-01), p. 5865-5875
    Abstract: IL-18 is now identified as a pleiotropic cytokine that acts as a cofactor for both Th1 and Th2 cell development. Type 1 diabetes is considered a Th1-type autoimmune disease, and to date, the suppressive effect of exogenous IL-18 on the development of diabetes has been reported in 10-wk-old nonobese diabetic (NOD) mice. In the present study we administered exogenous IL-18 systemically in 4-wk-old NOD mice using i.m. injection of the IL-18 expression plasmid DNA (pCAGGS-IL-18) with electroporation. Contrary to previous reports, the incidence of diabetes development was significantly increased in NOD mice injected with pCAGGS-IL-18 compared with that in control mice. Systemic and pancreatic cytokine profiles deviated to a Th1-dominant state, and the the frequency of glutamic acid decarboxylase-reactive IFN-γ-producing CD4+ cells was also high in the IL-18 group. Moreover, it was suggested that the promoting effect of IL-18 might be associated with increased peripheral IL-12, CD86, and pancreatic IFN-inducible protein-10 mRNA expression levels. In conclusion, we demonstrate here that IL-18 plays a promoting role as an enhancer of Th1-type immune responses in diabetes development early in the spontaneous disease process, which may contribute to elucidating the pathogenesis of type 1 diabetes.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.171.11.5865
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2003
    detail.hit.zdb_id: 1475085-5
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