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  • The American Association of Immunologists  (4)
  • Lehman, Amy  (4)
  • 1
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    Therapeutic treatment of multi-organ system, obstructive pulmonary and scleradermatous chronic graft-versus-host disease with the BTK and ITK inhibitor Ibrutinib (TRAN3P.873)
    The American Association of Immunologists ; 2014
    In:  The Journal of Immunology Vol. 192, No. 1_Supplement ( 2014-05-01), p. 202.12-202.12
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 192, No. 1_Supplement ( 2014-05-01), p. 202.12-202.12
    Abstract: Chronic GVHD (cGVHD) is dependent on the ability of donor bone marrow (BM) B cells to produce pathogenic antibody (Ab) deposited in target organs, which is associated with increased germinal centers (GCs). BTK is necessary for B cells to enter GCs and ITK is necessary for T cell activation. We hypothesized that alloreactive GC B cells and T follicular helper cells require BTK or ITK and inhibition by ibrutinib (Ib) would prevent cGVHD. We evaluated the therapeutic effect of Ib in two models of cGVHD: a MHC-disparate (B6→B10.BR) multi-organ model complicated by bronchiolitis obliterans (BO) and a sclerodermatous (SCL) minor-mismatch (LP/J→B6) model. Mice treated with Ib had a decrease in pathogenic Ab, collagen deposition and GC B cells in target organs similar to healthy control mice. In contrast to cGVHD mice, pulmonary function in Ib treated mice was similar to control mice. To confirm that BTK and ITK are required for cGVHD we used donor mice with an ablation of BTK or ITK. Absence of BTK in B cells impeded GCs, Ab deposition and BO. Mice transplanted with T cells lacking ITK and WT BM did not develop BO. In the SCL model, mice treated with Ib did not develop clinical signs of cGVHD including less alopecia and SCL lesions. Furthermore, there was a decrease in lymphocyte infiltration surrounding the bronchioles and nephrons in treated mice. The inhibition of TEC-family kinases with Ib is a novel therapeutic for multi-organ system cGVHD with BO or SCL manifestations.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.192.Supp.202.12
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2014
    detail.hit.zdb_id: 1475085-5
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  • 2
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    IL-12 Enhances the Antitumor Actions of Trastuzumab via NK Cell IFN-γ Production
    The American Association of Immunologists ; 2011
    In:  The Journal of Immunology Vol. 186, No. 6 ( 2011-03-15), p. 3401-3409
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 186, No. 6 ( 2011-03-15), p. 3401-3409
    Abstract: The antitumor effects of therapeutic mAbs may depend on immune effector cells that express FcRs for IgG. IL-12 is a cytokine that stimulates IFN-γ production from NK cells and T cells. We hypothesized that coadministration of IL-12 with a murine anti-HER2/neu mAb (4D5) would enhance the FcR-dependent immune mechanisms that contribute to its antitumor activity. Thrice-weekly therapy with IL-12 (1 μg) and 4D5 (1 mg/kg) significantly suppressed the growth of a murine colon adenocarcinoma that was engineered to express human HER2 (CT-26HER2/neu) in BALB/c mice compared with the result of therapy with IL-12, 4D5, or PBS alone. Combination therapy was associated with increased circulating levels of IFN-γ, monokine induced by IFN-γ, and RANTES. Experiments with IFN-γ–deficient mice demonstrated that this cytokine was necessary for the observed antitumor effects of therapy with IL-12 plus 4D5. Immune cell depletion experiments showed that NK cells (but not CD4+ or CD8+ T cells) mediated the antitumor effects of this treatment combination. Therapy of HER2/neu-positive tumors with trastuzumab plus IL-12 induced tumor necrosis but did not affect tumor proliferation, apoptosis, vascularity, or lymphocyte infiltration. In vitro experiments with CT-26HER2/neu tumor cells revealed that IFN-γ induced an intracellular signal but did not inhibit cellular proliferation or induce apoptosis. Taken together, these data suggest that tumor regression in response to trastuzumab plus IL-12 is mediated through NK cell IFN-γ production and provide a rationale for the coadministration of NK cell-activating cytokines with therapeutic mAbs.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1000328
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2011
    detail.hit.zdb_id: 1475085-5
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  • 3
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    Interleukin-21 Enhances NK Cell Activation in Response to Antibody-Coated Targets
    The American Association of Immunologists ; 2006
    In:  The Journal of Immunology Vol. 177, No. 1 ( 2006-07-01), p. 120-129
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 177, No. 1 ( 2006-07-01), p. 120-129
    Abstract: NK cells express an activating FcR (FcγRIIIa) that mediates Ab-dependent cellular cytotoxicity and the production of immune modulatory cytokines in response to Ab-coated targets. IL-21 has antitumor activity in murine models that depends in part on its ability to promote NK cell cytotoxicity and IFN-γ secretion. We hypothesized that the NK cell response to FcR stimulation would be enhanced by the administration of IL-21. Human NK cells cultured with IL-21 and immobilized IgG or human breast cancer cells coated with a therapeutic mAb (trastuzumab) secreted large amounts of IFN-γ. Increased secretion of TNF-α and the chemokines IL-8, MIP-1α, and RANTES was also observed under these conditions. NK cell IFN-γ production was dependent on distinct signals mediated by the IL-21R and the FcR and was abrogated in STAT1-deficient NK cells. Supernatants derived from NK cells that had been stimulated with IL-21 and mAb-coated breast cancer cells were able to drive the migration of naive and activated T cells in an in vitro chemotaxis assay. IL-21 also enhanced NK cell lytic activity against Ab-coated tumor cells. Coadministration of IL-21 and Ab-coated tumor cells to immunocompetent mice led to synergistic production of IFN-γ by NK cells. Furthermore, the administration of IL-21 augmented the effects of an anti-HER2/neu mAb in a murine tumor model, an effect that required IFN-γ. These findings demonstrate that IL-21 significantly enhances the NK cell response to Ab-coated targets and suggest that IL-21 would be an effective adjuvant to administer in combination with therapeutic mAbs.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.177.1.120
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2006
    detail.hit.zdb_id: 1475085-5
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  • 4
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    IFN-α-Induced Signal Transduction, Gene Expression, and Antitumor Activity of Immune Effector Cells Are Negatively Regulated by Suppressor of Cytokine Signaling Proteins
    The American Association of Immunologists ; 2007
    In:  The Journal of Immunology Vol. 178, No. 8 ( 2007-04-15), p. 4832-4845
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 178, No. 8 ( 2007-04-15), p. 4832-4845
    Abstract: Proteins belonging to the suppressors of cytokine signaling (SOCS) family have been shown to regulate cytokine signal transduction in various cell types but their role in modulating the response of immune cells to IFN-α has not been fully explored. We hypothesized that SOCS proteins would inhibit the antitumor activity of IFN-α-stimulated immune cells. Transcripts for SOCS1, SOCS2, SOCS3, and cytokine-inducible Src homology 2-containing protein were identified in total human PBMC (PBMCs, NK cells, and T cells) within 1–2 h of stimulation with IFN-α (103–105 U/ml). Immunoblot analysis confirmed the expression of these factors at the protein level. Transcripts for SOCS proteins were rapidly but variably induced in PBMCs from patients with metastatic melanoma following the i.v. administration of IFN-α-2b (20 million units/m2). Overexpression of SOCS1 and SOCS3, but not SOCS2, in the Jurkat T cell line inhibited IFN-α-induced phosphorylated STAT1 and the transcription of IFN-stimulated genes. Conversely, small inhibitory RNA-mediated down-regulation of SOCS1 and SOCS3 in Jurkat cells and normal T cells enhanced the transcriptional response to IFN-α. Loss of SOCS1 or SOCS3 in murine immune effectors was associated with enhanced IFN-induced phosphorylated STAT1, transcription of IFN-stimulated genes, and antitumor activity. Of note, IFN-α treatment eliminated melanoma tumors in 70% of SOCS1-deficient mice, whereas IFN-treated SOCS-competent mice all died. The antitumor effects of IFN-α in tumor-bearing SOCS1-deficient mice were markedly inhibited following depletion of CD8+ T cells. These results indicate that the antitumor response of immune effector cells to exogenous IFN-α is regulated by SOCS proteins.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.178.8.4832
    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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