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  • The American Association of Immunologists  (6)
  • 1
    Online Resource
    Online Resource
    CD4 T Cells Play Major Effector Role and CD8 T Cells Initiating Role in Spontaneous Autoimmune Myocarditis of HLA-DQ8 Transgenic IAb Knockout Nonobese Diabetic Mice
    The American Association of Immunologists ; 2006
    In:  The Journal of Immunology Vol. 176, No. 12 ( 2006-06-15), p. 7715-7725
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 176, No. 12 ( 2006-06-15), p. 7715-7725
    Abstract: In humans, spontaneous autoimmune attack against cardiomyocytes often leads to idiopathic dilated cardiomyopathy (IDCM) and life-threatening heart failure. HLA-DQ8 transgenic IAb knockout NOD mice (NOD.DQ8/Ab0; DQA1*0301, DQB1*0302) develop spontaneous anticardiomyocyte autoimmunity with pathology very similar to human IDCM, but why the heart is targeted is unknown. In the present study, we first investigated whether NOD/Ab0 mice transgenic for a different DQ allele, DQ6, (DQA1*0102, DQB1*0602) would also develop myocarditis. NOD.DQ6/Ab0 animals showed no cardiac pathology, implying that DQ8 is specifically required for the myocarditis phenotype. To further characterize the cellular immune mechanisms, we established crosses of our NOD.DQ8/Ab0 animals with Rag1 knockout (Rag10), Ig H chain knockout (IgH0), and β2-microglobulin knockout (β2m0) lines. Adoptive transfer of purified CD4 T cells from NOD.DQ8/Ab0 mice with complete heart block (an indication of advanced myocarditis) into younger NOD.DQ8/Ab0 Rag10 animals induced cardiac pathology in all recipients, whereas adoptive transfer of purified CD8 T cells or B lymphocytes had no effect. Despite the absence of B lymphocytes, NOD.DQ8/Ab0IgH0 animals still developed complete heart block, whereas NOD.DQ8/Ab0β2m0 mice (which lack CD8 T cells) failed to develop any cardiac pathology. CD8 T cells (and possibly NK cells) seem to be necessary to initiate disease, whereas once initiated, CD4 T cells alone can orchestrate the cardiac pathology, likely through their capacity to recruit and activate macrophages. Understanding the cellular immune mechanisms causing spontaneous myocarditis/IDCM in this relevant animal model will facilitate the development and testing of new therapies for this devastating disease.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.176.12.7715
    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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  • 2
    Online Resource
    Online Resource
    Absence of IFN-γ or IL-12 Has Different Effects on Experimental Myasthenia Gravis in C57BL/6 Mice
    The American Association of Immunologists ; 2000
    In:  The Journal of Immunology Vol. 164, No. 10 ( 2000-05-15), p. 5236-5244
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 164, No. 10 ( 2000-05-15), p. 5236-5244
    Abstract: Immunization with acetylcholine receptor (AChR) causes experimental myasthenia gravis (EMG). Th1 cells facilitate EMG development. IFN-γ and IL-12 induce Th1 responses: we investigated whether these cytokines are necessary for EMG development. We immunized wild-type (WT) C57BL/6 mice and IFN-γ and IL-12 knockout mutants (IFN-γ−/−, IL-12−/−) with Torpedo AChR (TAChR). WT and IFN-γ−/− mice developed EMG with similar frequency, IL-12−/−mice were resistant to EMG. All strains synthesized anti-AChR Ab that were not IgM or IgE. WT mice had anti-AChR IgG1, IgG2b, and IgG2c, IFN-γ−/− mice had significantly less IgG2c, and IL-12−/− mice less IgG2b and IgG2c. All mice had IgG bound to muscle synapses, but only WT and IFN-γ−/− mice had complement; WT mice had both IgG2b and IgG2c, IFN-γ−/− only IgG2b, and IL-12−/− neither IgG2b nor IgG2c. CD4+ cells from all AChR-immunized mice proliferated in response to AChR and recognized similar epitopes. After stimulation with TAChR, CD4+ cells from IFN-γ−/− mice secreted less IL-2 and similar amounts of IL-4 and IL-10 as WT mice. CD4+ cells from IL-12−/− mice secreted less IFN-γ, but more IL-4 and IL-10 than WT mice, suggesting that they developed a stronger Th2 response to TAChR. The EMG resistance of IL-12−/− mice is likely due to both reduction of anti-TAChR Ab that bind complement and sensitization of modulatory Th2 cells. The reduced Th1 function of IFN-γ−/− mice does not suffice to reduce all complement-fixing IgG subclasses, perhaps because as in WT mice a protective Th2 response is missing.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.164.10.5236
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2000
    detail.hit.zdb_id: 1475085-5
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  • 3
    Online Resource
    Online Resource
    Transgenic Expression of IL-10 in T Cells Facilitates Development of Experimental Myasthenia Gravis
    The American Association of Immunologists ; 2001
    In:  The Journal of Immunology Vol. 166, No. 8 ( 2001-04-15), p. 4853-4862
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 166, No. 8 ( 2001-04-15), p. 4853-4862
    Abstract: Ab to the acetylcholine receptor (AChR) cause experimental myasthenia gravis (EMG). Th1 cytokines facilitate EMG, whereas Th2 cytokines might be protective. IL-10 inhibits Th1 responses but facilitates B cell proliferation and Ig production. We examined the role of IL-10 in EMG by using wild-type (WT) C57BL/6 mice and transgenic (TG) C57BL/6 mice that express IL-10 under control of the IL-2 promoter. We immunized the mice with doses of AChR that cause EMG in WT mice or with low doses ineffective at causing EMG in WT mice. After low-dose AChR immunization, WT mice did not develop EMG and had very little anti-AChR serum Ab, which were mainly IgG1, whereas TG mice developed EMG and had higher levels of anti-AChR serum Ab, which were mainly IgG2, in addition to IgG1. At the higher doses, TG mice developed EMG earlier and more frequently than WT mice and had more serum anti-AChR Ab. Both strains had similar relative serum concentrations of anti-AChR IgG subclasses and IgG and complement at the muscle synapses. CD8+-depleted splenocytes from all AChR-immunized mice proliferated in the presence of AChR and recognized a similar epitope repertoire. CD8+-depleted splenocytes from AChR-immunized TG mice stimulated in vitro with AChR secreted significantly more IL-10, but less of the prototypic Th1 cytokine IFN-γ, than those from WT mice. They secreted comparable amounts of IL-4 and slightly but not significantly reduced amounts of IL-2. This suggests that TG mice had reduced activation of anti-Torpedo AChR Th1 cells, but increased anti-AChR Ab synthesis, that likely resulted from IL-10-mediated stimulation of anti-AChR B cells. Thus, EMG development is not strictly dependent on Th1 cell activity.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.166.8.4853
    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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  • 4
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    Online Resource
    Cloning and Characterization of the Guinea Pig Eosinophil Eotaxin Receptor, C-C Chemokine Receptor-3: Blockade Using a Monoclonal Antibody In Vivo
    The American Association of Immunologists ; 1998
    In:  The Journal of Immunology Vol. 161, No. 11 ( 1998-12-01), p. 6139-6147
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 161, No. 11 ( 1998-12-01), p. 6139-6147
    Abstract: Certain C-C chemokines, signaling via the eotaxin receptor C-C chemokine receptor-3 (CCR3), are thought to be central mediators of eosinophil accumulation in allergic inflammation. To investigate the role of CCR3 in vivo, we cloned the guinea pig eotaxin receptor (guinea pig CCR3) from a genomic DNA library. We isolated a single-exon open reading frame coding for a 358-amino acid chemokine receptor protein with 67 and 69% homology to human and murine CCR3, respectively. When expressed in stable transfectants, this receptor bound 125I-labeled guinea pig eotaxin, 125I-labeled human monocyte chemotactic protein-3, and 125I-labeled human RANTES. In chemotaxis assays, guinea pig CCR3 transfectants responded only to guinea pig eotaxin, with a maximal effect at 100 nM. mAbs were raised that bound selectively to both guinea pig CCR3 transfectants and guinea pig eosinophils. One of these mAbs, 2A8, blocked both ligand binding to transfectants and their chemotaxis in response to eotaxin. The Ab also inhibited chemotaxis and the elevation of cytosolic calcium in guinea pig eosinophils in response to eotaxin. F(ab′)2 fragments of 2A8 were prepared that retained the ability to inhibit eosinophil calcium responses to eotaxin. Pretreatment of 111In-labeled eosinophils in vitro with F(ab′)2 2A8 selectively inhibited their accumulation in response to eotaxin in vivo. These data demonstrate that functional blockade of eosinophil chemokine receptors can be achieved in vivo and provide further support for the development of novel anti-inflammatory drugs targeting eosinophil recruitment through chemokine receptor antagonism.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.161.11.6139
    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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  • 5
    Online Resource
    Online Resource
    CD73 protects Treg and ILC in the control of Th cell mediated colitis (IRC5P.632)
    The American Association of Immunologists ; 2015
    In:  The Journal of Immunology Vol. 194, No. 1_Supplement ( 2015-05-01), p. 58.15-58.15
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 194, No. 1_Supplement ( 2015-05-01), p. 58.15-58.15
    Abstract: CD73 is a membrane-bound enzyme catalyzing the final step of the conversion of extracellular ATP to adenosine, which then binds to its receptors and signals via cAMP and non-cAMP-mediated pathways. While CD45RBlow helper T cells from wild-type and CD73 KO mice were both highly enriched in the FoxP3+ regulatory T cell transcription factor, cells from CD73 KO mice produced more IFN-γ and IL-17A and could not inhibit effector T cell proliferation and function in vitro. In vivo CD73 expression by both regulatory (CD45RBlow) and effector (CD45RBhigh) T cells was required for Treg to prevent effector T cell-induced colitis following adoptive transfer into immunodeficient Rag1 KO recipients. The cytokine profile in the intestine was skewed compared to the protective combination of wild-type CD45RBlow and wild-type CD45RBhigh. Donor CD45RBlow recovered from colitic mice had reduced FoxP3 and CD45RBhigh phenotype shifted from Th17 to Th1. If recipients lacked both Rag1 and CD73, wild-type CD45RBlow Th cells did not protect from T cell-induced colitis. CD45RBlow Th cells lost FoxP3, acquired Th1 and Th17 transcription factors, depleted recipient’s innate lymphoid cells and caused disease. Prior adoptive transfer of innate lymphoid cells protected these recipients from disease and maintained FoxP3 expression on cells of the CD45RBlow pool. Thus, CD73 on cells of both adaptive and innate immunity is required for effective regulatory T cell function in intestinal homeostasis.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.194.Supp.58.15
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2015
    detail.hit.zdb_id: 1475085-5
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  • 6
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    Online Resource
    A Critical Role for C5L2 in the Pathogenesis of Experimental Allergic Asthma
    The American Association of Immunologists ; 2010
    In:  The Journal of Immunology Vol. 185, No. 11 ( 2010-12-01), p. 6741-6752
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 185, No. 11 ( 2010-12-01), p. 6741-6752
    Abstract: The complement fragment C5a plays dual roles in the development of experimental allergic asthma. It protects from pulmonary allergy by a regulatory effect on dendritic cells during allergen sensitization, but is proallergic during the effector phase. C5a can bind to two distinct receptors (i.e., C5a receptor and C5a receptor-like 2 [C5L2]). The functional role of C5L2 in vivo remains enigmatic. In this study, we show in two models of OVA- and house dust mite (HDM)-induced experimental allergic asthma that C5L2-deficient mice are protected from the development of airway hyperresponsiveness, Th2 cytokine production, eosinophilic airway inflammation, serum IgE, or mucus production. Surprisingly, HDM-induced experimental asthma in C5L2-deficient mice was associated with increased pulmonary IL-17A production and increased airway neutrophil numbers. To directly assess the role of C5L2 on myeloid dendritic cells (mDCs) during allergen sensitization, we performed single or repeated adoptive transfers of C5L2-deficient mDCs into wild-type mice. HDM-pulsed C5L2-deficient mDCs induced strong Th2 cytokine production, which was associated with marked IFN-γ and IL-17A production, decreased eosinophil numbers, and reduced IgE production as compared with HDM-pulsed mDCs from wild-type mice. HDM stimulation of C5L2−/− mDCs in vitro resulted in production of Th17-promoting cytokine IL-23, which was absent in wild-type mDCs. Our findings suggest that C5L2 acts at the mDC/T cell interface to control the development of Th1 and Th17 cells in response to airway HDM exposure. Furthermore, it drives Th2 immune responses independent of mDCs, suggesting a complex role for C5L2 in the development of experimental allergic asthma.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1000892
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2010
    detail.hit.zdb_id: 1475085-5
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