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1.
J Clin Invest ; 120(6): 2218-29, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20458139

ABSTRACT

IgE-mediated hypersensitivity is central to the pathogenesis of asthma and other allergic diseases. Although neutralization of serum IgE with IgE-specific antibodies is in general an efficacious treatment for allergic asthma, one limitation of this approach is its lack of effect on IgE production. Here, we have developed a strategy to disrupt IgE production by generating monoclonal antibodies that target a segment of membrane IgE on human IgE-switched B cells that is not present in serum IgE. This segment is known as the M1' domain, and using genetically modified mice that contain the human M1' domain inserted into the mouse IgE locus, we demonstrated that M1'-specific antibodies reduced serum IgE and IgE-producing plasma cells in vivo, without affecting other immunoglobulin isotypes. M1'-specific antibodies were effective when delivered prophylactically and therapeutically in mouse models of immunization, allergic asthma, and Nippostrongylus brasiliensis infection, likely by inducing apoptosis of IgE-producing B cells. In addition, we generated a humanized M1'-specific antibody that was active on primary human cells in vivo, as determined by its reduction of serum IgE levels and IgE plasma cell numbers in a human PBMC-SCID mouse model. Thus, targeting of human IgE-producing B cells with apoptosis-inducing M1'-specific antibodies may be a novel treatment for asthma and allergy.


Subject(s)
Antibodies, Monoclonal/pharmacology , Antibodies/immunology , B-Lymphocytes/drug effects , Hypersensitivity, Immediate/immunology , Mice, SCID/immunology , Animals , Antibodies, Monoclonal/immunology , Asthma/immunology , B-Lymphocytes/immunology , Humans , Hypersensitivity/immunology , Immunization , Mice , Mice, Transgenic , Nippostrongylus/drug effects , Nippostrongylus/immunology
2.
J Immunol ; 184(8): 4307-16, 2010 Apr 15.
Article in English | MEDLINE | ID: mdl-20231694

ABSTRACT

It has been suggested that IL-17RC forms a complex with IL-17RA to mediate the functions of IL-17A and IL-17F homodimers as well as IL-17A/F heterodimers. It is still unclear whether IL-17RC is absolutely required for the signaling of IL-17 cytokines in vivo. By using Il-17rc-deficient mice, we show that IL-17RC is essential for the signaling of IL-17A, IL-17F, and IL-17A/F both in vitro and in vivo. IL-17RC does not preassociate with IL-17RA on the cell surface; rather IL-17A can induce the formation of an IL-17RC and IL-17RA complex. This process is not dependent on the intracellular similar expression to fibroblast growth factor genes and IL-17Rs (SEFIR) domain of IL-17RC, but the SEFIR is essential in IL-17A signal transduction. Finally, Il-17rc(-/-) mice develop much milder disease in an experimental autoimmune encephalomyelitis model, supporting an essential role for IL-17RC in mediating immune-mediated CNS inflammation.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/metabolism , Interleukin-17/physiology , Receptors, Interleukin/physiology , Signal Transduction/immunology , Animals , Cell Line, Transformed , Cells, Cultured , Central Nervous System/immunology , Central Nervous System/pathology , Coculture Techniques , Encephalomyelitis, Autoimmune, Experimental/pathology , Humans , Interleukins/physiology , Mice , Mice, Congenic , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Molecular Sequence Data , Receptors, Interleukin/deficiency , Receptors, Interleukin/genetics
3.
Nat Med ; 15(7): 766-73, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19561618

ABSTRACT

Uncontrolled T helper type 1 (T(H)1) and T(H)17 cells are associated with autoimmune responses. We identify surface lymphotoxin-alpha (LT-alpha) as common to T(H)0, T(H)1 and T(H)17 cells and employ a unique strategy to target these subsets using a depleting monoclonal antibody (mAb) directed to surface LT-alpha. Depleting LT-alpha-specific mAb inhibited T cell-mediated models of delayed-type hypersensitivity and experimental autoimmune encephalomyelitis. In collagen-induced arthritis (CIA), preventive and therapeutic administration of LT-alpha-specific mAb inhibited disease, and immunoablated T cells expressing interleukin-17 (IL-17), interferon-gamma and tumor necrosis factor-alpha (TNF-alpha), whereas decoy lymphotoxin-beta receptor (LT-betaR) fusion protein had no effect. A mutation in the Fc tail, rendering the antibody incapable of Fcgamma receptor binding and antibody-dependent cellular cytotoxicity activity, abolished all in vivo effects. Efficacy in CIA was preceded by a loss of rheumatoid-associated cytokines IL-6, IL-1beta and TNF-alpha within joints. These data indicate that depleting LT-alpha-expressing lymphocytes with LT-alpha-specific mAb may be beneficial in the treatment of autoimmune disease.


Subject(s)
Autoimmune Diseases/therapy , Interleukin-17/physiology , Lymphocyte Depletion , Lymphotoxin-alpha/antagonists & inhibitors , Th1 Cells/immunology , Animals , Antibodies, Monoclonal/therapeutic use , Arthritis, Experimental/therapy , Autoimmune Diseases/etiology , Autoimmune Diseases/immunology , Inflammation/etiology , Mice , Mice, Inbred DBA
4.
Nat Immunol ; 10(1): 48-57, 2009 Jan.
Article in English | MEDLINE | ID: mdl-19011627

ABSTRACT

Here we have identified a surface protein, TIGIT, containing an immunoglobulin variable domain, a transmembrane domain and an immunoreceptor tyrosine-based inhibitory motif that was expressed on regulatory, memory and activated T cells. Poliovirus receptor, which is expressed on dendritic cells, bound TIGIT with high affinity. A TIGIT-Fc fusion protein inhibited T cell activation in vitro, and this was dependent on the presence of dendritic cells. The binding of poliovirus receptor to TIGIT on human dendritic cells enhanced the production of interleukin 10 and diminished the production of interleukin 12p40. Knockdown of TIGIT with small interfering RNA in human memory T cells did not affect T cell responses. TIGIT-Fc inhibited delayed-type hypersensitivity reactions in wild-type but not interleukin 10-deficient mice. Our data suggest that TIGIT exerts immunosuppressive effects by binding to poliovirus receptor and modulating cytokine production by dendritic cells.


Subject(s)
Dendritic Cells/immunology , Immune Tolerance , Membrane Proteins/metabolism , Receptors, Immunologic/metabolism , T-Lymphocytes/immunology , Amino Acid Sequence , Animals , CHO Cells , Cell Communication , Cell Differentiation , Cells, Cultured , Cricetinae , Cricetulus , Dendritic Cells/cytology , Dendritic Cells/metabolism , Down-Regulation , Humans , Immunologic Memory , Interleukin-10/biosynthesis , Interleukin-12 Subunit p40/metabolism , Membrane Proteins/chemistry , Membrane Proteins/genetics , Mice , Mice, Inbred C57BL , Molecular Sequence Data , Protein Binding , Receptors, Immunologic/chemistry , Receptors, Immunologic/genetics , Receptors, Virus/genetics , Receptors, Virus/metabolism , Sequence Alignment , T-Lymphocytes/metabolism
5.
Arterioscler Thromb Vasc Biol ; 22(3): 517-22, 2002 Mar 01.
Article in English | MEDLINE | ID: mdl-11884300

ABSTRACT

10C12, a human antibody F(ab')2, which specifically binds to the gamma-carboxyglutamic acid domain of factor IX/factor IXa (F.IX/IXa), interferes with all known coagulation processes in which F.IX/IXa is involved. In a rabbit model of carotid artery injury, intravenous administration of 10C12 or heparin decreased thrombosis dose dependently. The dose that resulted in a 90% reduction of thrombus mass (ED90) was a 30-microg/kg bolus of 10C12 or a 100-U/kg bolus plus 1.0 U x kg(-1) x min(-1) infusion of heparin. Heparin, at and below the ED90, significantly prolonged coagulation times and cuticle bleeding times. In contrast, 10C12 had no effect on coagulation or bleeding times at doses up to 4 times the ED90. To further evaluate the effect of 10C12 on bleeding, it was compared with heparin in a novel model of blood loss. At the ED90 of heparin, blood loss induced by a standardized injury to the vasculature of the rabbit tibia increased to more than 2 times that of saline controls. In contrast, the dose of 10C12 required to produce a similar increase in blood loss was more than 30 times the ED90. The antithrombotic potency and relative safety of this fully human antibody suggests that it may have therapeutic value for treatment of thrombotic disorders.


Subject(s)
Anticoagulants/therapeutic use , Carotid Artery Thrombosis/prevention & control , Factor IX/antagonists & inhibitors , Factor IXa/antagonists & inhibitors , Immunoglobulin Fab Fragments/therapeutic use , Animals , Anticoagulants/adverse effects , Anticoagulants/pharmacology , Blood Coagulation/drug effects , Disease Models, Animal , Dose-Response Relationship, Drug , Factor IX/immunology , Factor IXa/immunology , Hemorrhage/etiology , Heparin/adverse effects , Heparin/pharmacology , Heparin/therapeutic use , Humans , Immunoglobulin Fab Fragments/adverse effects , Immunoglobulin Fab Fragments/pharmacology , Kinetics , Rabbits , Reproducibility of Results , Tibia/blood supply
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