Showing papers by "Jeffrey V. Ravetch published in 2001"

Dendritic Cells Induce Peripheral T Cell Unresponsiveness under Steady State Conditions in Vivo

Abstract: Dendritic cells (DCs) have the capacity to initiate immune responses, but it has been postulated that they may also be involved in inducing peripheral tolerance. To examine the function of DCs in the steady state we devised an antigen delivery system targeting these specialized antigen presenting cells in vivo using a monoclonal antibody to a DC-restricted endocytic receptor, DEC-205. Our experiments show that this route of antigen delivery to DCs is several orders of magnitude more efficient than free peptide in complete Freund's adjuvant (CFA) in inducing T cell activation and cell division. However, T cells activated by antigen delivered to DCs are not polarized to produce T helper type 1 cytokine interferon γ and the activation response is not sustained. Within 7 d the number of antigen-specific T cells is severely reduced, and the residual T cells become unresponsive to systemic challenge with antigen in CFA. Coinjection of the DC-targeted antigen and anti-CD40 agonistic antibody changes the outcome from tolerance to prolonged T cell activation and immunity. We conclude that in the absence of additional stimuli DCs induce transient antigen-specific T cell activation followed by T cell deletion and unresponsiveness.

IgG Fc Receptors

Abstract: Since the description of the first mouse knockout for an IgG Fc receptor seven years ago, considerable progress has been made in defining the in vivo functions of these receptors in diverse biological systems. The role of activating Fc gamma Rs in providing a critical link between ligands and effector cells in type II and type III inflammation is now well established and has led to a fundamental revision of the significance of these receptors in initiating cellular responses in host defense, in determining the efficacy of therapeutic antibodies, and in pathological autoimmune conditions. Considerable progress has been made in the last two years on the in vivo regulation of these responses, through the appreciation of the importance of balancing activation responses with inhibitory signaling. The inhibitory FcR functions in the maintenance of peripheral tolerance, in regulating the threshold of activation responses, and ultimately in terminating IgG mediated effector stimulation. The consequences of deleting the inhibitory arm of this system are thus manifested in both the afferent and efferent immune responses. The hyperresponsive state that results leads to greatly magnified effector responses by cytotoxic antibodies and immune complexes and can culminate in autoimmunity and autoimmune disease when modified by environmental or genetic factors. Fc gamma Rs offer a paradigm for the biological significance of balancing activation and inhibitory signaling in the expanding family of activation/inhibitory receptor pairs found in the immune system.

Anti-inflammatory Activity of IVIG Mediated Through the Inhibitory Fc Receptor

Abstract: The molecular basis for the anti-inflammatory property of intravenous gamma globulin (IVIG) was investigated in a murine model of immune thrombocytopenia. Administration of clinically protective doses of intact antibody or monomeric Fc fragments to wild-type or Fcgamma receptor-humanized mice prevented platelet consumption triggered by a pathogenic autoantibody. The inhibitory Fc receptor, FcgammaRIIB, was required for protection, because disruption either by genetic deletion or with a blocking monoclonal antibody reversed the therapeutic effect of IVIG. Protection was associated with the ability of IVIG administration to induce surface expression of FcgammaRIIB on splenic macrophages. Modulation of inhibitory signaling is thus a potent therapeutic strategy for attenuating autoantibody-triggered inflammatory diseases.

Enhancement of antibody-mediated immune responses

Abstract: The present invention is related to enhancing the function of anti-tumor antibodies by regulating FcηRIIB-mediated activity. In particular, disrupting SHIP activation by FcηRIIB enhances cytotoxicity elicited by a therapeutic antibody in vivo in a human. The invention further provides an antibody, e.g., an anti-tumor antibody, with a variant Fc region that results in binding of the antibody to FcηRIIB with reduced affinity. A variety of transgenic mouse models demonstrate that the inhibiting FcηRIIB molecule is a potent regulator of cytotoxicity in vivo.

T Cell Studies in a Peptide-Induced Model of Systemic Lupus Erythematosus

Abstract: We have previously reported that immunization with a peptide mimetope of dsDNA on a branched polylysine backbone (DWEYSVWLSN-MAP) induces a systemic lupus erythematosus-like syndrome in the nonautoimmune BALB/c mouse strain. To understand the mechanism underlying this breakdown in self tolerance, we examined the role of T cells in the response. Our results show that the anti-foreign and anti-self response induced by immunization is T cell dependent and is mediated by I-E(d)-restricted CD4(+) T cells of the Th1 subset. In addition, generation of the critical T cell epitope requires processing by APCs and depends on the presence of both DWEYSVWLSN and the MAP backbone. The breakdown in self tolerance does not occur through cross-reactivity between the T cell epitope of DWEYSVWLSN-MAP and epitopes derived from nuclear Ags. In this induced-model of SLE, therefore, autoreactivity results from the activation of T cells specific for foreign Ag and of cross-reactive anti-foreign, anti-self B cells. Despite the fact that tissue injury is mediated by Ab, the critical initiating T cell response is Th1.

Activating and inhibitory immunoglobulin-like receptors

Abstract: Introduction: Fc Receptors: Activation-inhibition receptor pairing (J. V. Ravetch).- Part A: Gene Structure, Expression, and Evolution: Phylogeny of Paired Ig-like Receptors (G. Dennis Jr., C.-C. Chen, H. Kubagawa, and M. D. Cooper) Genomic organization of the ILT11 gene, a novel member of the Leukocyte Receptor Cluster (LRC) (H. Wende, A. Ziegler, and A. Volz). Regulated expression of non-polymorphic gp49 molecules on mouse natural killer cells (L. L. Wang and W. M. Yokoyama). Regulation of human FcaR gene expression (T. Shimokawa, T. Tsuge, and C. R).- Part B: Structural Features of Receptor Protein: Molecular recognition by Ig-like receptors, KIRs and FcgRs (K. Maenaka, P. A. van der Merwe, D. I. Stuart, P. Sondermann, and E. Y. Jones). Ig modules as discrete structural units to exploit functional and structural aspects of Ig-like receptors (L. Vangelista and O. Burrone). Structural studies on the leukocyte co-stimulatory molecule, B7-1 (S. Ikemizu, E. Y. Jones, D. I. Stuart, and S. J. Davis). ITIM-bearing receptors in platelets (D. C. Snell, J.-M. Pasquet, and S. P. Watson). Identification of Fca/m receptor expressed on B lymphocytes and macrophages (A. Shibuya, K. Shibuya, Y. Shimizu, K. Yotsumoto, and H. Nakauchi). Functional characterization of mouse CD94 by using a novel monoclonal antibody (N.Toyama-Sorimachi, H. Yagita, F. Kitamura, A. Kawasaki, S. Koyasu, and H. Karasuyama). Interaction of human cytomegalovirus glycoproteins with immunoreceptors (D. Cosman, J. Chalupny, M.-L. Hsu, C. Sutherland, J. Mllberg, M. Kubin, N. Fanger, and L. Borges). Function of gp49A in mast cell activation (M. Ono, K. H. Lee, and T. Takai). The Fc receptor family structure based strategies for the development of anti-inflammatory drugs (P. M. Hogarth, M. S. Powell, L. J. Harris, B. Wines, G. Jamieson).- Part C: Signaling Events and Physiological Roles: The mouse gp49 family (H. R. Katz). Regulation of B-cellantigen receptor signaling by CD72 (T. Tsubata, C. Wakabayashi, and T. Adachi). A role for the SH2-containing inositol phosphatase in the biology of natural killer cells and stem cells (T. Ghansah, J. M. Ninos, and W. G. Kerr). SHIP1-mediated negative regulation of cell activation and proliferation by FcgRIIB (M. Daron, P. Bruhns, R. Lesourne, O. Malbec, and W. H. Fridman). The preBCR signaling through Igb regulates locus accessibility for ordered immunoglobulin gene rearrangements (K. Maki, K. Nagata, F. Kitamura, T. Takemori, and H. Karasuyama). Regulation of phospolipase C-g2 and phosphoinositide 3-kinase by adaptor proteins in B cells (T. Kurosaki). Fc receptor signaling during phagocytosis (E. Garca-Garca and C. Rosales). Molecular mechanism of paired immunoglobulin-like receptor B (PIR-B)-mediated inhibitory signal (A. Maeda, A. M. Scharenberg, S. Tsukada, J. B. Bolen, J.-P. Kinet, and T. Kurosaki). IgE stabilizes its high affinity receptor (FceRI) on mast cells in vitro and ex vivo: The mechanism of IgE-mediated FceRI up-regulation and its physiological meaning (S. Kubo, K. Matsuoka, C. Taya, F. Kitamura, H. Yonekawa, and H. Karasuyama). Autoimmune arthritis and Goodpastures syndrome induced in Fcg receptor-deficient mice (T. Takai and A. Nakamura). Receptors involved in human NK cell activation in the process of natural cytotoxicity (L. Moretta, R. Biassoni, C. Bottino, M. C. Mingari, and A. Moretta). The regulation of PD-1/PD-L1 pathway and autoimmune diseases (T. Okazaki, Y. Iwai, H. Nishimura, and T. Honjo). Identification of the functional recognition site on MHC class I for a NK cell lectin-like receptor (N. Matsumoto, M. Mitsuki, K. Tajima, W. M. Yokoyama, and K. Yamamoto). Characterization of Tm1 cells, a NKR+ subset of memory-phenotype CD8+ T cells (N. Anfossi, V. Pascal, S. Ugolini, and E. Vivie). How do killer cell Ig-like receptors inhibit natural killer cells? (E. O. Long, D. N. Burshtyn, C. C. Stebbins, an

Enhancement of antibody-mediated cytotoxicity.

Abstract: The present invention is related to enhancing the function of anti-tumor antibodies by regulating Fc gamma RIIB-mediated activity. In particular, disrupting SHIP activation by Fc gamma RIIB enhances cytotoxicity elicited by a therapeutic antibody in vivo in a human. The invention further provides an antibody, e.g., an anti-tumor antibody, with a variant Fc region that results in binding of the antibody to Fc gamma RIIB with reduced affinity. A variety of transgenic mouse models demonstrate that the inhibiting Fc gamma RIIB molecule is a potent regulator of cytotoxicity in vivo.