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Patent US7544357 - Methods for treating autoimmune diseases in a subject and in vitro ... - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign inPatentsThe invention provides a method for treating an autoimmune disease in a subject by administering an interferon antagonist and a Flt3 ligand (Flt3L) antagonist. The invention also provides compositions containing one or more interferon antagonists, and one or more Flt3L antagonists, an in vitro assay...http://www.google.com/patents/US7544357?utm_source=gb-gplus-sharePatent US7544357 - Methods for treating autoimmune diseases in a subject and in vitro diagnostic assaysAdvanced Patent SearchPublication numberUS7544357 B2Publication typeGrantApplication numberUS 10/466,023PCT numberPCT/US2002/000343Publication dateJun 9, 2009Filing dateJan 8, 2002Priority dateJan 9, 2001Fee statusPaidAlso published asCA2433806A1, CA2433806C, CN1529617A, CN100536919C, CN101612402A, DE60239522D1, EP1351707A2, EP1351707A4, EP1351707B1, EP1351707B9, EP2236156A2, EP2236156A3, US20020160974, US20040067232, US20090263474, WO2002067760A2, WO2002067760A3Publication number10466023, 466023, PCT/2002/343, PCT/US/2/000343, PCT/US/2/00343, PCT/US/2002/000343, PCT/US/2002/00343, PCT/US2/000343, PCT/US2/00343, PCT/US2000343, PCT/US2002/000343, PCT/US2002/00343, PCT/US2002000343, PCT/US200200343, PCT/US200343, US 7544357 B2, US 7544357B2, US-B2-7544357, US7544357 B2, US7544357B2InventorsJacques F. Banchereau, Anna Karolina Palucka, Patrick BlancoOriginal AssigneeBaylor Research InstituteExport CitationBiBTeX, EndNote, RefManPatent Citations (80), Non-Patent Citations (105), Referenced by (10), Classifications (62), Legal Events (2) External Links: USPTO, USPTO Assignment, EspacenetMethods for treating autoimmune diseases in a subject and in vitro diagnostic assays
US 7544357 B2Abstract
The invention provides a method for treating an autoimmune disease in a subject by administering an interferon antagonist and a Flt3 ligand (Flt3L) antagonist. The invention also provides compositions containing one or more interferon antagonists, and one or more Flt3L antagonists, an in vitro assay for determining a subject's risk for developing an autoimmune disease, and kits for use, inter alia, with the assay.
This application claims the priority to U.S. Provisional Patent Application Ser. No. 60/260,541, filed Jan. 9, 2001, the entire contents of which are hereby incorporated by reference.
This invention relates to treating autoimmune diseases and diagnostic assays related to autoimmune diseases.
Autoimmune diseases are devastating and crippling diseases, and occur when a patient's own immune system turns against itself by attacking the patient's own body or tissues. One example of an autoimmune disease is systemic lupus erythematosus (SLE), which is characterized by multi-organ involvement and immunological abnormalities that include the presence of autoreactive T cells and B cells. Autoantibodies against the nucleosome appear to be a hallmark characteristic of SLE and suggest that inappropriate handling of dying (apoptotic) cells may represent a key pathogenic event in the development of SLE. SLE results from the dysregulation of both the humoral and the cellular limbs of the immune system indicating that the initial alteration may be at the level of cells that enroll and control the immune effectors, namely the dendritic cells (DCs).
Three subsets of DC precursors (“DCpre”) circulate in the blood: (1) CD14+ monocytes, (2) CD11c+ myeloid DCpre and (3) CD11c− plasmacytoid (lymphoid) DCpre. Monocytes can differentiate into cells displaying features of immature DCs or macrophages (MΦ). The immature DCs become mature DCs upon treatment with CD40L and/or LPS or when cultured with a combination of cytokines including TNF, IL-1 and IL-6. CD11c+ myeloid DCpre give rise to interstitial DC (intDC), Langerhans cells (LC) or MΦ depending on local cytokine environment.
The autoantibodies (autoAbs) in SLE can be characterized in three major categories: (1) anti-nuclear and anti-double stranded DNA antibodies; (2) autoAbs directed against the surface of endothelial cells and platelets (anti-phospholipids/12 glycoprotein); and (3) autoAbs directed against molecules on the surface of hematopoietic cells (see, e.g., review of Cabral and Alarcon-Segovia (1998) Curr. Opin. Rheumatol. 10:409). In addition to the direct damage caused by cellular and/or tissue antigen-antibody interactions, many of the disease's symptoms result from indirect damage through the deposition of immune complexes on tissues. This mechanism has been shown to be responsible for some forms of SLE nephritis, arthritis, and vasculitis (Laihta, R. G. 1999. Systemic Lupus Brythematosus. Academic Press; Kammer, G. M., and G. C. Tsokos. 1999. Lupus, Humana Press). Defects in immune complex clearance, including include Fc receptor (“FcR”) and C3b-receptor (“C3b-R”) dysfunction, as well as genetic defects in complement proteins and C-reactive protein (all of which are essential players in the removal of anti-DNA/nucleosome complexes) can contribute to the development of SLE (Lahita, R. G. 1999. Academic Press; Kammer, G. M., and G. C. Tsokos. 1999 Humana Press). B cells play a major role in SLE pathogenesis, as they are responsible for the production of autoantibodies and hypergammaglobulinemia.
FMS-like tyrosine kinase 3 (“Flt3”) is a member of the type III tyrosine kinase receptor family which also includes KIT (c-kit RTK), FMS (M-CSF RTK) and platelet-derived growth factor (PDGF) receptor. Similar to the ligands for the KIT and FMS receptors, stem cell factor and M-CSF, respectively, the Flt3 receptor is activated by a cognate molecule, termed Flt3-ligand (“Flt3L”). Flt3 is a variant form of a tyrosine kinase receptor that is related to the c-fms and c-kit receptors (Rosnet et al. Oncogene, 6,1641-1650, 1991). Flt3L is a hematopoietic cytokine that has been shown to facilitate the expansion of DCs and the generation of antitumor immune responses (see U.S. Pat. No. 5,554,512, “Ligands for Flt3 Receptors”). Flt3L has been found to regulate the growth and differentiation of progenitor and stem cells (Blazar et al. (2001) Biology of Blood and Marrow Transplantation 7:197-207 and see U.S. Pat. No. 5,843,423). Flt3L treatment of monocyte cell cultures was shown to result in a marked expansion in the absolute number of myeloid- and lymphoid-related DCs and a reduction in the proportion of donor splenic T cells (Blazar et al).
The present invention is directed to methods for treating an autoimmune disease in a subject which comprises administering to the subject an effective amount of (a) at least one interferon antagonist that reduces activity of a type I interferon, and (b) at least one Flt3 ligand (Flt3L) antagonist that reduces activity of Flt3L, to thereby reduce differentiation of monocytes into dendritic cells in the subject and treat the autoimmune disease.
FIG. 1 is a schematic representation of interactions between dendritic cell subsets in SLE which shows the relationship between lymphoid (plasmacytoid) DCs and/or their products, e.g., type I interferons, and the differentiation of myeloid DCs. The differentiation of myeloid DCs initiate the cascade of antigen presentation that leads to differentiation of autoreactive T cells and B cells contributing to SLE pathogenesis.
FIGS. 2A-2E are photographic illustrations showing purified monocytes from normal donors which cluster and acquire dendritic cell morphology when cultured with serum from patients with SLE but not when cultured with autologous (AS) serum Monocytes are cultured with AS serum (FIG. 2C) or SLE serum (FIGS. 2A-2B). FIG. 2D depicts a cluster of veiled cells induced by SLE sera. In FIG. 2E, Giemsa staining of cytospun monocytes cultured for 24 hours with SLE serum reveals cells with morphology typical of mature DCs. (“SLE-DCs”=SLE serum induced DCs).
FIGS. 4A-4E are graphic illustrations of flow cytometry results showing that monocytes cultured with SLE serum capture soluble antigens. Enriched monocytes were cultured with SLE serum (FIGS. 4D and 4E) (SLE 1 and SLE2 denote serum from two different patients with SLE) or with AS serum (FIG. 4C) and their endocytic activity was determined using FITC-dextran (FITC-DX) uptake at 4� C. (thin-line) and 37� C. (thick-line). Monocytes cultured with GM-CSF and IFN-α (“GM-IFNα”) (FIG. 4B) as well as those cultured with GM-CSF and IL-4 (“GM/IL-4”) (FIG. 4A) (which is a standard for in vitro DC cultures) exhibit comparable levels of FITC-DX uptake. Monocytes cultured with AS serum do not take up FITC-DX.
FIG. 12 is a graphic illustration showing that peripheral blood mononuclear cells (PBMCs) from patients with SLE secrete IFN-α in vitro in response to viral triggering. Total PBMCs were cultured in 96-well plates with or without influenza virus (10 μg/mL). Supernatants were harvested after culturing for 24 hours and assayed for IFN-α release by ELISA. “All −” represents levels in control cultures without virus. “+” denotes cultures with virus. “ND” denotes normal donor.
The present invention is directed to methods for treating an autoimmune disease in a subject which comprises administering to the subject an effective amount of (a) one or more interferon antagonists that reduce activity of a type I interferon, and (b) one or more Flt3 ligand (Flt3L) antagonists that reduce activity of a Flt3L, to thereby reduce differentiation of monocytes into dendritic cells in the subject and treat the autoimmune disease. Additionally, the present invention provides a composition useful for inhibiting monocyte differentiation into dendritic cells (DCs) which are capable of antigen presentation, which comprises: (a) at least one interferon antagonist that reduces activity of interferon, and (b) at least one Flt3 ligand antagonist that reduces activity of a Flt3 ligand. For example, one component of the composition can be an antagonist that reduces or inhibits the binding or interaction between the type I interferon (e.g., IFN-α) and its receptor. This composition also includes an antagonist that reduces or inhibits binding or interaction between a Flt3L and its receptor.
As used herein, “SLE-DCs” refers to dendritic cells which are obtained by culturing monocytes with serum obtained from a patient with SLE (“SLE serum”).
As used herein, an “interferon antagonist” encompasses a antibody, an antigen-binding fragment of an antibody, a polypeptide, a peptidomimetic, a nucleic acid encoding a polypeptide, an organic molecule or any combination thereof which is capable of reducing the activity or function of a type I interferon in a cell within a subject or a cell in vitro.
As used herein, “polypeptide” encompasses peptides and proteins of any length, without regard to function.
As used herein, a “type I interferon” includes IFN-α, IFN-β, IFN-varpi and IFN-tau. Oritani et al. ((2001) Cytokine Growth Factor Rev. 12(4):33748) provide a description of other examples of a type I interferon.
As used herein, an “Flt3L antagonist” encompasses an antibody, an antigen-binding fragment of an antibody, a polypeptide, a peptidomimetic, a nucleic acid encoding a polypeptide, an organic molecule or any combination thereof which is capable of reducing the activity of Flt3L. For example, the Flt3L antagonist can interfere with the interaction between Flt3 ligand (“Flt3L”) and its receptor so as to inhibit differentiation of progenitor cells into dendritic cells. The reduction in generation of antigen-presenting cells can be achieved by one or more different mechanisms. For example, Flt3L can contribute to unabated DC activation that can in turn drive auto-antigen presentation in SLE, therefore, Flt3L is a target for therapeutic intervention. Flt3L likely plays a role in the development or the sustainment of the SLE autoimmune disease making an antagonist of Flt3L function useful for the treatment of autoimmune diseases.
The term “human monoclonal antibody” (HuMAb) as used herein, means HuMAbs obtainable from human B cells (e.g., whether the antibody is prepared by culturing the immortalized and/or activated human B cells or recombinantly from human B cell cDNAs encoding such a HuMAb and whether or not the antibody is bound to a molecule which can alter its biological activity, e.g., a receptor or ligand, an enzyme, a toxin, a carrier, etc.) and antibodies that are made by recombining the variable portions of a HuMAb of the present invention of one isotype (e.g., an IgG4) with the constant region of a human antibody of another isotype (e.g., a human IgG1, IgG2, IgG3, IgG4, IgA, IgD, IgM or IgE). Recombinant methods for making these HuMAbs are known in the art (see U.S. Pat. No. 5,959,085).
In one embodiment of the invention, nucleic acids encoding peptides which block function of a type I interferon and/or a Flt3L are administered to a subject. For example, virus based vectors (an example of a gene transfer vectors) can be used for delivery of these nucleic acids into the subject so that translation of the peptides occurs in vivo. The gene transfer vector may be any construct which is able to replicate within a host cell and includes, but is not limited to, plasmids, DNA viruses, retroviruses, as well as isolated nucleotide molecules. Retrovirus or adenovirus based vectors can be used, for example. Adenoviruses have attracted increasing attention as expression vectors, especially for human gene therapy (Berkner, Curr. Top. Microbiol. Immunol., 158:39-66 (1992)). Such vectors contain all or a part of a viral genome, such as long term repeats (“LTRs”), promoters (e.g., CMV promoters, SV40 promoter, RSV promoter), enhancers, and so forth In any case, the vector may comprise elements of more than one virus. Examples of adenoviruses which can be employed in the present invention are well-known in the art and include more than 40 different human adenoviruses, e.g., Ad12 (subgenus A), Ad3 and Ad7 (Subgenus B), Ad2 and Ad5 (Subgenus C), Ad8 (Subgenus D), Ad4 (Subgenus E), Ad40 (Subgenus F) (Wigand et al, In: Adenovirus DNA, Doerfler, Ed., Martinus Nijhoff Publishing, Boston, pp. 408-441 (1986)). Methods for producing adenovirus vectors are well-known in the art (Berkner et al, Nucleic Acids Res., 11:6003-6020 (1983); van Doren et al, Mol. Cell. Biol., 4:1653-1656 (1984); Ghosh-Choudhury et al Biochem. Biophys. Res. Commun., 147:964-973 (1987); McGrory et al, Virol., 163:614-617 (1988); and Gluzman et al In: Eurkaryotic Viral Vectors, Ed. Gluzman, Y. pages 187-192, Cold Spring Harbor Laboratory (1982)). The resulting vectors are introduced (e.g., by transfection or by transformation, or by infection, or by injection, etc.) into a host cell which may be in vivo in the subject or in vitro. Liposome-mediated transfer of the gene transfer vector may also be carried out in the present invention.
This invention provides for pharmaceutical compositions including therapeutically effective amounts of polypeptide compositions and compounds, together with suitable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or carriers. Such compositions may be liquids or lyophilized or otherwise dried formulations and include diluents of various buffer content (e.g., Tris-HCl., acetate, phosphate), pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., TWEEN™ 20, TWEEN™ 80, Pluronic F68, bile acid salts), solubilizing agents (e.g., glycerol, polyethylene glycerol), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., Thimerosal, benzyl alcohol, parabens), bulking substances or tonicity modifiers (e.g., lactose, mannitol), covalent attachment of polymers such as polyethylene glycol to the compound, complexation with metal ions, or incorporation of the compound into or onto particulate preparations of polymeric compounds such as polylactic acid, polglycolic acid, hydrogels, etc, or onto liposomes, micro emulsions, micelles, unilamellar or multi lamellar vesicles, erythrocyte ghosts, or spheroplasts. Such compositions will influence the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance of the compound or composition. The choice of compositions will depend on the physical and chemical properties of the composition.
SLE Sera Induces Monocytes to Differentiate into Cells with Properties Like Dendritic Cells
Normal monocytes were exposed to SLE sera in vitro: within 12-24 hours, clustering of monocytes was noted; and within 24-48 hours, clustered cells displayed fine cytoplasmic projections reminiscent of DC cultures (FIGS. 2A and 2B). Only SLE serum induced monocytes to cluster with 12-24 hours and acquire veiled cell morphology (FIGS. 2A-2B compared to AS in FIG. 2C).
Cell culture and phenotypic analysis: Monocytes were isolated from blood mononuclear cells, after Ficoll-Paque™ gradient, by depletion of T-cells, B-cells and NK cells using purified anti-CD3, anti-CD19, anti-CD56 and anti-glycophorin A antibodies followed by immunomagnetic depletion (Dynabeads). Enriched CD14+monocytes were cultured in 6 well plates (1�106/well) for 3 days in the presence of GM-CSF at 100 ng/mL and IFN-α at 1000 UI/mL; or GM-CSF at 100 ng/mL and IL-4 at 20 ng/mL; or lupus serum; or autologous serum On Day 3, cells were harvested and stained with anti-CD14-PE antibody, anti-CD83-PE antibody, anti-HLA-DR-PrCP (peridnine chlorophyll protein) antibody, anti-mannose-receptor-PE antibody, anti-CD80 PE (phycoerythrin) antibody, anti-CD86-PE antibody, anti-CD40 PE antibody, anti-CD16-PE antibody, anti-CD32 PE antibody, anti-CD64-PE antibody and anti-CD1a-FITC antibody.
SLE-DCs Present Antigens from Captured Apoptotic Cells
The non-normal and inappropriate processing of apoptotic cells by the immune system is considered as one of the pathogenic events in SLE. Thus, it was next determined whether SLE-DCs can present antigens from captured apoptotic cells. To this end, SLE-DCs were shown to be able to capture apoptotic cell fragments in culture (FIGS. 7A-7B).
Only IFN-α Containing Active SLE Sera Induce Monocytes to Become SLE-DCs
Experiments were performed to determine whether all SLE sera were able to direct monocyte differentiation into DCs. Monocytes were cultured with 19 different SLE sera to be tested for their ability to stimulate a mixed leukocyte response or mixed lymphocyte reaction (MLR). As shown in Table 1, monocytes cultured with autologous serum were only able to induce very low T cell proliferation (negative control), and monocytes cultured with GM-CSF/IL-4 to produce DCs elicited a 100% MLR (positive control), the mean proliferation was 7.5% (�6.4%, n=5). When monocytes cultured with SLE sera were evaluated in the same way, considering 20% proliferation as a cut-off point (mean+2SD of autologous serum cultured monocytes) 11 of the 19 sera induced monocytes to become allostimulatory DCs with mean proliferation of 41%�15%. As sera from patients with dermatomyositis were unable to reproduce this skewing and since the patients with dermatomyositis were treated with the same steroid regimen as SLE patients, it was concluded that the effects of SLE sera were independent of the steroids. Furthermore, sera from two newly diagnosed untreated patients efficiently differentiated monocytes into SLE-DCs. Importantly, of those 11 sera that induced SLE-DCs, 7 sera that were tested for the IFN-α levels contained more than 190 pg/mL IFN-α, while most of other sera unable to induce SLE-DCs contained less IFN-α than could be detected in the assay (12 pg/mL) (Table 1). Furthermore, the DCs inducing capacity of SLE sera was related to the disease activity. In FIGS. 9A-9B, a graph shows the relation of SLE disease activity to the inducing activity of SLE-DCs. Monocytes were cultured with 11 different SLE sera taken from either patients with active lupus (SLE Disease Activity Index (SLEDAI)>6) or inactive lupus (SLEDAI<6), and the generated cells were tested for their ability to induce T cell proliferation. As controls, monocytes were cultured with GM-CSF and IL-4. The vertical axis shows the percent of induced allostimulatory capacity. Therefore, the ability of SLE sera to skew monocyte differentiation toward DCs was disease-specific and correlated with the levels of IFN-α.
The Ability of SLE Sera to Induce SLE-DCs is Abolished by Blocking IFN-α
The ability of the DCs to skew the differentiation of monocytes toward the generation of antigen-presenting cells was related to the level of IFN-α in SLE serum The phenotype of SLE-DCs was reminiscent of that induced by GM-CSF and IFN-α and therefore, SLE sera were pre-incubated with an anti-IFN-α neutralizing antibody. The cells cultured with such sera were tested for their ability to induce the differentiation of monocytes into DCs as measured by their ability to induce MLR. The ability of SLE sera to induce functional DCs was inhibited by neutralization of IFN-α, but not by the isotype control (as shown in FIG. 10) nor other blocking antibodies to IL-4, CD40-L and IL-10, which indicates that IFN-α is necessary for the induction of SLE-DCs. FIG. 10 illustrates the blocking of IFN-α in monocyte cell cultures serum obtained from SLE patients. The addition of an interferon blocking antibody resulted in a much decreased ability to induce the proliferation of allogeneic CD4+ T cells. The results show that DCs inducing activity of SLE serum is dependent on IFN-α and is abolished by blocking IFN-α in SLE serum used to culture monocytes. Purified monocytes were cultured with SLE serum, or serum pre-incubated for 30 min at saturating concentration of IFN-α blocking Ab (SLE ab) (Biosource) or with the corresponding concentration of isotype control (SLE ctrl). After three days, the cells were assessed for their ability to induce the proliferation of allogeneic CD4+ T-cells.
Patients with SLE Have High Serum Levels of IFN-α
Serum levels of IFN-α in pediatric SLE patients was determined. As shown in FIG. 11, serum taken from SLE patients had much higher levels of IFN-α than serum obtained from healthy subjects (controls). Serum was obtained from patients with SLE. The serum was assayed for IFN-α using an ELISA kit (BioSource, according to manufacturer's recommendations) which is based on the international reference standard for human interferon (approved by National Institutes of Health). The calorimetric reaction was developed using HRP and TNB. Absorbances at 450 nm were determined with a microplate reader. The assay's extended range protocol was used which allowed determination of serum levels in the range from 10 to 5000 pg/mL.
PBMC SLE Patients Can Secrete IFN-αin Response to Viral Triggering
When exposed to influenza virus, PBMCs from SLE patients released high levels of IFN-α when compared to the level of IFN-α released from PBMCs from healthy adults which were exposed to influenza virus (see FIG. 12).
IFN-α Induces BAFF/Blys Expression on Monocytes and BCMA Expression on PBMC
A novel member of the TNF family, designated BAFF/Blys-L (for B-cell activating factor belonging to the TNF family), is found on DCs and T-cells and binds to two receptors on B-cells, namely, BCMA and TACI, and induces their proliferation and immunoglobulin secretion. Therefore, it was determined whether IFN-α would regulate the expression of both molecules (i.e., BCMA and TACI) on the respective cell types. As shown in FIGS. 13A-13B, IFN-α, but not other factors, induces high levels of BAFF/Blys in monocytes as determined by real-time PCR. Furthermore, IFN-α induces BCMA expression on normal PBMCs.
Screening Patient Serum for Induction of Monocyte Differentiation in Vitro Diagnostic Assay
Serum from a patient is screened for its ability to induce monocyte differentiation to dendritic cells which differentiation can then be blocked by neutralizing type I interferon.
Following the procedures outlined in detail in Example 1, patient serum was obtained. Following the procedures outlined in Example 1, an aliquot of patient serum is added to an aliquot of purified monocytes from normal patients. After about three days, the degree of differentiation of the monocytes to dendritic cells is assessed by any means known in the art. Exemplary assay methods include direct morphological analysis, phenotypic analysis by flow cytometry, antigen capture measurable by FITC-Dextran uptake, and induction of allogeneic na�ve CD4+ T cells measurable by thymidine incorporation. This in vitro diagnostic assay includes a known set of standards in order to classify the results obtained with the sample of serum obtained from the patient. Briefly, serum from a normal patient, i.e., a patient known not to be suffering from an autoimmune disease is run through the assay and the results obtained are used as the standard indicative of low risk for developing an autoimmune disease. Similarly, serum from a patient known to have an autoimmune disease, such as SLE, is taken and used in the assay and the results obtained are used as the standard indicative of high risk for developing an autoimmune disease. Patient serum which supports a high degree of monocyte differentiation to dendritic cells that can be blocked by type I interferon, is considered to place the patient at high risk for developing an autoimmune disease. The “high degree” of monocyte differentiation is determined by comparing the amount of monocyte differentiation in the assay using the patient's serum with the standards previously established for high risk, low risk and any other middle risk values. Each level of risk for developing an autoimmune disease is associated with a level of monocyte differentiation observed in the assay. If the patient serum does not support a high degree of monocyte differentiation to dendritic cells that can be blocked by type I interferon, then the patient's level of risk for developing an autoimmune disease is little or no risk. For a patient diagnosed with an autoimmune disease, periodic evaluation of the patient's serum in this assay provides a method to monitor for a disease flare or progression
TNF Inhibits Type I Interferon Secretion by pDCs
Kadowaki et al. (J. Exp. Med. 2000, 192:1785-96) disclose that autocrine IFN-α supports pDCs survival while the autocrine INF-α induces their maturation into mature pDCs, which are unable to produce IFN-α. Thus, studies were performed to determine whether or not adding neutralizing TNF antibodies to cultures of normal pDCs sustained their IFN-α production in response to viral triggering.
TNF Inhibits pDC Ontogeny
Studies were next performed to determine whether the effect of TNF on pDC is restricted to their maturation/IFN-α production or whether TNF, a major pro-inflammatory cytokine involved in the regulation of myeloid dendritic cells differentiation, also affects differentiation of pDCs from hematopoietic progenitors. For these studies, CD34+CD45RA− hematopoietic progenitors were sorted to over 90% purity by flow cytometry and subsequently cultured in the presence of Flt3L (100 ng/mL, R&D), thrombopoietin (TPO, 30 ng/mL, R&D), and either interleukin-6 (IL-6, 25 ng/mL, R&D), or tumor necrosis factor (TNF, 100 ng/mL, R&D), in the first week of culture at a density of between 2/5�105 to 5�105/well. Thereafter, the cells were washed and cultured for about an additional 3 weeks with Flt3L (100 ng/mL) only.
The Level of Flt3L is Increased in Serum from Subjects Suffering from SLE
As described in the above examples, unabated DC induction is believed to drive the devastating autoimmune response in SLE and, as described herein, may be controlled by targeting IFN-α and Flt3L together. However, other cytokines, which are termed herein as “DC-poietins”, can mobilize and/or activate DCs to differentiate into antigen presenting cells in vivo. This mobilization or activation of DCs can occur in many different ways. For example, such DC-poietins can increase differentiation of preDC cells into mature dendritic cells which can go on to increase an immunogeneic response and worsen the autoimmune responses. As another example, the DC-poietins can increase the actual generation of newly matured DCs which contribute to the autoimmune responses in the subject, or the DC-poietins can increase the activity of mature DCs.
Serum Levels of Flt3L Correlate with Autoimmune Disease Activity
It was determined that serum levels of Flt3L correlate with disease activity as measured by the SLE Disease Activity Index (SLEDAI). As shown in FIG. 18, there was a significant positive correlation (p=0.02), indicating that those individuals with high serum levels of Flt3L also had displayed high SLE disease activity. Therefore, the occurrence of elevated levels of Flt3L in the serum is an indicator of autoimmune risk or active autoimmune disease in a subject.
Flt3L Permits Monocyte Differentiation into DCs
Monocytes isolated from healthy donors' peripheral blood mononuclear cells (PBMCs) were either isolated by positive selection using CD14 beads or enriched by adherence and subsequently cultured for 2 days in a complete culture medium (RPMI1640 supplemented with 10% heat-inactivated fetal calf serum) with Flt3L (100 ng/mL) and IL-3 (10 ng/mL) and/or IFN-α (1000 U/mL). Control cultures were carried out with GM-CSF and IL-4. FIG. 19A shows cells cultured with Flt3L/IFN-α (1000 u/mL). FIG. 19B shows cells cultured with GM-CSF (100 ng/mL)/IL-4 (5 ng/mL). FIG. 19C shows cells cultured with IFN-α (1000 u/mL)/IL-3 (10 ng/mL). FIG. 19D shows cells cultured with Flt3L/IFN-α (1000 u/mL)/IL-3 (10 ng/mL). After 2 days of culture, cytospun monocytes were stained with Giemsa. Thus, monocytes cultured with Flt3L and IFN-α differentiate into cells displaying features of DCs as determined by morphology (FIGS. 19A-19D), phenotype (CD14 low, DC-SIGN+, CD40+, HLA-DR+, CD11c+) and function, i.e., the capacity to induce proliferation of allogeneic CD4+ T cells which is a hallmark of dendritic cell function (FIG. 20). In FIG. 20, 105 purified allogeneic CD4+ T cells were cultured for 5 days with graded numbers of antigen presenting cells (horizontal axis). T cell proliferation was measured by thymidine incorporation (vertical axis, cpm�103) following culture with media supplemented with Flt3L. FIG. 21 shows a diagram summarizing several pathways in the development and differentiation of subsets of DC which can be altered by blocking the activity of Flt3L and IFN-α. These therapeutic targets include 1) differentiation pathway from hematopoietic progenitor cells into pDC, which can be blocked either by TNF or by Flt3L antagonist or by a combination of both TNF and Flt3L antagonist with the end result being inhibited interferon production through the inhibition of the differentiation of cells that can make interferon, 2) pDCs maturation pathway, which can be accelerated by TNF with the end result being that pDCs become non-interferon producing cells thus decreasing levels of interferon, 3) differentiation pathway from monocytes to dendritic cells, which can be blocked by an interferon antagonist or by a Flt3L antagonist or by a combination of interferon antagonist and a Flt3L antagonist, with the end result being inhibited differentiation of dendritic cells that are otherwise able to capture and present apoptotic cells and drive autoimmune disease by inducing the differentiation of autoreactive B cells and autoreactive T cells.
Neutralizing Flt3L in SLE Serum Inhibits SLE Serum-Induced Monocyte Differentiation into Dendritic Cells
Monocytes are cultured with serum obtained from a patient with SLE. An effective amount of a monoclonal antibody which specifically binds Flt3L (anti-Flt3L monoclonal antibody) is added, at the saturating concentration, Le., a concentration ranging between about 1-10 fold molar excess, to the monocyte cell culture under suitable culture conditions for monocyte differentiation. After three days of incubation, a lower number of monocytes had differentiated into DCs than in an identical monocyte culture which had not received the monoclonal antibody. Therefore, the monoclonal antibody to Flt3L which neutralizes the activity of Flt3L in the culture inhibits SLE-induced monocyte differentiation into DCs.
Addition of a Composition of a Flt3L Antagonist and an Interferon Antagonist to Monocytes Grown in SLE Serum Inhibits Monocyte Differentiation Int Antigen Presenting DCs
A method for treating an autoimmune disease in a subject is exemplified herein whereby a therapeutic composition of the invention is administered to the subject in order to reduce or inhibit the generation of antigen presenting cells which cause the stimulation of autoreactive T cells and of autoreactive B cells which produce auto-antibodies in the subject.
A therapeutic composition is prepared with an amount of (a) an anti-Flt3L monoclonal antibody and (b) an amount of an anti-IFN-α monoclonal antibody which is equal to about 1-10 fold the level of Flt3L and IFN-α, respectively, in the serum of the patient to be treated. Methods for preparing monoclonal antibodies to Flt3L are known, for example one such method is in Example 6 of U.S. Pat. No. 5,843,423, “Methods of Stimulating hematopoietic cells with flt3-ligand.” Methods for preparing monoclonal antibodies to IFN-α are known and, for example, some such methods are set out in U.S. Pat. No. 5,919,453.
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(1999) Biomed Pharmacother. 53(2): 90-92, entitled "Anti-IFN alpha immunization raises the IFN alpha-neutralizing capacity of serum-an adjuvant to antiretroviral tritherapy."* Cited by examinerReferenced byCiting PatentFiling datePublication dateApplicantTitleUS7888481Feb 6, 2009Feb 15, 2011Baylor Research InstituteAnti-interferon alpha monoclonal antibodies and methods for useUS8080638Feb 9, 2006Dec 20, 2011Baylor Research InstituteAnti-interferon alpha monoclonal antibodies and methods for useUS8163885May 6, 2009Apr 24, 2012Argos Therapeutics, Inc.Humanized antibodies against human interferon-alphaUS8333965Dec 18, 2012Baylor Research InstituteAnti-inteferon alpha monoclonal antibodies and methods for useUS8361463Feb 1, 2012Jan 29, 2013Argos Therapeutics, Inc.Humanized antibodies against human interferon-alphaUS8658771Dec 19, 2012Feb 25, 2014Argos Therapeutics, Inc.Humanized antibodies against human interferon-alphaUS20080160030 *Feb 9, 2006Jul 3, 2008Banchereau Jacques FAnti-Interferon Alpha Monoclonal Antibodies and Methods for UseUS20090155286 *Sep 30, 2005Jun 18, 2009Michel GillietType I interferon blocking agents for prevention and treatment of psoriasisUS20090214565 *Feb 6, 2009Aug 27, 2009Jacques BanchereauAnti-Interferon Alpha Monoclonal Antibodies and Methods For UseUS20110213125 *May 6, 2009Sep 1, 2011Novo Nordisk A/SHumanized Antibodies Against Human Interferon-Alpha* Cited by examinerClassifications U.S. Classification424/130.1, 424/136.1, 530/388.23, 530/387.2, 424/133.1, 530/388.24, 530/388.1, 530/387.1, 424/145.1, 424/131.1International ClassificationA61P3/10, A61K45/06, A61K38/17, A61K38/19, A61P21/04, A61P31/00, A61P19/00, A61P19/02, G01N33/58, G01N33/53, A61P17/02, A61P31/18, A61K38/00, G01N21/78, A61K38/21, C07K16/40, A61P19/08, A61P25/00, A61P17/06, A61P29/00, G01N21/76, A61P37/06, A61P7/00, G01N33/577, G01N33/564, G01N33/68, A61P7/06, C12P21/08, C07K16/22, A61K39/395, C07K16/24, C07K16/18Cooperative ClassificationG01N33/564, A61K38/191, A61K2039/505, A61K38/179, A61K38/1793, C07K16/22, G01N33/6863, G01N2800/24, G01N33/6866, C07K16/249, C07K2317/73, C07K16/24European ClassificationC07K16/24H, A61K38/17C, G01N33/68D, A61K38/19A, C07K16/22, C07K16/24, G01N33/68D2, G01N33/564Legal EventsDateCodeEventDescriptionSep 30, 2003ASAssignmentOwner name: BAYLOR RESEARCH INSTITUTE, TEXASFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:BANCHEREAU, JACQUES F.;PALUCKA, ANNA KAROLINA;BLANCO, PATRICK;REEL/FRAME:014017/0075;SIGNING DATES FROM 20030610 TO 20030613Nov 29, 2012FPAYFee paymentYear of fee payment: 4RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services

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Patent US6575335 - Self-contained viscous liquid dispenser - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign in<nobr>Advanced Patent Search</nobr>PatentsA viscous liquid dispenser includes a housing that defines an internal liquid reservoir. A dispensing pump mechanism is disposed in communication with the reservoir and has a delivery end extending from the housing for manual operation by a user. A mounting mechanism is configured as an integral component...http://www.google.com/patents/US6575335?utm_source=gb-gplus-sharePatent US6575335 - Self-contained viscous liquid dispenserAdvanced Patent SearchPublication numberUS6575335 B2Publication typeGrantApplication numberUS 09/964,290Publication dateJun 10, 2003Filing dateSep 26, 2001Priority dateDec 19, 2000Fee statusLapsedAlso published asCN1742662A, CN1749123A, CN100496365C, US6533145, US6543651, US6575334, US6648179, US6729502, US20020074353, US20020074354, US20020074356, US20020079331, US20020084286, US20020084288Publication number09964290, 964290, US 6575335 B2, US 6575335B2, US-B2-6575335, US6575335 B2, US6575335B2InventorsRichard P. Lewis, Cleary E. Mahaffey, Pamela J. Mayberry, Paul F. Tramontina, David J. Powling, Mark A. Bennett, Randall M. BachtelOriginal AssigneeKimberly-Clark Worldwide, Inc.Export CitationBiBTeX, EndNote, RefManPatent Citations (99), Non-Patent Citations (11), Referenced by (28), Classifications (7), Legal Events (5) External Links: USPTO, USPTO Assignment, EspacenetSelf-contained viscous liquid dispenserUS 6575335 B2Abstract A viscous liquid dispenser includes a housing that defines an internal liquid reservoir. A dispensing pump mechanism is disposed in communication with the reservoir and has a delivery end extending from the housing for manual operation by a user. A mounting mechanism is configured as an integral component of the housing and provides the dispenser with the ability to be detachably connected to complimentary mounting structure on a wall surface. The configuration of the dispenser allows for a significantly increased capacity (volume) without a corresponding increase in the weight of the dispenser materials as compared to conventional dispensers.
Patent CitationsCited PatentFiling datePublication dateApplicantTitleUS1586398Jul 20, 1920May 25, 1926Special Mary E BobrickLiquid dispenoerUS2184439May 18, 1938Dec 26, 1939Schwarcz Leonard BDispensing valveUS2545988Oct 10, 1947Mar 20, 1951Bobrick Mfg CorpLiquid dispenserUS2605021Jul 14, 1949Jul 29, 1952Spencer Churchill Henry WinstoDispenser for an inverted container with means for locking said container thereto and a self-closing outlet elementUS2622539Mar 8, 1947Dec 23, 1952Martin Orlie ELiquid soap dispenser having a valve and plunger mechanismUS2628569Jun 26, 1947Feb 17, 1953West Disinfecting CoValve assemblyUS3533526Oct 14, 1968Oct 13, 1970Adell Intern IncPlastic bottle-attachment meansUS3721370May 15, 1970Mar 20, 1973M BlumDispenser apparatus for disposable cartonUS3952918Mar 18, 1974Apr 27, 1976Highland LaboratoriesFluid dispenser apparatusUS3955715Mar 13, 1975May 11, 1976Topor Alan CBath and shower modular dispenser arrangementUS4018363Oct 6, 1975Apr 19, 1977Steiner American CorporationSoap dispenserUS4036406Apr 8, 1976Jul 19, 1977Georgia-Pacific CorporationDispenser for liquidsUS4120619Aug 29, 1977Oct 17, 1978Sterling-Winthrop Group LimitedReciprocating pumps for dispensing pastes, liquids and other substancesUS4142651Apr 29, 1977Mar 6, 1979Norbert LeopoldiFluid dispenser with flexible outlet tube and pinching valveUS4159788Sep 12, 1977Jul 3, 1979Doyel John SWall mounted fluid dispenserUS4164306Apr 3, 1978Aug 14, 1979Towlsaver, Inc.Soap dispenser including removable soap supply container positioner and stabilizerUS4166553Jun 7, 1977Sep 4, 1979Fraterrigo Salvatore GDisposable dispensing-proportioning container for semi-fluid pasty products in general, and cosmetics products in particularUS4174056May 10, 1977Nov 13, 1979Ciba-Geigy CorporationPump type dispenser with continuous flow featureUS4236655Sep 5, 1978Dec 2, 1980S.A.Y. Industries, Inc.Container with flexible nozzleUS4248398Feb 7, 1979Feb 3, 1981Doyel John SWall mounted fluid dispenserUS4314658Jan 30, 1980Feb 9, 1982Laauwe Robert HViscous product dispensing squeeze bottle having a self-venting automatic shut-off valveUS4330071Oct 15, 1980May 18, 1982Ab Tranas RostfriaDispensing device for discharging a liquid or pasty product from a container, containing such a productUS4349133Sep 12, 1979Sep 14, 1982Christine William CDispenser and refill packageUS4360130Oct 15, 1980Nov 23, 1982Duskin Franchise Kabushiki KaishaDispenser, particularly for liquid soapUS4394938Aug 11, 1980Jul 26, 1983Sani-Fresh International, Inc.Dispenser and package for liquid or granular materialsUS4410109May 4, 1982Oct 18, 1983Quality Engineering Co., Inc.Leak detection system and check valve for use thereinUS4421254Nov 17, 1981Dec 20, 1983Donald SpectorWall-mounted aromatic liquid dispenser assemblyUS4470523Aug 12, 1981Sep 11, 1984Donald SpectorLiquid soap dispenser and adhesive wall mounting assemblyUS4489857Mar 22, 1982Dec 25, 1984Bobrick Washroom Equipment, Inc.Liquid dispenserUS4493440Aug 8, 1983Jan 15, 1985United States Borax & Chemical CorporationWall-mounted soap dispenserUS4502617Jan 31, 1983Mar 5, 1985Stoelting, Inc.Flavor decanter and pumpUS4519530Feb 25, 1983May 28, 1985Schmidt Gerhard S ESelf-closing dispenserUS4546904Sep 20, 1982Oct 15, 1985Sani-Fresh International, Inc.Dispenser and package for liquid or granular materialsUS4561571Aug 29, 1983Dec 31, 1985Chen Jason K SWashing liquid supplierUS4570833Aug 26, 1983Feb 18, 1986Vanderjagt John APumping systemUS4573612Nov 28, 1983Mar 4, 1986Kimberly-Clark LimitedLiquid soap dispenserUS4621749Feb 21, 1984Nov 11, 1986Go-Jo IndustriesDispensing apparatusUS4646945Jun 28, 1985Mar 3, 1987Steiner Company, Inc.Vented discharge assembly for liquid soap dispenserUS4650095Aug 7, 1985Mar 17, 1987United States Borax & Chemical CorporationDisposable wall-mounted dispensing containerUS4660747Jun 12, 1986Apr 28, 1987Aco Lakemedel AbValve elementUS4662195Sep 13, 1984May 5, 1987United States Borax & Chemical CorporationWall-mounted soap dispenserUS4673109Oct 18, 1985Jun 16, 1987Steiner Company, Inc.Liquid soap dispensing systemUS4679709Jun 12, 1985Jul 14, 1987Highland LaboratoriesDispenser mounting systemUS4705195Jan 24, 1986Nov 10, 1987Sani-Fresh International, Inc.Valve apparatus for liquid dispensersUS4805814Aug 3, 1987Feb 21, 1989National Products DivisionContainer for liquids having a mounting boss for storage of a removable dispenserUS4811870Mar 29, 1984Mar 14, 1989The Dyson-Kissner-Moran CorporationLiquid container with rotatable spoutUS4834269Dec 4, 1986May 30, 1989Cone Robert LLiquid containerUS4886192May 27, 1987Dec 12, 1989Steiner Company, Inc.Liquid soap dispenserUS4895276Nov 10, 1988Jan 23, 1990Sani-Fresh International, Inc.Dual liquid cartridge dispenserUS4949877May 11, 1989Aug 21, 1990Bobrick Washroom Equipment, Inc.Fluid dispenser valveUS4964544Aug 16, 1988Oct 23, 1990Bobrick Washroom Equipment, Inc.Push up dispenser with capsule valveUS4972973Oct 5, 1989Nov 27, 1990Burroughs Wellcome Co.Insulated container for liquidsUS4972978Dec 13, 1988Nov 27, 1990Georgia-Pacific CorporationDispenser having an improved metering chamberUS4974753Nov 6, 1989Dec 4, 1990James River CorporationLiquid dispenser container and holder systemUS4978036Nov 15, 1988Dec 18, 1990Koller Enterprises, Inc.Dispensing valveUS4991747Oct 11, 1988Feb 12, 1991Risdon CorporationFor dispensing liquidsUS4993600Oct 10, 1989Feb 19, 1991James River CorporationLiquid dispenser pumpUS5042691Jan 19, 1990Aug 27, 1991Scott Paper CompanyDual liquid cartridge dispenserUS5044900Mar 1, 1990Sep 3, 1991Knight Tool Company, Inc.Positive displacement shuttle pumpUS5079013Aug 30, 1990Jan 7, 1992Belanger Richard ANonspilling, valve for equalizing interior and exterior pressure, cups, bottlesUS5131568Sep 20, 1990Jul 21, 1992Ringuette Paul GStorage and dispenser systemUS5154328Jul 24, 1990Oct 13, 1992L'orealUnit for dispensing at least one fluid product, in particular a cosmetic or pharmaceutical product, having a pressure actuated, self-sealing, closure outletUS5165577May 20, 1991Nov 24, 1992Heiner OphardtDisposable plastic liquid pumpUS5174476May 6, 1991Dec 29, 1992Steiner Company, Inc.Liquid soap dispensing systemUS5178300Jun 6, 1990Jan 12, 1993Shlomo HavivFluid dispensing unit with one-way valve outflowUS5183182Feb 11, 1991Feb 2, 1993Better Living ProductsLiquid dispenser for vertical wall mountingUS5184760Oct 11, 1991Feb 9, 1993Primary Delivery Systems, Inc.Metered side dispensing cap for tubesUS5186368Nov 6, 1990Feb 16, 1993ValoisShutter for the outlet channel of a dispenser head for semi-liquid substances, and a dispenser head advantageously associated therewithUS5190191Mar 13, 1991Mar 2, 1993Reyman Mark EApparatus for measured and unmeasured dispensing of viscous fluidsUS5209377Aug 6, 1992May 11, 1993Steiner Robert LDisposable refill cartridge for a liquid soap dispensing systemUS5213236Dec 6, 1991May 25, 1993Liquid Molding Systems, Inc.Dispensing valve for packagingUS5217147Mar 9, 1992Jun 8, 1993Kaufman Products Inc.Liquid dispenser with compression chamberUS5261557Oct 13, 1992Nov 16, 1993Scott Paper CompanyDecorative window for paper and soap product dispensersUS5265772Oct 19, 1992Nov 30, 1993Gojo Industries, Inc.Dispensing apparatus with tube locatorUS5275309May 18, 1992Jan 4, 1994Lykes Pasco, Inc.One way valve with unitary valve elementUS5282552Nov 23, 1992Feb 1, 1994Hygiene-Technik Inc.Disposable plastic liquid pumpUS5303851Nov 12, 1992Apr 19, 1994Jeffrey M. LibitSpray or dispensing bottle with integral pump molded thereinUS5305916Dec 7, 1992Apr 26, 1994Kabushiki Kaisha San-AiDrip free, volume-adjustable, automatic liquid dispenserUS5307962May 3, 1993May 3, 1994Lin Hui YuContainer mounted pump with improved check valve structureUS5316135Aug 24, 1992May 31, 1994Caplast GmbhContainerUS5322198Jun 25, 1993Jun 21, 1994Ricoh Company, Ltd.Pump-equipped liquid supply systemUS5339995Mar 30, 1993Aug 23, 1994Liquid Molding Systems, Inc.Dispensing valve for packagingUS5339999Jun 18, 1991Aug 23, 1994Nestec S.A.Easy cleaning metering deviceUS5363993Dec 15, 1992Nov 15, 1994Sar S.P.A.Plastic dispenser for liquids or other substancesUS5373970Dec 23, 1993Dec 20, 1994Hygiene-Technik Inc.Liquid soap dispenser for simplified replacement of soap reservoirUS5377877Apr 23, 1993Jan 3, 1995Liquid Molding Systems, Inc.Dispensing valve for packagingUS5379919Jan 3, 1994Jan 10, 1995L'orealUnit for dispensing at least one fluid product, in particular, a cosmetic or pharmaceutical product, having a pressure actuated, self-sealing closure outletUSD246338Jul 5, 1974Nov 15, 1977Georgia-Pacific CorporationDispenser for liquidsUSD253441Mar 6, 1978Nov 20, 1979Towlsaver, Inc.Combined soap dispenser casing, dispensing lever and dispensing nozzleUSD268154Dec 10, 1980Mar 8, 1983Sani-Fresh International, Inc.Dispenser for soap productsUSD299399Apr 28, 1986Jan 17, 1989 Fluid dispenserUSD312184Jul 27, 1989Nov 20, 1990Georgia-Pacific CorporationSoap dispenser casingUSD321453Mar 22, 1989Nov 12, 1991 Liquid dispenser housingUSD332544May 8, 1991Jan 19, 1993Steiner Company, Inc.Reservoir for a liquid soap dispenserUSD342176May 1, 1990Dec 14, 1993Steiner Company, Inc.Refill container for a liquid dispenserUSD345664Apr 10, 1992Apr 5, 1994Scott Paper CompanyDual cartridge liquid soap dispenserUSD345877Apr 10, 1992Apr 12, 1994Scott Paper CompanyDual cartridge liquid soap dispenserUSD349827Aug 20, 1993Aug 23, 1994Scott Paper CompanyLiquid soap dispenserUSD350665Nov 23, 1993Sep 20, 1994Hygiene-Technik Inc.Liquid dispenserNon-Patent CitationsReference1EPO Search Report-PCT/US02/05698, Jul. 8, 2002.2EPO Search Report�PCT/US02/05698, Jul. 8, 2002.3PCT Search Report-PCT/US01/44905, Apr. 17, 2002.4PCT Search Report�PCT/US01/44905, Apr. 17, 2002.5PCT Search Report-PCT/US01/48975, May 21, 2002.6PCT Search Report�PCT/US01/48975, May 21, 2002.7U.S. Ser. No. 09/741,570, filed Dec. 19, 2000.8U.S. Ser. No. 09/911,073, filed Jul. 23, 2001.9U.S. Ser. No. 09/911,361, filed Jul. 23, 2001.10U.S. Ser. No. 09/964,289, filed Sep. 26, 2001.11U.S. Ser. No. 09/997,278, filed Nov. 28, 2001.Referenced byCiting PatentFiling datePublication dateApplicantTitleUS7028922 *Jan 13, 2004Apr 18, 2006Leonard Brian TSoap dispenser system and valve arrangement thereforUS7051903Sep 30, 2003May 30, 2006Kimberly-Clark Worldwide, Inc.Viscous liquid dispenser having leak prevention deviceUS7066355Jun 25, 2004Jun 27, 2006Kimberly-Clark Worldwide, Inc.Self-contained viscous liquid dispenser with a foaming pumpUS7114639Dec 23, 2003Oct 3, 2006Kimberly-Clark Worldwide, Inc.Vent plug for self-contained viscous liquid dispenserUS7261221Dec 19, 2003Aug 28, 2007Innovation And Design, Inc.Inverted dispensing system and apparatusUS7325704Dec 28, 2004Feb 5, 2008Rieke CorporationInverted dispensing pump with vent baffleUS7328819Sep 27, 2004Feb 12, 2008Kimberly-Clark Worldwide, Inc.Self-contained liquid dispenser with a spray pump mechanismUS7389893Sep 10, 2003Jun 24, 2008Rieke CorporationInverted dispensing pumpUS7461762Apr 17, 2003Dec 9, 2008Rieke CorporationPump dispensersUS7527178Dec 30, 2003May 5, 2009Kimberly-Clark Worldwide, Inc.Electronic viscous liquid dispenserUS7641077May 8, 2007Jan 5, 2010Rieke CorporationPump dispensersUS7857170Nov 1, 2006Dec 28, 2010Gotohti.Com Inc.Wall plate system for dispensersUS7938297Dec 2, 2009May 10, 2011Rieke CorporationPump dispensersUS8261950Oct 20, 2008Sep 11, 2012Georgia-Pacific Consumer Products LpPumping dispenserUS8302820 *Sep 21, 2007Nov 6, 2012Packaging Innovation LtdDispenser mechanismUS8418889Jan 11, 2010Apr 16, 2013Rieke CorporationInverted dispenser pump with liquid inlet cup valveUS8528795Feb 28, 2011Sep 10, 2013Rieke CorporationLiquid dosing devicesUS8550307 *Mar 31, 2011Oct 8, 2013Brightwell Dispensers LimitedDispensing device with a disposable pumpUS8556130Jan 14, 2011Oct 15, 2013Rieke CorporationPump dispensersUS8651328Jul 14, 2011Feb 18, 2014Georgia-Pacific Consumer Products LpPumping dispenser shieldUS8678240Mar 23, 2007Mar 25, 2014Packaging Innovation LimitedDispenser with actuating means unengaged with the dispensing meansUS8746510Sep 11, 2012Jun 10, 2014Georgia-Pacific Consumer Products LpPumping dispenserUS20100206909 *Sep 21, 2007Aug 19, 2010O'brien MichaelDispenser mechanismUS20120248148 *Mar 31, 2011Oct 4, 2012Etienne BunozDispensing device with a disposable pumpWO2005065510A1Nov 15, 2004Jul 21, 2005Kimberly Clark CoElectronic viscous liquid dispenserWO2005067774A1Oct 29, 2004Jul 28, 2005Randall Marc BachtelVent plug for self-contained viscous liquid dispenserWO2005067775A1Oct 29, 2004Jul 28, 2005Kimberly Clark CoMounting structure for viscous liquid dispenserWO2006011933A1Mar 28, 2005Feb 2, 2006Kimberly Clark CoSelf-contained viscous liquid dispenser with a foaming pump* Cited by examinerClassifications U.S. Classification222/156, 222/181.3, 222/325, 222/383.1International ClassificationA47K5/12Cooperative ClassificationA47K5/1204European ClassificationA47K5/12C1Legal EventsDateCodeEventDescriptionAug 2, 2011FPExpired due to failure to pay maintenance feeEffective date: 20110610Jun 10, 2011LAPSLapse for failure to pay maintenance feesJan 17, 2011REMIMaintenance fee reminder mailedNov 16, 2006FPAYFee paymentYear of fee payment: 4Jan 23, 2002ASAssignmentOwner name: KIMBERLY-CLARK WORLDWIDE, INC., WISCONSINFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:LEWIS, RICHARD P.;MAHAFFEY, CLEARY E.;MAYBERRY, PAMELA J.;AND OTHERS;REEL/FRAME:012508/0484;SIGNING DATES FROM 20011008 TO 20011017Owner name: KIMBERLY-CLARK WORLDWIDE, INC. 401 NORTH LAKE STREFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:LEWIS, RICHARD P. /AR;REEL/FRAME:012508/0484;SIGNING DATES FROM 20011008 TO 20011017RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services©2012 Google

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text: _.zk=function(){this.R=[];this.H=[]};_.Tia=function(a){_.Gb(a.R)&&(a.R=a.H,a.R.reverse(),a.H=[])};_.Dk=function(a){_.Tia(a);return a.R.pop()};_.h=_.zk.prototype;_.h.Ee=function(){return this.R.length+this.H.length};_.h.Ed=function(){return _.Gb(this.R)&&_.Gb(this.H)};_.h.clear=function(){this.R=[];this.H=[]};_.h.contains=function(a){return _.Fb(this.R,a)||_.Fb(this.H,a)};_.h.remove=function(a){var b=this.R;var c=(0,_.vb)(b,a);0<=c?(_.Ib(b,c),b=!0):b=!1;return b||_.Jb(this.H,a)}; _.h.Id=function(){for(var a=[],b=this.R.length-1;0<=b;--b)a.push(this.R[b]);for(var c=this.H.length,b=0;bOmar Saleem - Google+Press question mark to see available shortcut keysHomeCollectionsJoin Google+Send FeedbackHelpRegionPrivacy Policy - Terms of Service - Maps Terms©2017 GoogleSearchSign inAboutSearchSign inOmar SaleemAboutOmar's interestsView allOmar's posts Post has shared contentOmar SaleemPublic41wOriginally shared by Shannan Muskopf - 1 commentPink Floyd + Asteroid = Mesmerizing.Discovery Channel - Large Asteroid Impact Simulation no plus ones no comments no shares Post has shared contentOmar SaleemPublic48wOriginally shared by Neuroscience Roi-Girard - 5 commentsBright light alters metabolismSurfing internet before sleep. Scientists found bright light exposure increased insulin resistance compared to dim light exposure in both the morning and the evening. In the evening, bright light also caused higher peak glucose (blood sugar) levels.Read more -https://www.sciencedaily.com/releases/2016/05/160518141416.htm #neurocience #light #aging #brain #neurons #synapses no plus ones no comments no shares Post has shared contentOmar SaleemPublic49wOriginally shared by Engadget - 1 commentGoogle Science Journal studies the world through your phone http://engt.co/20nfxXWGoogle Science Journal studies the world through your phoneengadget.com no plus ones no comments no shares Post has attachmentOmar SaleemPublic50wSo proudIndia's little known ice hockey team no plus ones no comments no shares Post has attachmentOmar SaleemPublic52wThe brain as a model for future supercomputersphys.org no plus ones no comments no shares Post has attachmentOmar SaleemPublicNov 16, 2015How I feel after my morning #Drewstanton #Cardinals #NFL #Seahawks #mondaymotivation Gfycat GIFgfycat.com one plus one 1 no comments no shares Post has shared contentOmar SaleemPublicNov 9, 2015Originally shared by annarita ruberto - 13 commentsNovember 8, 1895: Roentgen's Discovery of X-RaysOver the course of one short year at the turn of the 20th century, one man's accidental discover revolutionized the practice of medicine.In 1895, Wilhelm Conrad Roentgen was a little-known German physicist researching the behavior of cathode rays. In those days, no one knew anything about electrons or radiation. Roentgen was running high-voltage current through vacuum tubes to study the escaping cathode rays. He was surprised to find, though, when he covered the tube with black cardboard, that some invisible rays were still able to illuminate a screen coated with platinobarium 9 feet (2.7 meters) away [source: American Physical Society>> http://www.aps.org/publications/apsnews/200111/history.cfm].He called the unknown phenomena "X-rays."In short time, Roentgen discovered that X-rays could also be captured on photographic plates. Using his wife's hand as a test subject — what a gentleman! — he was floored by the resulting image. X-rays passed easily through skin and muscle, but were blocked by bone and metal. For the first time, we could see inside the human body without raising a scalpel.The medical community leaped on the invention, which Roentgen generously refused to patent. Within a year, the first diagnoses of broken bones and swallowed coins were being made by X-ray [source: APS>> http://www.aps.org/publications/apsnews/200111/history.cfm]. Soon the mysterious rays were being used to treat cancerous tumors and skin diseases.The dangerous effects of X-ray exposure weren't known initially, but now doctors and technicians take special precautions to avoid the side effects of radiation [source: British Library>> http://www.bl.uk/learning/artimages/bodies/xray/roentgen.html].Roentgen received the very first Nobel Prize in Physics in 1901 for his discovery.► Source>>http://history.howstuffworks.com/historical-events/10-history-happiest-accidents8.htm#page=7► Image source and explanation: One of the earliest photographic plates from Roentgen's experiments was a film of his wife, Bertha's hand with a ring, produced on Friday, November 8, 1895.>> http://www.ovo.com/en/wilhelm-rontgen-science/#science_history #Roentgen #Xraysdiscovery #medicine #health no plus ones no comments no shares Post has attachmentOmar SaleemPublicOct 31, 2015Redesigned to maximize value. Get things done and that leaky faucet fixed! #Joblyt Joblytplay.google.com no plus ones no comments no shares Post has attachmentOmar SaleemPublicOct 28, 2015Why Cuban cab drivers earn more than doctors no plus ones no comments no shares Post has attachmentOmar SaleemPublicMay 9, 2015This is the place and the area. +Faisal Saleem+Rehana Khan +Ahmad Saleem +Mohammad Saleem295 York Sthttp://goo.gl/maps/Q71XtGoogle Mapsgoo.gl 2 plus ones 2 no comments no sharesLooks like you've reached the endLooks like you've reached the endUnable to load more. RetryWait while more posts are being loaded

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Billy Graham Commemorative Print & A Life in Pictures Bundle (Billy Graham in New York, 1991): Ken Garfield - Christianbook.com
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Revision as of 16:47, 20 September 2011 (view source)
Revision as of 23:09, 19 April 2013 (view source)
{{Michigan-stub}} ''[[United States|United States ]] > [[Michigan|Michigan]] > Oakland County''

''[[United States|United States]] [[Image:Gotoarrow.png]] [[Michigan]] [[Image:Gotoarrow.png]]'' ''Oakland County''
Guide to '''Oakland County Michigan genealogy.''' Birth records, marriage records, death records, census records, family history, and military records.
| county = Oakland County
| seat = Pontiac
| building address = Oakland County Courthouse
1200 N Telegraph Rd.
Pontiac, MI 48341
Phone:248.858.0572
 [http://www.oakgov.com/circuit/'''Oakland County Website'''] }}
[http://www.oakgov.com/circuit/ Oakland County Courthouse]
1200 N Telegraph Rd.
Pontiac, MI 48341
Phone: (248) 858-0572

County Clerk has birth and death records from 1867,
marriage and naturalization records from 1827. <ref name="HBG">''Handybook for Genealogists: United States of America'', 10th ed. (Draper, Utah: Everton Pub., 2002), Oakland County, Michigan page 349, {{WorldCat|50140092|disp=At various libraries (WorldCat)}}; {{FHL|1049485|item|disp=FHL Book 973 D27e 2002}}.</ref>
Avon (extinct) - now Rochester Hills
*[http://www.billiongraves.com/pages/cemetery/cemetery.php?cemetery_id=51535 Oak Hill Cemetery, Holly (Township)] BillionGraves
*[http://billiongraves.com/pages/cemetery/cemetery.php?cemetery_id=159030 St. Mary's Cemetery, Milford Township] BillionGraves
[[Oakland County, Michigan#Cemeteries|Oakland County, Michigan Cemeteries]]
Irwin I. Cohn Michigan Jewish Cemetery Index - [http://98.130.55.106/index.php?option=com_content&task=view&id=68&Itemid=57 online index] to more than 64,000 Jewish burials from the mid-1800’s to 1999.
:- [[1st_Regiment,_Michigan_Cavalry|1st Regiment, Michigan Cavalry]], Company G
:- [[1st Regiment, Michigan Cavalry|1st Regiment, Michigan Cavalry]], Company G
marriage and naturalization records from 1827. [1]
Retrieved from "https://www.familysearch.org/wiki/en/index.php?title=Oakland_County,_Michigan_Genealogy&oldid=1309757"

value: This website is a nonprofit organization and website offering genealogical records, education, and software. It is operated by The Church of Jesus Christ of Latter-day Saints , and is closely connected with the church's Family History Department.


text:
December industrial production boosts recovery hopes | Business | The Guardian
December industrial production boosts recovery hopes
• UK industrial production growth outstrips forecasts
• Hopes of upward revision to
0.1% GDP growth figure
Statfjord A oil platform in the North Sea - the wider measure of industrial production including North Sea oil was up 0.5% in December. Photograph: EPA
Wednesday 10 February 2010 06.04 EST
Last modified on Wednesday 10 February 2010 06.14 EST
British manufacturing output rose more than expected in December, boosting hopes the economy is on the road to recovery.
The Office for National Statistics said today that manufacturing rose by 0.9% on the month, from an upwardly revised 0.2% in November. This was three times faster than economists had forecast.
The broader measure of industrial production, which includes North Sea oil and gas output and accounts for 17% of the economy, also rose by slightly more than expected, growing by 0.5% on the month. Analysts had forecast a rise of 0.2%.
Howard Archer, chief UK economist at research group IHS Global Insight, said: "Manufacturing output surged in December while November's performance was revised up to show a modest gain, thereby providing a very welcome boost to recovery hopes after some recent disappointments."
He noted that industrial production grew by 0.4% quarter-on-quarter during the last three months of the year, rather than the 0.1% that had been estimated, and said it gave "a modest lift to hopes that overall GDP growth of 0.1% quarter-on-quarter could be revised up."
The ONS said the figures implied an upward revision of less than 0.1 percentage points to the GDP estimate, other things being equal.
Manufacturing was down 1.9% in the year to December and industrial production was down 3.6% during the same period.

value: This website is a British news and media website owned by the Guardian Media Group. It contains nearly all of the content of the newspapers The Guardian and The Observer, as well as a substantial body of web-only work produced by its own staff, including a rolling news service.


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