US20040241171A1 - Leukocyte inactivation module - Google Patents

Leukocyte inactivation module Download PDF

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Publication number
US20040241171A1
US20040241171A1 US10/489,831 US48983104A US2004241171A1 US 20040241171 A1 US20040241171 A1 US 20040241171A1 US 48983104 A US48983104 A US 48983104A US 2004241171 A1 US2004241171 A1 US 2004241171A1
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United States
Prior art keywords
leukocytes
ligand
module
activity
module according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US10/489,831
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English (en)
Inventor
Martin Scholz
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Individual
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Individual
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Publication of US20040241171A1 publication Critical patent/US20040241171A1/en
Priority to US12/114,349 priority Critical patent/US7850969B2/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a leukocyte inactivation module (LIM) and a process for reducing the activity of leukocytes.
  • LIM leukocyte inactivation module
  • SIRS Systemic Immune Response Syndrome
  • MODS Multiple Organ Dysfunction Syndrome
  • the activated leukocytes in particular, neutrophils
  • the activated leukocytes should be removed from the blood stream and inactivated immediately.
  • the cells still living produce and secrete pathogenic substances (cytokines, enzymes, oxygen radicals etc.) that are responsible for the actual pathogenesis.
  • pathogenic substances cytokines, enzymes, oxygen radicals etc.
  • the enzyme elastase produced by activated neutrophils is secreted in a higher amount.
  • Elastase acts inter alia on the extracellular matrix of the vessel wall and cleaves interendothelial cell-cell contacts resulting in an increased permeability of the vessel walls, in edema, in enhanced inflammation and the like.
  • Apoptosis is one of the most important regulation elements of the immune system.
  • the apoptosis of immunrelevant cells results in a normalisation of the activity of the immune system after an immune response, e.g. against microbial pathogens.
  • the immune system must kill those immune cells acting on endogenous structures or on natural antigens from the environment (e.g. autoimmune diseases or allergies).
  • T-cells being activated via so-called antigen-presenting cells (apc) usually receive several pieces of information.
  • the antigen processed by the apc is presented in the group of the MHC-I or MHC-II molecule.
  • the cell becomes apoptotic.
  • Another essential mechanism resulting in apoptosis is started via the Fas/FasL pathway.
  • endothelial cells of the vessel walls or other epithelial cells can express FasL thus protecting the tissue from entering activated immune cells.
  • the present invention is to provide a device suitable for reducing the activity of leukocytes, thereby reducing the secretion of pathogenic substances by the leukocytes. Furthermore, the present invention is to provide a process for reducing the activity of leukocytes using such device.
  • the present inventors carried out investigations with cytomegalovirus-infected retinal pigment epithelial cells from the human eye and found that, due to the contact with FasL on the epithelial cells, activated neutrophils lost their ability to maintain or increase the adhesion to the epithelial cells.
  • This surprising result is supposed to be a protecting mechanism of the endothelium and the respective tissue against inflammatory incidents.
  • the functional loss of the neutrophil-effector-mechanisms could be observed within minutes after cell-cell contact and seems to be largely independent of the apoptotic signal pathway in the neutrophils.
  • the Fas/FasL pathway or other early inhibitory mechanisms of the leukocyte-effector functions can be employed for the experimental and clinical use for acute excessive immune reactions.
  • the present invention provides a module for reducing the activity of leukocytes, which comprises a carrier and a ligand that is linked to the carrier and is suitable for interacting with a leukocyte receptor. Furthermore, the present invention provides a process for reducing the activity of leukocytes using said module.
  • the advantage of the present invention is that after binding the activated leukocytes in the leukocyte inactivation module (LIM), the damaging activity of the cells is inhibited within minutes. This is due to the contact of specific receptors on the cell membrane of the leukocytes with the respective ligands in the LIM.
  • the ligands can be proteins inducing, after contact with the receptor on the cell membrane, a signal that stimulates leukocytes to reduce the secretory activity and the immunogenicity.
  • a possibility to achieve this is the induction of apoptosis via relevant receptor-ligand interactions, e.g. Fas/FasL.
  • the module according to the present invention is suitable for being introduced into the patient's blood stream using a Shaldon catheter or into the circulation of a heart-lung machine.
  • the module preferably consists of a plastic housing with a diameter of e.g. 10 cm.
  • the blood inlet nozzle and the blood outlet nozzle are adapted to the tube connections of the heart-lung machine.
  • a carrier in the module e.g. a three dimensionally folded polyester membrane with modified surface for the adhesion of activated leukocytes and for their inactivation and killing (e.g induction of apoptosis) via receptor-induced signals.
  • the carrier material can be any material that is suitable for binding ligands.
  • binding used herein comprises both covalent and non-covalent binding, e.g. salt binding, hydrophobic interactions and affinity binding, of a ligand to the carrier.
  • the ligand may be bound directly or indirectly to the carrier.
  • the indirect binding comprises binding via a binding mediator, e.g. a long-chain molecule, for a better presentation of the ligand or via a cell comprising the ligand and being bound to the carrier via another binding interaction.
  • the LIM according to the present invention is suitable for any leukocytes, i.e. for B-lymphocytes, T-lymphocytes, granulocytes, neutrophils.
  • Fas-expressing (Fas+) and Fas-deleted (Fas ⁇ ; expresses no Fas on the surface) Jurkat cells as test cells were added to the wells in a concentration of 1 ⁇ 10 6 /ml for 24 hours.
  • the apoptosis rate and the necrosis rate were determined quantitatively by flow cytometry using an annexin binding assay.
  • Fas-Jurkat cells showed no significant increase in the annexin V binding property after cultivation in the pre-treated wells. In contrast thereto, a significant induction of apoptosis showed in dependency on the concentration of the IgM antibody. Fas+ Fas ⁇ 0 ng 24.81% 24.29% (control value) 10 ng 31.38% 27.57% 50 ng 40.95% 26.20% 100 ng 89.31% 29.65%
  • FIG. 1 shows the results of the example of the present invention.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Immunology (AREA)
  • Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Genetics & Genomics (AREA)
  • Veterinary Medicine (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biotechnology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Microbiology (AREA)
  • Hematology (AREA)
  • Biochemistry (AREA)
  • General Engineering & Computer Science (AREA)
  • Cell Biology (AREA)
  • Transplantation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • External Artificial Organs (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Immobilizing And Processing Of Enzymes And Microorganisms (AREA)
US10/489,831 2001-09-27 2002-09-16 Leukocyte inactivation module Abandoned US20040241171A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US12/114,349 US7850969B2 (en) 2001-09-27 2008-05-02 Leukocyte inactivation module

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10147638A DE10147638B4 (de) 2001-09-27 2001-09-27 Leukozyten-Inaktivierungs-Modul (LIM)
DE10147638.8 2001-09-27
PCT/DE2002/003466 WO2003031473A1 (de) 2001-09-27 2002-09-16 Leukozyten-inaktivierungs-modul (lim)

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/114,349 Continuation US7850969B2 (en) 2001-09-27 2008-05-02 Leukocyte inactivation module

Publications (1)

Publication Number Publication Date
US20040241171A1 true US20040241171A1 (en) 2004-12-02

Family

ID=7700470

Family Applications (2)

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US10/489,831 Abandoned US20040241171A1 (en) 2001-09-27 2002-09-16 Leukocyte inactivation module
US12/114,349 Expired - Fee Related US7850969B2 (en) 2001-09-27 2008-05-02 Leukocyte inactivation module

Family Applications After (1)

Application Number Title Priority Date Filing Date
US12/114,349 Expired - Fee Related US7850969B2 (en) 2001-09-27 2008-05-02 Leukocyte inactivation module

Country Status (15)

Country Link
US (2) US20040241171A1 (de)
EP (1) EP1430085B1 (de)
JP (1) JP5503826B2 (de)
CN (1) CN100346822C (de)
AT (1) ATE438661T1 (de)
BR (1) BR0212816A (de)
CA (1) CA2461900A1 (de)
DE (4) DE20121877U1 (de)
HU (1) HUP0401803A2 (de)
MX (1) MXPA04002736A (de)
NO (1) NO20041682L (de)
PL (1) PL368596A1 (de)
RU (1) RU2327490C2 (de)
WO (1) WO2003031473A1 (de)
ZA (1) ZA200402205B (de)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100306144A1 (en) * 2009-06-02 2010-12-02 Scholz Martin B System and method for classifying information
US20200059262A1 (en) * 2017-04-28 2020-02-20 Yamaha Corporation Receiving apparatus and signal transmitting system

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE20121877U1 (de) 2001-09-27 2003-09-18 Leukocare Gmbh Leukozyten-Inaktivierungs-Modul (LIM)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5639376A (en) * 1994-01-10 1997-06-17 Hemasure, Inc. Process for simultaneously removing leukocytes and methylene blue from plasma
US5840083A (en) * 1989-01-27 1998-11-24 F.B. Rice & Co. Implant device having biocompatiable membrane coating
US6797514B2 (en) * 2000-02-24 2004-09-28 Xcyte Therapies, Inc. Simultaneous stimulation and concentration of cells

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69119683T2 (de) * 1990-07-27 1996-10-02 Pall Corp Filtereinrichtung zur Entfernung von Leukozyten und Methode zur Verwendung
CA2180328A1 (en) * 1994-01-10 1995-07-13 Franco Castino Device and process for removing leukocytes and viral inactivating agents from blood
JPH08173528A (ja) * 1994-12-26 1996-07-09 Terumo Corp 血液処理システム
WO1997012632A1 (en) * 1995-10-05 1997-04-10 Tkb Associates Limited Partnership Methods for treatment of diseases associated with a deficiency of fas ligand activity
AU2674097A (en) * 1996-04-17 1997-11-07 Cytotherapeutics, Inc. Method and device for delivery of apoptosis-inducing molecules
JPH1076004A (ja) * 1996-09-05 1998-03-24 Kanegafuchi Chem Ind Co Ltd 体液処理用吸着材及び体液処理用吸着器
WO1998046242A1 (en) * 1997-04-11 1998-10-22 Stanford University Treatment of cancer by the administration of fas ligand expressing non-tumorigenic cells
US6204055B1 (en) * 1999-04-12 2001-03-20 Isis Pharmaceuticals, Inc. Antisense inhibition of Fas mediated signaling
DE60027863T2 (de) * 1999-03-17 2006-12-07 Jimro Co., Ltd., Takasaki Apherese von leukozyten aus blut zur behandlung von hiv
JP2001103977A (ja) * 1999-10-12 2001-04-17 National Institute Of Animal Health ブタＦａｓリガンドの構造遺伝子
DE20121877U1 (de) 2001-09-27 2003-09-18 Leukocare Gmbh Leukozyten-Inaktivierungs-Modul (LIM)

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5840083A (en) * 1989-01-27 1998-11-24 F.B. Rice & Co. Implant device having biocompatiable membrane coating
US5639376A (en) * 1994-01-10 1997-06-17 Hemasure, Inc. Process for simultaneously removing leukocytes and methylene blue from plasma
US6797514B2 (en) * 2000-02-24 2004-09-28 Xcyte Therapies, Inc. Simultaneous stimulation and concentration of cells

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100306144A1 (en) * 2009-06-02 2010-12-02 Scholz Martin B System and method for classifying information
US20200059262A1 (en) * 2017-04-28 2020-02-20 Yamaha Corporation Receiving apparatus and signal transmitting system
US10784923B2 (en) * 2017-04-28 2020-09-22 Yamaha Corporation Receiving apparatus and signal transmitting system

Also Published As

Publication number Publication date
DE20121877U1 (de) 2003-09-18
DE10294578D2 (de) 2004-08-26
JP2005507908A (ja) 2005-03-24
EP1430085A1 (de) 2004-06-23
CN100346822C (zh) 2007-11-07
RU2327490C2 (ru) 2008-06-27
EP1430085B1 (de) 2009-08-05
DE50213747D1 (de) 2009-09-17
CA2461900A1 (en) 2003-04-17
BR0212816A (pt) 2004-10-05
US20080292643A1 (en) 2008-11-27
RU2004112762A (ru) 2005-04-20
WO2003031473A1 (de) 2003-04-17
ATE438661T1 (de) 2009-08-15
MXPA04002736A (es) 2005-09-08
PL368596A1 (en) 2005-04-04
JP5503826B2 (ja) 2014-05-28
DE10147638A1 (de) 2003-04-17
CN1558915A (zh) 2004-12-29
DE10147638B4 (de) 2004-05-27
US7850969B2 (en) 2010-12-14
NO20041682L (no) 2004-04-26
HUP0401803A2 (hu) 2004-11-29
ZA200402205B (en) 2004-08-16

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