DE19952509A1 - Polyclonal antiserum against human leucocyte antigen-G, useful for predicting success of in vitro fertilization and for prognosis of melanoma - Google Patents

Polyclonal antiserum against human leucocyte antigen-G, useful for predicting success of in vitro fertilization and for prognosis of melanoma

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Publication number
DE19952509A1
DE19952509A1 DE19952509A DE19952509A DE19952509A1 DE 19952509 A1 DE19952509 A1 DE 19952509A1 DE 19952509 A DE19952509 A DE 19952509A DE 19952509 A DE19952509 A DE 19952509A DE 19952509 A1 DE19952509 A1 DE 19952509A1
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hla
polyclonal antiserum
antiserum against
soluble hla
vitro fertilization
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Hans Grosse-Wilde
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GROSSE WILDE HANS
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GROSSE WILDE HANS
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/5743—Specifically defined cancers of skin, e.g. melanoma
    • 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
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2833—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against MHC-molecules, e.g. HLA-molecules
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/689—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to pregnancy or the gonads
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

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Abstract

Polyclonal antiserum (A) against the peptides (I) EEETRNTKAHAQTDRM; and (II) MSVRESRSLSENL, is new. An Independent claim is also included for use of soluble human leukocyte antigen (HLA)-G for inhibiting proliferation of T lymphocytes.

Description

Die Erfindung betrifft den Nachweis von HLA-G Molekülen mittels polyklonaler Antiseren, die Verwendung des Nachweises zur Ermittlung von Behandlungs- und Erkrankungsrisiken sowie die Verwendung löslicher HLA-G Moleküle zu therapeutischen Zwecken.The invention relates to the detection of HLA-G molecules using polyclonal antisera, the use of the Evidence to determine treatment and Risks of disease and the use of soluble HLA-G Molecules for therapeutic purposes.

HLA Moleküle sind die Genprodukte von eng gekoppelt vererbten Genorten (HLA Genorte), die zumeist hochpolymorph sind (multiple Allelie) sind und auf dem kurzen Arm von Chromosom 6 (C6p21) lokalisiert sind. HLA ist die Abkürzung für Humane Leukozyten Antigene.HLA molecules are the closely linked gene products inherited gene locations (HLA gene locations), mostly are highly polymorphic (multiple allelia) and on the short arm of chromosome 6 (C6p21) are localized. HLA is the abbreviation for human leukocyte antigens.

Ein analoger und für andere Tierspezies verwendeter Begriff ist MHC = Major Histocompatibility Complex, da MHC Genprodukte eine große Relevanz für die Gewebeverträglichkeit im Rahmen der Transplantation haben.An analog and used for other animal species The term is MHC = Major Histocompatibility Complex, because MHC gene products are of great relevance to the Tissue tolerance as part of the transplant to have.

HLA bzw. MHC Moleküle sind an der Reaktionskette des Immunsystems beteiligt, auf einen Reiz mit einer zellulären Immunreaktion spezifisch zu reagieren. Nach heutiger Kenntnis sind die zentralen Aufgaben von HLA Molekülen, bestimmten Rezeptoren auf T-Lymphozyten (T- Zell-Rezeptor) Peptide zu präsentieren. Diese Peptide können einer intrazellulären Produktion oder einer exogenen Zufuhr von (Glyko-)Proteinen, d. h. Antigenen entstammen. HLA and MHC molecules are on the reaction chain of the Immune system involved in a stimulus with a cellular immune response to respond specifically. To Today's knowledge is the central task of HLA Molecules, certain receptors on T lymphocytes (T- Cell receptor) to present peptides. These peptides can be an intracellular production or a exogenous supply of (glyco) proteins, d. H. Antigens come from.  

Aufgrund ihrer Molekülstruktur und biologischen Funktion werden 3 Klassen von HLA Genprodukten unterschieden: HLA Klasse I, Klasse II, Klasse III.Because of their molecular structure and biological function There are 3 classes of HLA gene products: HLA Class I, Class II, Class III.

HLA Klasse I Moleküle bzw. Antigene werden auf nahezu allen Soma-Zellen exprimiert, d. h. sind membranständige Heterodimere, die aus einer schweren (alpha) Kette und einer leichten (beta) Kette bestehen. Letzteres ist das bekannte beta-2-Mikroglobulin, dessen Strukturgen auf Chromosom 15q liegt. Jede alpha Kette eines HLA Klasse I Moleküls besteht aus einem zytoplasmatischen, transmembranalen und extrazytoplasmatischen Teil. Typische HLA Klasse I Genorte sind die HLA-A, HLA-B und HLA-C Loci.HLA class I molecules or antigens are almost on all soma cells expressed, i.e. H. are membrane-bound Heterodimers consisting of a heavy (alpha) chain and a light (beta) chain. The latter is that known beta-2-microglobulin, whose structural gene Chromosome 15q lies. Every HLA class I alpha chain Molecule consists of a cytoplasmic, transmembrane and extracytoplasmic part. Typical HLA class I loci are HLA-A, HLA-B and HLA-C loci.

Der Polymorphismus der HLA Klasse I Antigene liegt in der Varianz der Aminosäurensequenzen primär im extrazytoplasmatischen Teil (Exon 2 und Exon 3) der schweren Kette, die eine Vertiefung oder Grube bildet, in die Peptide zur Präsentation eingelagert werden. Die unterschiedlichen AA-Sequenzen verschiedener HLA Antigene "diktieren", welche Peptide eingelagert bzw. den T-Zell- Rezeptoren präsentiert werden können.The polymorphism of the HLA class I antigens lies in the Variance of the amino acid sequences primarily in extracytoplasmic part (exon 2 and exon 3) of the heavy chain that forms a depression or pit in the peptides are stored for presentation. The different AA sequences of different HLA antigens "dictate" which peptides are stored or which T-cell Receptors can be presented.

In letzter Zeit wurden auf C6p21 sog. nicht-klassische HLA Klasse I Genorte bzw. Genprodukte identifiziert, die als HLA-E, HLA-F, HLA-G und HLA-H bezeichnet werden. Alle 4 Genorte sind nur gering polymorph (→ geringe Peptid- Varianz) und zeigen eine begrenzte Gewebeexpression.Lately, so-called non-classical ones have appeared on C6p21 HLA class I gene locations or gene products identified that referred to as HLA-E, HLA-F, HLA-G and HLA-H. All 4 gene locations are only slightly polymorphic (→ low peptide Variance) and show limited tissue expression.

HLA-G ist insbesondere im Rahmen der Immunbiologie einer Schwangerschaft intensiver untersucht worden. An der planzentaren Grenzfläche zwischen maternalem und fetalem Gewebe, den Synzytiotrophoblasten, werden keine HLA-A, B, C Antigene exprimiert sondern HLA-G, das gering bzw. gar nicht polymorph ist. Somit kann das Immunsystem der Schwangeren den "HLA-differenten" Fetus nicht als fremd erkennen.HLA-G is one particularly in the context of immunobiology Pregnancy has been studied more intensively. At the vegetal interface between maternal and fetal Tissue, the syncytiotrophoblast, are not HLA-A, B, C  Antigens express HLA-G, which is low or even is not polymorphic. Thus, the immune system Pregnant women do not consider the "HLA-different" fetus strange detect.

Eine zweite Funktion von HLA-G ist die Liganden- Interaktion mit einem Inhibitionsrezeptor auf sog. natürlichen Killer(NK)-Zellen (KIR = Killer-Inhibitor- Rezeptor). Sowohl membranständige als auch lösliche HLA-G Moleküle können somit über eine KIR-Bindung die Aktion von NK-Zellen inhibieren.A second function of HLA-G is the ligand Interaction with an inhibition receptor on so-called natural killer (NK) cells (KIR = killer inhibitor Receptor). Both membrane-based and soluble HLA-G Molecules can do the action via a KIR bond inhibit of NK cells.

Lösliche HLA Moleküle lassen sich z. B. mittels SDS-PAGE und Westernblot bzw. ELISA nachweisen. Extrem schwierig war dies bisher für den proteinchemischen Nachweis von löslichem HLA-G (solubles HLA-G = sHLA-G), da nahezu keine spezifischen Reagentien (monoklonale Antikörper) entwickelt worden sind.Soluble HLA molecules can e.g. B. using SDS-PAGE and Western blot or ELISA. Extremely difficult was previously for the protein chemical detection of soluble HLA-G (solubles HLA-G = sHLA-G), since almost no specific reagents (monoclonal antibodies) have been developed.

Ausgehend von den beschriebenen Eigenschaften und Funktionen liegt der vorliegenden Erfindung die Aufgabe zu Grunde einen spezifischen Nachweis von löslichem und/oder membranständigem HLA-G zu ermöglichen und diesen spezifischen Nachweis zur Ermittlung von Behandlungs- und Erkrankungsrisiken zu nutzen.Based on the described properties and Functions, the object of the present invention based on a specific proof of soluble and / or enable membrane-based HLA-G and this specific evidence to determine treatment and To use disease risks.

Basierend auf einer vergleichenden Analyse der AA- Sequenzen von allen bisher bekannten HLA Klasse I Allelen (HLA-A, B, C, E, F, G, H) wurden im Kaninchen polyklonale Antiseren gegen definierte Peptidsequenzen erzeugt, die für HLA-G spezifisch (membranständig und löslich) sind. Gemäß einer ersten Lehre der Erfindung wird ein erstes polyklonales Antiserum gegen die Peptid-Sequenz EEETRNTKAHAQTDRM (16mer) zur Verfügung gestellt, welches gemäß einer zweiten Lehre zur spezifischen Detektion von membranständigen und/oder löslichen HLA-G Molekülen verwandt wird.Based on a comparative analysis of the AA- Sequences from all known HLA class I alleles (HLA-A, B, C, E, F, G, H) were polyclonal in rabbits Antisera generated against defined peptide sequences are specific for HLA-G (membrane-bound and soluble). According to a first teaching of the invention, a first polyclonal antiserum against the peptide sequence EEETRNTKAHAQTDRM (16mer) provided which  according to a second teaching on the specific detection of membrane-bound and / or soluble HLA-G molecules is used.

Das erste polyklonale Antiserum gegen die Peptid-Sequenz EEETRNTKAHAQTDRM ist spezifisch für die alpha-1 Domäne des HLA-G's.The first polyclonal antiserum against the peptide sequence EEETRNTKAHAQTDRM is specific for the alpha-1 domain of the HLA-G.

Ein weiteres polyklonales Antiserum spezifisch für die Intron-4 Sequenz von sHLA-G soll die Etablierung eines sensitiven kompetitiven ELISA Formats ermöglichen. Gemäß einer dritten Lehre wird ein zweites polyklonales Antiserum gegen die Peptid-Sequenz MSVRESRSLSENL (13mer) zur Verfügung gestellt, welches gemäß einer vierten Lehre zur spezifischen Detektion von löslichen HLA-G Molekülen verwandt wird.Another polyclonal antiserum specific for the Intron-4 sequence of sHLA-G is said to establish a sensitive competitive ELISA format. According to a third teaching becomes a second polyclonal Antiserum against the peptide sequence MSVRESRSLSENL (13mer) provided, which according to a fourth teaching for the specific detection of soluble HLA-G molecules is used.

Gemäß einer fünften Lehre der Erfindung wird der Spiegel von löslichem HLA-G im Blutplasma/serum zur Vorhersage der Erfolgsaussichten für eine in-Vitro Fertilisation verwandt. Erste klinische Daten weisen auf eine diagnostische Relevanz von sHLA-G Bestimmungen im Blutplasma/serum von Frauen mit Fertilitätsstörungen (in­ vitro Fertilisations(IVF)-Therapie) hin: hohe sHLA-G Plasma/Serumspiegel (präovulatorisch!) sind mit einem verbesserten IVF-Therapie-Erfolg assoziiert (p < 0.01).According to a fifth teaching of the invention, the mirror of soluble HLA-G in blood plasma / serum to predict the prospects of success for in-vitro fertilization related. Initial clinical data point to one diagnostic relevance of sHLA-G determinations in Blood plasma / serum from women with fertility disorders (in in vitro fertilization (IVF) therapy): high sHLA-G Plasma / serum levels (preovulatory!) Are with one associated with improved IVF therapy success (p <0.01).

Gemäß einer sechsten Lehre der Erfindung wird der Spiegel von löslichem HLA-G im Blutplasma/serum zur Prognose des Erkrankungsverlaufs von an malignem Melanom erkrankten Patienten verwandt. Erste Analysen sprechen für eine Beziehung zwischen sHLA-G und Prognose von Malignem- Melanom(MM)-Patienten: hohe sHLA-G Plasmaspiegel erscheinen mit einer schlechten Prognose der MM-Patienten assoziiert.According to a sixth teaching of the invention, the mirror of soluble HLA-G in blood plasma / serum to predict the Disease course of malignant melanoma Patient related. Initial analyzes speak for one Relationship between sHLA-G and prognosis of malignant Melanoma (MM) patients: high sHLA-G plasma levels  appear with a poor prognosis of MM patients associated.

Schließlich wird gemäß einer sechsten Lehre die Verwendung von löslichem HLA-G zur Hemmung der Proliferation von T-Lymphozyten vorgeschlagen. Es gibt in der Literatur Hinweise, daß membranständiges HLA-G die Proliferation von T-Lymphozyten hemmt, was als Hinweis für eine immunsuppressive Potenz von HLA-G spricht. Der Mechanismus ist jedoch unklar. Therapeutisch könnte der Einsatz von gentechnisch erzeugtem sHLA-G (über Transfektanten) relevant werden. Erste invitro Hinweise der Hemmung von T-Zell-Proliferationen durch sHLA-G liegen vor.Finally, according to a sixth teaching Use of soluble HLA-G to inhibit the Proliferation of T lymphocytes suggested. There is in the literature evidence that membrane-bound HLA-G die Inhibits proliferation of T lymphocytes, which is indicative speaks for an immunosuppressive potency of HLA-G. The However, mechanism is unclear. Therapeutically, the Use of genetically engineered sHLA-G (over Transfectants) become relevant. First in vitro notes inhibition of T cell proliferation by sHLA-G are available.

Claims (10)

1. Polyklonales Antiserum gegen die Peptid-Sequenz EEETRNTKAHAQTDRM.1. Polyclonal antiserum against the peptide sequence EEETRNTKAHAQTDRM. 2. Verwendung eines polyklonales Antiserum gegen die Peptid-Sequenz EEETRNTKAHAQTDRM zur spezifischen Detektion von membranständigen und/oder löslichen HLA-G Molekülen.2. Use a polyclonal antiserum against the Peptide sequence EEETRNTKAHAQTDRM for specific Detection of membrane-bound and / or soluble HLA-G Molecules. 3. Polyklonales Antiserum gegen die Peptid-Sequenz MSVRESRSLSENL.3. Polyclonal antiserum against the peptide sequence MSVRESRSLSENL. 4. Verwendung eines polyklonales Antiserum gegen die Peptid-Sequenz MSVRESRSLSENL zur spezifischen Detektion von löslichen HLA-G Molekülen.4. Use a polyclonal antiserum against the Peptide sequence MSVRESRSLSENL for specific detection of soluble HLA-G molecules. 5. Verwendung eines polyklonales Antiserum gegen die Peptid-Sequenz MSVRESRSLSENL in einem sensitiven kompetitiven ELISA Format.5. Use a polyclonal antiserum against the Peptide sequence MSVRESRSLSENL in a sensitive competitive ELISA format. 6. Verwendung des Spiegels von löslichem HLA-G im Blutplasma/serum zur Vorhersage der Erfolgsaussichten für eine in-Vitro Fertilisation.6. Using the level of soluble HLA-G in Blood plasma / serum to predict the chances of success for in vitro fertilization. 7. Verwendung nach Anspruch 6, dadurch gekennzeichnet, daß einem hohen Spiegel von löslichem HLA-G höhere Erfolgsaussichten für eine in-Vitro Fertilisation zugeordnet wird. 7. Use according to claim 6, characterized in that a high level of soluble HLA-G higher Prospects of success for in-vitro fertilization is assigned.   8. Verwendung des Spiegels von löslichem HLA-G im Blutplasma/serum zur Prognose des Erkrankungsverlaufs von an malignem Melanom erkrankten Patienten.8. Using the level of soluble HLA-G in the Blood plasma / serum to predict the course of the disease of patients suffering from malignant melanoma. 9. Verwendung nach Anspruch 8 dadurch gekennzeichnet, daß einem hohen Spiegel von löslichem HLA-G eine schlechte Prognose des Erkrankungsverlaufs von an malignem Melanom erkrankten Patienten zugeordnet wird.9. Use according to claim 8 characterized in that a high level of soluble HLA-G is bad Prognosis of the course of the disease of malignant melanoma is assigned to sick patients. 10. Verwendung von löslichem HLA-G zur Hemmung der Proliferation von T-Lymphozyten.10. Use of soluble HLA-G to inhibit the Proliferation of T lymphocytes.
DE19952509A 1999-11-03 1999-11-03 Polyclonal antiserum against human leucocyte antigen-G, useful for predicting success of in vitro fertilization and for prognosis of melanoma Withdrawn DE19952509A1 (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999042128A1 (en) * 1998-02-20 1999-08-26 Commissariat A L'energie Atomique Method for selecting tumours expressing hla-g, sensitive to anticancer treatment and uses
WO1999043851A1 (en) * 1998-02-25 1999-09-02 National University Of Ireland, Cork Hla linked pre-eclampsia and miscarriage susceptibility gene

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999042128A1 (en) * 1998-02-20 1999-08-26 Commissariat A L'energie Atomique Method for selecting tumours expressing hla-g, sensitive to anticancer treatment and uses
WO1999043851A1 (en) * 1998-02-25 1999-09-02 National University Of Ireland, Cork Hla linked pre-eclampsia and miscarriage susceptibility gene

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