DE10135615A1 - Treatment of antigen-presenting cells or their precursors, useful e.g. in treatment of leukemia, by suppressing allologous immune responses to tissue grafts - Google Patents

Abstract

Antigen-presenting cells (APC), either obtained from precursor cells (A) or already present, that have been subjected to at least one specific treatment, are new. Antigen-presenting cells (APC), either obtained from precursor cells (A) or already present, that have been subjected to at least one of the specific treatments below, are new: (a) treatment with binding agents against B7 (1 or 2), CD83, CD40, CTLA4, Fas and/or TRAIL (Tumor necrosis factor-related apoptosis-inducing ligand); (b) for at least partially immature dendritic cells (DC), in vitro incubation with allogenic lymphocytes (X) of a foreign stem cell transplant donor; (c) transfection with at least one gene for a Fas-binding or TRAIL-binding molecule; (d) treatment with aspirin; 1a,25-dihydroxyvitamin D3; 1a,25-dihydroxy-16-ene-23-yne- 26,27-hexafluoro-19-nor-Vitamin D3; Vitamin D3 and/or glucocorticoids, to maintain DC in a state where their immunostimulatory activity is limited; (e) transfection with a sequence that encodes interleukin-10; (f) treatment with interleukin-10; (g) treatment with interferon (a, beta or psi ) to induce synthesis of TRAIL; (h) transfection with a gene for a CTLA4 binding molecule; and (i) transfection with a gene for a CD83 binding molecule, optionally also binding molecules for B7 and CD40. In all cases the treatment is followed by incubation with (X). (A) are stem cells, monocytes, DC, CD34+ (progenitor) stem cells, or B cells of a patient who is to be treated with an allogenic bone marrow transplant that may also contain blood lymphocytes. Independent claims are also included for: (1) preparing APC; and (2) (A) treated with an inhibitor of hypusin biosynthesis, e.g. N1-guanyl-1,7-diaminoheptane, to inhibit production of functional eIF-5A, which thus inhibits CD83 biosynthesis.

Description

The present invention relates to cells presenting antigen, Process for the production of antigen presenting cells, pharmaceuticals containing cells presenting antigen and use of Antigen-presenting cells.

description

For almost 10 years have been used for various diseases and in Animal models developed and applied gene therapy methods. So far they have not yet become routine. Mostly it is the Treatment of genetically determined, serious diseases, for the other Therapies are not available. Furthermore, gene therapies are being used Treatment of severe and also not treatable Cancer used.

General information about transplants

Tissue transplantation to replace diseased organs is today an important medical therapy. In most cases there is a reaction the adaptive immune system against the graft the greatest threat to successful treatment adaptable immune system are presented by antigen Cells induced by activation of T helper lymphocytes. In the Transfusions of blood, which was the first and most commonly used Is graft, the ABO and Rh blood group antigens must be matched are avoided so that the rapid destruction of inappropriate erythrocytes is avoided becomes. With other tissues, the very polymorphic Major histocompatibility complexes (Tissue Tolerance Complexes, MHC) be matched to each other, since this almost always involves the immune response trigger. Unfortunately, the MHCs are almost perfectly matched except for relatives impossible because the degree of agreement in the MHC pattern is often too low.

Stem cell transplants for leukemia

Leukemia is cancer of the blood cells. Get 50 out of 1 million a year People leukemia. If leukemia develops, the Body has large amounts of abnormal blood cells. For most types of Leukemia, the abnormal cells are white blood cells.

leukemias

There are several types of leukemia, which essentially have two characteristics demonstrate. One characteristic is how quickly the disease develops and aggravated. The other is affected by the type of blood cell that is certainly.

Leukemia is either acute or chronic. In acute leukemia they are abnormal blood cells very immature blasts that do not function normally can execute. The number of blasts increases rapidly and the suffering quickly get worse. With chronic leukemia there are some blasts present, but generally these cells are more mature and can do some of them perform normal functions. The number of blasts also increases more slowly than in acute leukemia. In chronic leukemia Gradually worse.

Leukemia essentially appears in two main types, and white blood cells in lymphoid cells or myeloid cells. Accordingly, the Leukemia as lymphoblastic leukemia or myeloid leukemia.

• - Die Akute Lymphatische Leukämie (ALL) ist die häufigste Leukämie bei kleinen Kindern. Diese Erkrankung kann auch bei Erwachsenen, insbesondere ab dem 65. Lebensjahr, auftreten.
• - Akute Myeloische Leukämie (AML) kommt bei Erwachsenen und Kindern vor. Dieser Leukämietyp wird manchmal Akute Nicht-Lymphatische Leukämie (ANLL) genannt.
• - Chronische Lymphatische Leukämie (CHL) trifft meistens Erwachsene ab dem 55. Lebensjahr. Sie tritt manchmal auch bei jüngeren Erwachsenen auf, betrifft aber so gut wie nie Kinder.
• - Die Chronische Myeloische Leukämie (CML) kommt meist bei Erwachsenen vor. Eine geringe Zahl von Kindern entwickelt diesen Krebs auch.

The most common leukemias are:

• - Acute Lymphoblastic Leukemia (ALL) is the most common leukemia in young children. This disease can also occur in adults, especially from the age of 65.
• - Acute myeloid leukemia (AML) occurs in adults and children. This type of leukemia is sometimes called acute non-lymphoblastic leukemia (ANLL).
• - Chronic lymphocytic leukemia (CHL) mostly affects adults over the age of 55. It sometimes occurs in younger adults, but hardly ever affects children.
• - Chronic myeloid leukemia (CML) mostly occurs in adults. A small number of children also develop this cancer.

Symptoms of leukemia

Leukaemic cells are abnormal cells that function more normally Cannot exercise blood cells. You can't help the body To fight infections. For this reason, people develop with Leukemia often infections and have a fever.

People with leukemia often also have less healthy red blood cells and platelets so that not enough red blood cells for the Oxygen transport through the body is available. Due Anemia, patients are often pale and feel dull and tired. Is the The number of platelets too low, the patients tend to bleed easily and quickly develop blue hematomas.

Like all blood cells, leukemic cells circulate in the body. Due to the Number of abnormal cells and their location, patients with Leukemia show various symptoms.

In acute leukemia, symptoms appear quickly, as does the condition the patient deteriorates rapidly. With chronic leukemia the symptoms do not appear for a long time. If symptoms appear, are they usually mild first and the general condition of the patient is only gradually deteriorating.

Symptoms of leukemia

• - fever, chills, and other flu-like symptoms;
• - weakness and fatigue;
• - frequent infections;
• - loss of appetite and / or weight;
• - swollen or sensitive lymph nodes, liver, or spleen;
• - fast bleeding or bruising;
• - small red spots under the skin;
• - swollen or bleeding gums;
• - sweating, especially at night; and or
• - bone or joint pain.

In acute leukemia, the abnormal cells in the brain or in the Collect the spinal cord (central nervous system or CNS). The result can then cause headache, nausea, nausea, confusion, loss of Be in control of the muscles and strokes. Leukemic cells can also collect in the testicles and cause swelling there. Some patients develop painful eyes or skin. Leukemia can also the digestive tract, kidneys, lungs or other parts of the body influence.

With chronic leukemia, the abnormal cells can gradually get in collect different parts of the body. Chronic leukemia can Skin, CNS, digestive tract, kidneys and testicles.

Treatment of leukemia

Treating leukemia is complex. It varies with the type of Leukemia and is not the same in all patients. The treatment also depends of certain peculiarities of leukemic cells, the extent of Disease, whether the leukemia has been treated before. Age too the patient's symptoms and general health relevant factors.

Acute leukemia must be treated immediately. Patients with chronic Leukemia that show no symptoms do not need to be treated immediately. Unfortunately, chronic leukemia can rarely be cured.

treatment methods

Most patients with leukemia are treated with chemotherapy. Some are additionally irradiated and / or receive one Bone marrow transplantation (KMT, English: bone marrow transplantation = BMT) or biological therapies. In some cases, removal of the spleen can help. Patients receive one before a bone marrow transplant Whole-body radiation combined with chemotherapy to do that Destroying leukemia-producing bone marrow.

The healthy bone marrow can come from a donor or it can come from the patient. Then it will be before the high dose treatment Taken and treated outside the body to make leukemic cells remove. After that, a hospital stay of several weeks is necessary the graft grow and enough white blood cells (Leukocytes) such as T, B lymphocytes, neutrophils, basophils and eosinophils Granulocytes, platelets (platelets), monocytes and the like. a. subpopulations for the reconstitution (restoration) of the hematopoietic (hematopoietic Systems) can produce. In the meantime, the patient must go ahead Infections are protected.

The biological therapies include treatments with substances that the Affect immune response to cancer. Cytokines, like most of all Interferons, interleukins, and colony stimulating factors (CSF) are found z. B. used in some types of leukemia. You will mostly be with Combined chemotherapy or bone marrow transplant.

Bone marrow transplant

Bone marrow transplant patients are at increased risk for Infections, bleeding and other side effects from high doses of the Chemotherapy drugs and the radiation they receive. additionally There may be graft versus recipient responses (graft versus host disease (GVHD)). The liver, skin and digestive tract are the most frequently affected organs. GVHD can be mild or be severe and occur at any time after the transplant (also Years later). Immunosuppressants are given to reduce the risk of Reduce and treat GVHD.

Chronic myeloid leukemia

The mode of action of bone marrow transplants is explained below using the example of chronic myeloid leukemia:
All marrow bone marrow transplantation (BMT) has provided treatment options for chronic myeloid leukemia (CML) in the past 20-30 years. However, no suitable donors can be found for about 60% of the patients.

CML is identified in the early chronic phase by a single characterized transformative genetic abnormality. It is about t (9; 22) translocation (Philadelphia Chromosome, Ph), which the bcr-abl created Oncogen, the only factor that is essential for the Development of the disease is needed (Daley et al 1990). Compared to other tumor types in the chronic phase have CML patients relatively intact immune system (Lewalle et al 1996). CML is for one tumor-specific immune response accessible. In the past 20-30 Years ago, anti-tumor responses were from allologists Bone marrow transplants (allo-BMT) and most recently from donor Clinically, leukocyte infusions [Donor leukocyte infusion (DLI)] Treatment of CML exploited.

The detection and extinction of remaining tumor cells by Donor immune cells seem essential for the induction of a molecular one To be in remission. Grafts from which the T cells have been removed increase the risk of relapse to CML (Champlin et al 1988; Horowitz et al 1990). A stringent demonstration of the one generated by allo-BMT Anti-leukemia effect can be seen when DLI is administered as soon as the disease reappears. In this constellation, DLI can reinstate persistent molecular remission in up to 70% of cases (MacKinnon 2000). But DLI also has significant toxicity, caused by a GVHD connection. This often accompanies the Graft-versus-leukemia (GVL) effect. The mortality is included 50-90% (MacKinnon 2000).

• - Erhöhtes Risiko eines Rückfalls bei T-Zell-Exklusion aus dem Transplantat
• - Erhöhtes Risiko eines Rückfalls bei Abwesenheit von GVHD
• - BMT von syngenen Zwillingen ist weniger effektiv als passendes BMT von Geschwistern
• - Der Rückfall reagiert auf eine Absetzung einer Immunsuppression
• - Spender-Leukozyten-Infusionen sind bei einem Rückfall effektiv

Instructions for immune regulation in CML:

• - Increased risk of relapse if T-cell is excluded from the graft
• - Increased risk of relapse in the absence of GVHD
• - BMT from syngeneic twins is less effective than matching BMT from siblings
• - The relapse reacts to the discontinuation of immunosuppression
• - Donor leukocyte infusions are effective in relapse

The Allo-BMT presents a rather rough approach with significant ones Transplant-related morbidity and mortality. The risk of dying is 20-41% (Silver et al 1999). This form of immunotherapy also offers an up to 70% leukemia-free survival rate for the transplant recipients (Clift & Anasetti 1997). This GvHD overlays the desired one antileukaemic effect.

Bone marrow transplants are also used for other leukemias applied.

Graft-versus-host disease (GvHD)

Graft versus host disease (GvHD) is a major cause of morbidity and mortality after allogeneic transplantation and is assessed by donor T Lymphocytes caused in the graft. With HILA-compatible Transplantation is the GvHD response against minor histocompatibility antigens (minor histocompatibility antigens). APC presumably present the The recipient of the foreign tissue antigens the donor T lymphocytes, especially since the activity of the APC by chemo- and Radiotherapy-induced cytokines such as interleukin (IL) -1, IL-6 and TNFa are increased.

The GvHD mainly affects skin (small-spot rash), liver (cholestatic hepatitis) and intestines (diarrhea). It also comes to Drying up mucous membranes and conjunctiva (Sicca syndrome) and Myositis. To prevent GvHD, immunospuppression is carried out Cyclosporin through, possibly in combination with methotrexate and corticosteroids.

T cell depletion and graft versus leukemia effect

Depletion of T lymphocytes in the graft reduces the risk of one GVHD. At the same time, however, the risk of tumor recurrence increases because the Donor T lymphocytes also have the beneficial graft versus leukemia effect (GvL) convey. If you want the GvL effect while reducing the To maintain GvHD risk, one must partially deplete the T cells and the Gradually re-infuse donor T lymphocytes at later times.

Fas and trail

FasL is a potent apoptosis-inducing molecule (membrane protein) known. It communicates its effects via Fas a receptor that Cells occurs. If DCs are transfected with FasL, they induce apoptosis in T cells (Matsue et al 1999). FasL-transfected DCs can be one Ag-specific reduction in graft rejection. This is based on the interaction (apopose induction) of FasL on DCs and Fas- Receptor on the T cells (Min et al 2000).

TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is a recent one identified member of the tumor necrosis factor cytokine superfamily. TRAIL induces apoptosis in various tumor cell lines. It will also suspects that TRAIL plays a role in the death of lymphocytes (Simon et al 2001; Miura et al 2001).

Co-stimulatory molecules

Functional, mature DCs arise from circulating progenitor cells after one Maturation period. DCs can be fitted with a specific trim Marker molecules are characterized. These include accessory, costimulatory gene products like CD40, CD80, and CD86 as well as MHC class I and II. The CD83 molecule in particular is a well-characterized marker for complete mature DCs, since CD83 are not detected on immature DC precursors can. However, the functional significance of CD83 is unknown. Its stronger Presence in the course of ripening indicates an important function (Berchtold et al 1999).

Herpes Simplex Virus is unable to express expression of Suppress CD83 while producing others more typical of DCs Molecules such as CD25, CD40, CD80, CD86, CD95 and MHC class I and class Class II remains unaffected (Kruse et al 2000b). Interestingly, inhibition of CD83 expression on the plasma membrane leads to a dramatic reduction in DC-mediated T cell stimulation. Will through a specific inhibitor of eukaryotic initiation factor 5A, CD83 expression can be prevented, which also leads to a strong Reduction of DC-mediated T cell stimulation leads (Kruse et al 2000a). eIF-5A is a protein that is in the export path from specific RNAs the nucleus is involved.

eIF-5A is the only cellular protein known to contain the unusual amino acid hypusin. This modification appears to be necessary for cell division. Hypusin modification is a spermidine-dependent post-translational reaction that is catalyzed by two enzymes. This includes the transfer of the aminobutyl group of spermidine to the ε-NH ₂ group of lysine at position 50 in eIF-5A by the deoxyhypusin synthase (Kruse et al 2000a).

The intermediate that is generated is then hydroxylated by the deoxyhypusin hydroxylase. In this way the active form of eIF-5A is created. Although eIF-5A was originally referred to as an "initiation factor", recent in vitro and in vivo experiments have shown that eIF-5A is not an initiator of protein translation. eIF-5A appears to be part of a specific export path from the cell nucleus, which e.g. B. is used by the Rev / Rex class of retroviral RNA transport factors. It has also been shown that the eIF-5A protein collects on the nucleoplasmic side of the nuclear pore complex to interact with the general nuclear export receptor CRM1 and to migrate from the nucleus into the cytoplasm in mammalian cells. Studies of the amount of eIF-SA mRNA in human cells showed that eIF-5A is constitutively expressed in cell lines as well as various other tissues. In contrast, the eIF-5A gene is induced in primary lymphoid cells during the activation and / or proliferation of primary human blood cells. If an inhibitor of hypusin modification [GC7 (N ¹ -guanyl-1,7-diaminoheptane)] is used, the expression of CD83 and thus the full stimulatory activity of mature DCs is inhibited (Kruse et al 2000a).

The cell according to the invention is preferably a dendritic cell or a another antigen presenting cell or one of its precursors Cell.

The APCs are the switching points of the adaptable immune system. Only they can trigger or shut off a T cell-mediated immune response.

The allologic immune reactions - cannot be maintained without that Help and mediation of APCs and T-helper lymphocytes. Also the cytotoxic T cells are activated by APCs. They convey a cellular Immune response where cells are killed directly by the cytotoxic T cells become.

The molecular mechanisms of interaction - cell-cell contact - of APCs with the T helper and cytotoxic T lymphocytes is on Known receptor level down to the last detail.

Is it the antigen z. B. is a bacterial protein Immune response useful for the organism. However, if the antigen is one Transplant antigen, one speaks of a (pathological) Rejection.

In addition to the antigen to be presented (against which the producing antibodies) are different on the cell surface Receptors and auxiliary receptors at cell-cell contact and cell activation involved. An essential molecule of intercellular interaction in the Antigen presentation (contact of APCs with the T lymphocytes) are costimulating receptors with the designation B7 (CD80, CD86).

WO 0129192 discloses a method for producing antigen presenting cells Prevention of GvHD effects to use. Presenting the antigen Cells are, however, with dead or dying parts of the cell Transplant recipient co-incubated to present loaded antigen To get cells. The cell components should contain antigens for which a reduction in an immune response is desired. This step will not required according to the invention since cells of the recipient are used. In addition, further changes are brought about or immature DCs used to reduce a repulsive immune response.

The problem underlying the invention is, among other things, therapeutically usable products for the reduction of allologists Provide immune responses to bone marrow transplants.

• A) Gelöst wird das Problem durch die erfindungsgemäße Zelle, die vom Empfänger des Transplantats stammt und dadurch gekennzeichnet ist, dass eine der Funktionen co-stimulatorischer Rezeptoren, wie ein CD83-Rezeptor und/oder B7- und/oder CD40-Rezeptor supprimiert ist und/oder CTLA4- bindende Moleküle hinzugegeben werden, die CTLA4 an T-Zellen des Transplantats binden und/oder Fas-bindende Moleküle hinzugegeben werden, die Fas an T-Zellen des Transplantats binden und/oder TRAIL-Rezeptorbindende Moleküle hinzugegeben werden, die TRAIL-Rezeptoren an T-Zellen des Transplantats binden, oder Interleukin 10 (IL-10) hinzugegeben wird. Die Moleküle, die CD83, CD80, CD86, CD40 binden, blockieren costimulatorische Rezeptoren auf APCs. Durch die Blockade der Costimulation werden T-Zellen abgeschaltet und/oder sie werden in den programmierten Zelltod (Apoptose) getrieben und/oder sie differenzieren zu regulatorischen T-Zellen, wenn die T- Zellen gleichzeitig ein präsentiertes Antigen mit ihrem T-Zell-Rezeptor erkennen. Durch Moleküle, die Fas und/oder TRAIL-Rezeptoren an T-Zellen des Transplantats binden, können T-Zellen in den programmierten Zelltod (Apoptose) getrieben werden, wenn diese gleichzeitig ein präsentiertes Antigen mit ihrem T-Zell-Rezeptor erkennen. IL-10 behindert die Aktivierung von T-Zellen (Corinti et al 2001). Bei den bei dieser Methode erkannten Antigenen handelt es sich vorwiegend um Transplantationsantigene (Haupthistokompatibilitätskomplexe (HLA, MHC I,, MHC II), Rhesus Faktor, Nebenhistokompatibilitätsantigene (minor histocompatibility antigens)), da diese sich zwischen Spender und Empfänger des Transplantates unterscheiden. In einer bevorzugten Ausführung werden die Bindemoleküle vernetzt, was z. B. durch andere Bindemoleküle, wie z. B. Antikörper, geschehen kann, die wiederum die Bindemoleküle gegen CD83, CD80, CD86, CD40, CTLA4, Fas, TRAIL-Rezeptoren binden. Ein Vernetzen befördert den gewünschten Effekt.
• B) Die erfindungsgemäßen Zellen können auch ganz oder teilweise durch unreife dendritische Zellen (DC; z. B. in vitro abgeleitete) dargestellt werden. Durch die bei unreifen DCs fehlende Costimulation werden T-Zellen (wie in A.) abgeschaltet und/oder sie werden in den programmierten Zelltod (Apoptose) getrieben und/oder sie differenzieren zu regulatorischen T-Zellen. Die unreifen DCs verhalten sich wie DCs, deren Costimulation (siehe A.) geblockt wird (Dhodapkar et al 2001).
• C) Die erfindungsgemäße Zelle kann auch mit mindestens einem Gen für ein Fas- Bindemolekül transfiziert sein. Durch die Expression von FasL an der Plasmamembran von dendritischen Zellen können T-Zellen (wie in A.) zum programmierten Zelltod (Apoptose) gezwungen werden.
• D) Die erfindungsgemäße Zelle kann auch mit mindestens einem Gen für ein Tumor-Nekrosis-Faktor-related apoptosis-inducing ligand (TRAIL)-Rezeptor- Bindemolekül transfiziert sein. Durch die Expression von TRAIL-Rezeptor- Bindemolekülen an der Plasmamembran von dendritischen Zellen können T- Zellen (wie in A.) zum programmierten Zelltod (Apoptose) gezwungen werden.
• E) Die erfindungsgemäße Zelle kann auch durch Zugabe von Aspirin, 1a,25 Dihydroxyvitamin D3, 1a,25(OH)2-16-ene-23-yne-26,27-hexafluoro-19-norvitamin D3 (D3 analog), Vitamin D3, Glucocorticoide behandelt werden (Adorini et al 2001; Griffin et al 2001; Griffin et al 2000; Hackstein et al 2001; Penna & Adorini 2000; Penna & Adorini 2001)(WO 0124818). Durch diesen Eingriff verbleiben dendritische Zellen in einem Zustand, der die immunstimmulatorischen Eigenschaften der dendritischen Zellen einschränkt. Durch die reduzierte Costimulation werden T-Zellen (wie in A.) abgeschaltet und/oder sie werden in den programmierten Zelltod (Apoptose) getrieben und/oder sie differenzieren zu regulatorischen T-Zellen.
• F) Die erfindungsgemäße Zelle kann auch mit mindestens einem Gen für ein CTLA4-Bindemoleküle transfiziert sein. Durch die Expression von CTLA4- Bindemolekülen an der Plasmamembran von dendritischen Zellen können T- Zellen abgeschaltet und/oder in den programmierten Zelltod (Apoptose) getrieben und/oder zu regulatorischen T-Zellen differenziert werden.
• G) Die erfindungsgemäße Zelle kann auch mit mindestens einem Gen für ein CD83-Bindemolekül und/oder für B7 (CD80/CD86)-Bindemoleküle und/oder für ein CD40-Bindemolekül transfiziert sein. Durch die Expression von CD83- Bindemolekülen und/oder B7 (CD80/CD86)-Bindemolekülen und/oder CD40- Bindemolekülen im endoplasmatischen Retikulum und/oder Golgi und/oder extrazellulär und/oder an der Plasmamembran von dendritischen Zellen können T-Zellen abgeschaltet und/oder in den programmierten Zelltod (Apoptose) getrieben und/oder zu regulatorischen T-Zellen differenziert werden.
• H) Die erfindungsgemäße Zelle kann auch mit mindestens einem Gen für IL-10 transfiziert sein. Durch die Expression von IL-10 von dendritischen Zellen werden die dendritischen Zellen an der Aktivierung von T-Zellen gehindert (Corinti et al 2001), sodass T-Zellen abgeschaltet werden können und/oder in den programmierten Zelltod (Apoptose) getrieben und/oder zu regulatorischen T-Zellen differenziert werden.
• I) Die erfindungsgemäße Zelle kann durch Inkubation mit den Interferonen (IFNα oder IFNγ oder IFNβ) zur Synthese von Tumor-Nekrosis-Faktor-related apoptosis-inducing ligand (TRAIL) veranlaßt werden. Durch die Expression von TRAIL- an der Plasmamembran von dendritischen Zellen können T-Zellen (wie in A.) zum programmierten Zelltod (Apoptose) gezwungen werden (Liu et al 2001; Fanger et al 1999).

The problem is solved by cells of the recipient which are antigen-presenting cells or are cells from which antigen-presenting cells can be generated. In the case of the cells presenting the antigen, the dendritic cells, but also IB cells, are of particular interest. The cells presenting the antigen are to be incubated with allologic bone marrow transplants. These grafts contain lymphocytes. In a preferred embodiment, the antigen-presenting cells can also be incubated alone with the lymphocytes or T cells (T-lymphocytes). In a preferred embodiment, the cells presenting the antigen can also be incubated alone with the lymphocytes or T cells (T lymphocytes). Among the lymphocytes, the T cells are of particular interest because they trigger important reactions for the recipient / patient. One of the reactions is wanted and useful, the other is harmful and often leads to the death of the recipient. The useful response is the anti-leukemic GvL, the harmful response is the GVHD. The incubation of the antigen-presenting cells with the transplant and here in particular with the T cells occurring therein is said to switch off the GvHD reaction and to maintain only the GvL reaction. For this purpose, the cells presenting the antigen are selected or treated in such a way that they can no longer activate T cells, but can still present the recipient's alloantigens. If an alloreactive T cell encounters such an antigen-presenting cell, it is permanently shut down, or sent to programmed cell death (apoptosis), or converted into a regulatory T cell. A regulatory T cell is understood to be a T cell that prevents immune responses to specific antigens, here alloantigens. The following shows ways to solve the problem:

• A) The problem is solved by the cell according to the invention, which originates from the recipient of the transplant and is characterized in that one of the functions of co-stimulatory receptors, such as a CD83 receptor and / or B7 and / or CD40 receptor, is suppressed and / or CTLA4-binding molecules are added which bind CTLA4 to T-cells of the transplant and / or Fas-binding molecules are added which bind Fas to T-cells of the transplant and / or TRAIL-receptor-binding molecules are added which are TRAIL- Binding receptors to T-cells of the graft, or Interleukin 10 (IL-10) is added. The molecules that bind CD83, CD80, CD86, CD40 block costimulatory receptors on APCs. By blocking the costimulation, T cells are switched off and / or they are driven into programmed cell death (apoptosis) and / or they differentiate into regulatory T cells if the T cells simultaneously present an antigen with their T cell receptor detect. Molecules that bind Fas and / or TRAIL receptors to T cells in the transplant can drive T cells into programmed cell death (apoptosis) if they simultaneously recognize a presented antigen with their T cell receptor. IL-10 hinders the activation of T cells (Corinti et al 2001). The antigens recognized by this method are predominantly transplantation antigens (main histocompatibility complexes (HLA, MHC I, MHC II), rhesus factor, secondary histocompatibility antigens (minor histocompatibility antigens)), since these differ between donor and recipient of the transplant. In a preferred embodiment, the binding molecules are crosslinked, which, for. B. by other binding molecules, such as. B. Antibodies can happen, which in turn bind the binding molecules against CD83, CD80, CD86, CD40, CTLA4, Fas, TRAIL receptors. Networking promotes the desired effect.
• B) The cells according to the invention can also be represented in whole or in part by immature dendritic cells (DC; eg derived in vitro). Due to the lack of costimulation in immature DCs, T cells (as in A.) are switched off and / or they are driven into programmed cell death (apoptosis) and / or they differentiate into regulatory T cells. The immature DCs behave like DCs whose costimulation (see A.) is blocked (Dhodapkar et al 2001).
• C) The cell according to the invention can also be transfected with at least one gene for a Fas binding molecule. The expression of FasL on the plasma membrane of dendritic cells can force T cells (as in A.) to programmed cell death (apoptosis).
• D) The cell according to the invention can also be transfected with at least one gene for a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor binding molecule. The expression of TRAIL receptor binding molecules on the plasma membrane of dendritic cells can force T cells (as in A.) to programmed cell death (apoptosis).
• E) The cell according to the invention can also by adding aspirin, 1a, 25 dihydroxyvitamin D3, 1a, 25 (OH) 2-16-ene-23-yne-26,27-hexafluoro-19-norvitamin D3 (D3 analog), vitamin D3, glucocorticoids are treated (Adorini et al 2001; Griffin et al 2001; Griffin et al 2000; Hackstein et al 2001; Penna & Adorini 2000; Penna & Adorini 2001) (WO 0124818). As a result of this intervention, dendritic cells remain in a state which limits the immunostimulatory properties of the dendritic cells. The reduced costimulation switches off T cells (as in A.) and / or drives them to programmed cell death (apoptosis) and / or differentiates them into regulatory T cells.
• F) The cell according to the invention can also be transfected with at least one gene for a CTLA4 binding molecule. By expressing CTLA4 binding molecules on the plasma membrane of dendritic cells, T cells can be switched off and / or driven into programmed cell death (apoptosis) and / or differentiated into regulatory T cells.
• G) The cell according to the invention can also be transfected with at least one gene for a CD83 binding molecule and / or for B7 (CD80 / CD86) binding molecules and / or for a CD40 binding molecule. By expressing CD83 binding molecules and / or B7 (CD80 / CD86) binding molecules and / or CD40 binding molecules in the endoplasmic reticulum and / or Golgi and / or extracellularly and / or on the plasma membrane of dendritic cells, T cells can be switched off and on / or driven into programmed cell death (apoptosis) and / or differentiated into regulatory T cells.
• H) The cell according to the invention can also be transfected with at least one gene for IL-10. Expression of IL-10 from dendritic cells prevents the dendritic cells from activating T cells (Corinti et al 2001), so that T cells can be switched off and / or driven into programmed cell death (apoptosis) and / or to be differentiated into regulatory T cells.
• I) The cell according to the invention can be induced by incubation with the interferons (IFNα or IFNγ or IFNβ) to synthesize tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). The expression of TRAIL- on the plasma membrane of dendritic cells can force T cells (as in A.) to programmed cell death (apoptosis) (Liu et al 2001; Fanger et al 1999).

One of the procedures (A.-I.) and / or any sequence of these procedures (A.-I.) is applied to the cell according to the invention with allogeneic in vitro Stem cells (e.g. including lymphocytes) or with allogeneic T cells or with a stranger's allogeneic lymphocytes Incubate stem cell graft donors (e.g. bone marrow). The named cells that made up the recipient of the graft and cancer patients, in particular those with leukemia, cancer cells can contain in a preferred embodiment of the method according to the invention the incubation with the graft are treated so that a Proliferation of these cells will fail to materialize. This is preferably done by Irradiation of these cells reached.

The one of these procedures and / or any sequence of these Procedures positively selected not alloreactive, but allologic T cells are given to the patient together with the allologic stem cells (e.g. Bone marrow), preferably into the bone marrow. In this way you get a graft versus leukemia effect (GvL), but none, or else a significantly reduced graft versus host disease (GvHD).

The CD83 binding molecules can preferably be antibodies, monoclonal antibodies, F (ab) ₂ , single chain antibodies (scFv), and / or F _ab fragments.

The proteins which have affine structures for B7 receptors can preferably be CTLA4, CTLA4 derivatives (e.g. CTLA4Ig), CD28, antibodies, F (ab) ₂ , scFv and / or F _ab fragments.

The proteins which have affine structures for CD40 receptors can preferably be CD40L, CD40L derivatives, antibodies, F (ab) ₂ , scFv and / or F _ab fragments.

The proteins which have affine structures for CTLA4 (CD152) receptors can preferably be antibodies, F (ab) ₂ , scFv and / or F _ab fragments. The proteins which have structures affine to Fas ligands can preferably be FasL, FasL derivatives, antibodies, F (ab) ₂ , scFv and / or F _ab fragments.

The proteins which have affine structures for TRAIL receptors can preferably be TRAIL, TRAIL derivatives, antibodies, F (ab) ₂ , scFv and / or F _ab fragments.

The method according to the invention can be based on genetic engineering interventions patient's own cells (pre-cells: stem cells, monocytes, DCs, CD34 + Stem cells, CD34 + progenitor stem cells and / or B cells) are based. The interventions are carried out using suitable probes and bring about the Reduction of CD83 molecules and possibly B7 molecules and / or CD40 molecules by hindering or preventing the Formation of the molecule on the surface of the antigen presenting cells and / or CTLA4 binding molecules, preferably antibodies, and / or the Production of Fas binding molecules, preferably FasL and / or the Production of TRAIL receptor binding molecules, preferably TRAIL and / or the production of IL-10.

Transfection of pre-cells (stem cells, monocytes, DCs, CD34 + Stem cells, CD34 + progenitor stem cells and / or B cells) or Antigen presenting cells cause expression of fas- Binding molecules and / or TRAIL receptor binding molecules and / or IL-10 and / or B7 binding molecules and / or CTLA4 binding molecules and / or CD83 binding molecules and / or CD40 binding molecules.

This is due to nucleic acids that are used for Fas binding molecules and / or TRAIL Receptor binding molecules and / or IL-10 and / or B7 binding molecules and / or CTLA4 binders and / or CD83 binders and / or CD40 Encode binding molecules, achieved.

The nucleic acids can be DNA, RNA, oligonucleotides, Act polynucleotides, ribozymes or peptide nucleic acids (PNA).

In a preferred embodiment, the DNA contains regulatory elements such as enhancers, promoters, polyA-coding 3 'ends for transcription of the DNA in RNA. The RNA in turn should contain regulatory elements for translating the RNA contained in protein.

For some of the expression products described (Fas, TRAIL receptor and CTLA4 binding molecules) becomes a localization in the plasma membrane of the Pre-cells and / or APCs targeted. For this, the nucleic acids are included provided a signal sequence that the transport of the expression products to Plasma membrane causes.

For other described expression products (B7, CD83 and CD40 In a preferred embodiment, binding molecules) become a localization in the endoplasmic reticulum, the Golgi apparatus, the Trans-Golgi Network or intracellular vesicles aimed for. Code for this purpose the nucleic acids a signal sequence that the whereabouts of the Expression products in the respective cell compartments.

The cells mentioned can be ex vivo by treatment with viruses, viral Vectors, bacterial vectors, plasmids generated by viral walk transfer, Electroporation techniques, iontophoresis, ballistic methods and / or other techniques for introducing molecules into eukaryotic cells are suitable to be transfected.

A named cell can be treated with viruses, viral vectors, bacterial vectors, plasmids generated by viral gene transfer, Electroporation techniques, iontophoresis, ballistic methods and / or other techniques for introducing molecules into a cell with increased Production of Fas binding molecule and / or TRAIL receptor binding molecule and / or CD83 binding molecules, CD40 binding molecules, 87 (CD80 / CD86) - Binding molecules, CTLA4 binding molecule, IL-10 are transfected, whereby T- Cells which have allologic antigens, e.g. B. presented on MHC molecules will bind to the cell presenting the antigen.

Molecules such as antibodies, proteins, peptides, Peptidomimetics, CTLA4, CTLA4 derivatives such as CTLA4Ig, CD28, CD40L and / or Components and / or combinations of these molecules, the z. B. B7-1, B7-2, Bind CD83, CD40, serve. Through these molecules one becomes present an alloantigen presentation stimulation and / or co- Stimulation of T cells hindered in with the cell of the invention Be brought in contact.

The molecules (Fas binding molecule, TRAIL receptor binding molecule, CD83- Binding molecules, CD40 binding molecules, B7 (CD80 / CD86) binding molecules, CTLA4- Binding molecule, IL-10 gene) can by vehicles such as liposomes, hydrogels, Cyclodextrins, nanocapsules, nanoparticles, bioadhesive microspheres and / or through electroporation techniques, iontophoresis, ballistic methods and / or other techniques for introducing molecules into the cell according to the invention are transferred.

Nucleic acids can in particular by viruses, viral vectors, bacterial Vectors, plasmids generated by electroporation techniques, iontophoresis, ballistic methods and / or other techniques for infiltrating Molecules in the cell presenting the monoantigenic antigen and / or Antigen presenting cell can be transferred.

The APC or pre-cell which is selected from the group consisting of stem cells, monocytes, DCs, CD34 + stem cells, CD34 + progenitor stem cells and / or B cells can be combined with an inhibitor of hypusin biosynthesis, e.g. B. GC7 (N ¹ -guanyl-1,7-diaminoheptane) to hinder the production of functional eIF-5A, which in turn hampers CD83 biosynthesis.

A medicament containing is also claimed according to the invention at least one cell according to the invention. Preferably that is Medicament according to the invention as an infusion solution for intravenous or formulated intraperitoneal application. The wording is chosen so that at Administration of the drug does not significantly affect the The antigen-representing cell according to the invention is effective.

Physiological saline is preferred as the infusion solution Consideration. Basically, there are other solutions that have a pH of 5.5 have up to 8.5, suitable. Also serum, for example human serum, autologous serum or serum of other species, solutions with Plasma substitutes, such as polyvinyl pyrrolidone, are suitable. Typically should 0.5 ml to 500 ml can be applied. These amounts and pH values are of course not absolutely, but can be done by a specialist, depending on Conditions and requirements, varied and tailored to specific needs of a patient.

The cell presenting the antigen according to the invention can in particular be used for Manufacture of a medicament for the treatment of immune reactions against Allologic tissue features or for the prevention of GvHD can be used.

According to the invention, a use is claimed in which the treating immune reactions in connection with allologic tissue characteristics, their gene sequences and / or partial sequences, in particular Major histocompatibility complexes, MHC I, MHC II, Rhesus Falktor, Minor histocompatibility antigens.

According to the invention, a use is claimed in which the In a preferred embodiment, binding molecules are crosslinked by what other binding molecules such as e.g. B. antibodies, can happen, which in turn the Binding molecules against CD83, CD80, CD86, CD40, CTLA4, Fas, TRAIL- Bind receptors. Such networking reinforces the effect of this Binding molecules.

A use is also claimed according to the invention in which the ex vivo selected cells are infused into the patient and the patient is then subjected to an in vivo treatment with IL-2. The ex vivo selected cells can also be incubated ex vivo with IL-2 or other stimulants such as phytohemaglutinin (PHA) and then infused into the patient. It has been shown that the GvL effect can be enhanced in this way. This effect is described in the literature (Klingemann HG 1995; Sykes M 1994; Uharek L 1998; Vourka-Karussis U 1995; Weiss L 1995; Weiss L 1999; Xun CQ 1995). Literature Adorini, L., Penna, G., Casorati, M., Davalli, AM, Gregori, S. 2001. Induction of transplantation tolerance by 1,25-dihydroxyvitamin D (3). Transplant Pro 33: 58-9.
Berchtold, S., Muhl-Zurbes, P., Heufler, C., Winklehner, P., Schuler, G., Steinkasserer, A. 1999. Cloning, recombinant expression and biochemical characterization of the murine CD83 molecule which is specifically upregulated during dendritic cell maturation. FEBS Lett 461: 211-6.
Corinti, S., Albanesi, C., 1a Sala, A., Pastore, S., Girolomoni, G. 2001. Regulatory activity of autocrine IL-10 on dendritic cell functions. J Immunol 166: 4312-8.
Dhodapkar, MV, Steinman, RM, Krasovsky, J., Munz, C., Bhardwaj, N. 2001. Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells. J Exp Med 193: 233-8.
Fanger, NA, Maliszewski, CR, Schooley, K ,, Griffith, TS 1999. Human dendritic cells mediate cellular apoptosis via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). J Exp Med 190: 1155-64.
Griffin, MD, Lutz, W., Phan, VA, Bachman, LA, McKean, DJ, Kumar, R. 2001. Dendritic cell modulation by lalpha, 25 dihydroxyvitamin D3 and its analogs: a vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo. Proc Natl Acad Sci USA 98: 6800-5.
Griffin, MD, Lutz, WH, Phan, VA, Bachman, LA, McKean, DJ, Kumar, R. 2000. Potent inhibition of dendritic cell differentiation and maturation by vitamin D analogs. Biochem Biophys Res Commun 270: 701-8.
Hackstein, H., Morelli, AE, Larregina, AT, Ganster, RW, Papworth, GD, et from 2001. Aspirin inhibits in vitro maturation and in vivo immunostimulatory function of murine myeloid dendritic cells. J Immunol 166: 7053-62.
Klingemann HG, PG 1995. Is there a place for immunotherapy with interleukin-2 to prevent relapse after autologous stem cell transplantation for acute leukemia? Leuk Lymphoma 16: 397-405
Kruse, M., Rosorius, O., Kratzer, F., Bevec, D., Kuhnt, C., et al. 2000a. Inhibition of CD83 cell surface expression during dendritic cell maturation by interference with nuclear export of CD83 mRNA. J Exp Med 191: 1581-90.
Kruse, M., Rosorius, O., Kratzer, F., Stelz, G., Kuhnt, C., et al. 2000b: Mature dendritic cells infected with herpes simplex virus type 1 exhibit inhibited T-cell stimulatory capacity. J Virol 74: 7127-36.
Liu, S., Yu, Y., Zhang, M., Wang, W., Cao, X. 2001. The involvement of tnfalpha-related apoptosis-inducing ligand in the enhanced cytotoxicity of ifnbeta-stimulated human dendritic cells to tumor cells , J Immunol 166: 5407-15.
Matsue, H., Matsue, K., Walters, M., Okumura, K., Yagita, H., Takashima, A. 1999. Induction of antigen-specific immunosuppression by CD95L cDNAtransfected 'killer' dendritic cells. Nat Med 5: 930-7.
Min, WP, Gorczynski, R., Huang, XY, Kushida, M., Kim, P., et al. 2000. Dendritic cells genetically engineered to express Fas ligand induce donorspecific hyporesponsiveness and prolong allograft'survival. J Immunol 164: 161-7.
Miura, Y., Misawa, N., Maeda, N., Inagaki, Y., Tanaka, Y., et al. 2001. Critical contribution of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to apoptosis of human CD4 + T cells in HIV-1 infected hu-PBL-NOD-SCID mice. J Exp Med 193: 651-60.
Penna, G., Adorini, L. 2000. 1 Alpha, 25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol 164: 2405-11.
Penna, G., Adorini, L. 2001. Inhibition of costimulatory pathways for T-cell activation by 1,25-dihydroxyvitamin D (3). Transplant Pro 33: 2083-4.
Simon, AK, Williams, O., Mongkolsapaya, J., Jin, B., Xu, XN, et al. 2001. Tumor necrosis factor-related apoptosis-inducing ligand in T cell development: sensitivity of human thymocytes. Proc Natl Acad Sci USA 98: 5158-63.
Sykes M, HM, Szot GL, Pearson DA. 1994. Interleukin-2 inhibits graftversus-host disease-promoting activity of CD4 + cells while preserving CD4- and CD8-mediated graft-versus-leukemia effects. Blood 83: 2560-2569.
Uharek L, GB, Zeis M, Dreger P, Steinmann J, Loffier H, Schmitz N. 1998. Abrogation of graft-vs.-leukemia activity after depletion of CD3 + T cells in a murine model of MHC-matched peripheral blood progenitor cell transplantation (PBPCT). Exp Hematol 26: 93-99
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Claims (28)

1. Antigen presenting line available from pre-lines selected from the group consisting of stem cells, monocytes, DCs, CD34 + stem cells, CD34 + progenitor stem cells, B cells of a patient to be treated with an allogeneic bone marrow transplant, which may also contain blood lymphocytes, and / or from already present antigen presenting cells (APC), whereby the pre-cells or the already existing (APC)
treatment with binding molecules against B7 (1 and / or 2) and / or CD83 and / or CD40 and / or CTLA4 and / or Fas and / or the TRAIL receptor on T cells, and these pre-cells or APC incubated in vitro with allogeneic lymphocytes from a foreign stem cell transplant donor,
and / or completely or partially immature dendritic cells (DC; e.g. in vitro derived) are used and these are incubated in vitro with allogeneic lymphocytes from a foreign stem cell transplant donor,
and / or the said cells are transfected with at least one gene for a Fas binding molecule and these are incubated in vitro with allogeneic lymphocytes from a foreign stem cell transplant donor,
and / or the cells mentioned are transfected with at least one gene for a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor binding molecule and these are incubated in vitro with allogeneic lymphocytes including blood lymphocytes from a foreign stem cell transplant donor,
and / or the cells mentioned by adding aspirin, 1a, 25 dihydroxyvitamin D3, 1a, 25 (OH) 2-16-ene-23-yne-26,27-hexafluoro-19-nor-vitamin D3 (D3 analog), Vitamin D3, glucocorticoid dendritic cells are kept in a state which limits the immunostimulatory properties of the dendritic cells and these are incubated in vitro with sllogged lymphocytes from a foreign stem cell transplant donor,
and / or the said cells are transfected with at least one genetic sequence for interleukin 10 (IL-10) and these are incubated in vitro with allogeneic lymphocytes from a foreign stem cell transplant donor,
and / or the named cells are prevented from activating T cells by adding Interleukin 10 and these are incubated in vitro with allogeneic lymphocytes from a foreign stem cell transplant donor,
and / or the cells mentioned by adding interferon a or g or b (IFNa or IFNg or IFNb) for the synthesis of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and this in vitro with allogeneic lymphocytes of a foreign stem cell - graft donors are incubated,
and / or the cells mentioned are transfected with at least one gene for CTLA4 binding molecules and these are incubated in vitro with allogeneic lymphocytes from a foreign stem cell transplant donor,
and / or the cells mentioned are transfected with at least one gene for CD83 binding molecules and optionally for CD40 binding molecules and optionally for B7 (CD80 / CD86) binding molecules and these are incubated in vitro with allogeneic lymphocytes from a foreign stem cell transplant donor. 2. Cell according to claim 1, wherein the cell from the receiver of the Transplant originate and in cancer patients, especially those with Leukaemias, cancer cells may contain before incubation with the Graft to be treated so that these cells proliferate is absent, especially by irradiating these cells. 3. Cell according to one of claims 1 and / or 2, characterized in that transfection of pre-cells (stem cells, monocytes, DCs, CD34 + stem cells, CD34 + progenitor stem cells and / or B-lines) or APC an expression of Fas binding molecules and / or TRAIL Receptor binding molecules and / or IL-10 and / or B7 binding molecules and / or CTLA4 binding molecules and / or CD83 binding molecules and / or CD40 binding molecules. 4. Cell according to at least one of claims 1 to 3 containing Nucleic acids, the Fas binding molecules and / or TRAIL receptor Binding molecules and / or IL-10 and / or B7 binding molecules and / or CTLA4 binders and / or CD83 binders and / or CD40 Encode binding molecules. 5. Cell according to at least one of claims 1 to 4, in which the CD83 binding molecules are preferably antibodies, monoclonal antibodies, F (ab) 2, single-chain antibodies (scFv), and / or F _ab fragments. 6. Cell according to at least one of claims 1 to 5, wherein the proteins which have affine structures for B7 receptors CTLA4, CTLA4 derivatives (z. B. CTLA4Ig), CD28, antibodies, F (ab) ₂ , scFv and / or F _ab fragments. 7. The cell according to the invention according to at least one of claims 1 to 6, wherein the proteins which have structures affine to CD40 receptors are CD40L, CD40L derivatives, antibodies, F (ab) ₂ , scFv and / or Fab fragments. 8. The cell according to the invention according to at least one of claims 1 to 7, wherein the proteins which have affine structures for CTLA4 (CD152) receptors are antibodies, F (ab) ₂ , scFv and / or F _ab fragments. 9. Cell according to at least one of claims 1 to 8, wherein the proteins which have structures affine to Fas receptors are FasL, FasL derivatives, antibodies, F (ab) ₂ , scFv and / or F _ab fragments. 10. Cell according to at least one of claims 1 to 9, wherein the proteins that have affine structures for the TRAIL receptor are TRAIL, TRAIL derivatives, antibodies, F (ab) ₂ , scFv and / or F _ab fragments. 11. Cell according to at least one of claims 1 to 10, characterized characterized in that the nucleic acids DNA, RNA, oligonucleotides, Polynucleotides, ribozymes, peptide nucleic acids (PNA) are. 12. Cell according to at least one of claims 1 to 11, characterized characterized that the DNA regulatory elements like enhancers, Promoters, polyA-coding 3 'ends for transcription of the DNA in Contains RNA, the RNA regulatory elements for translating the RNA into Contains protein. 13. Cell according to at least one of claims 1 to 12, wherein the Encode nucleic acids for a signal sequence or the Expression products have a signal sequence that the transport of Expression products to the plasma membrane causes. 14. Cell according to at least one of claims 1 to 13, wherein the Encode nucleic acids for a signal sequence or the Expression products have a signal sequence that the whereabouts of Expression products in the endoplasmic reticulum, the Golgi Apparatus, the Trans-Golgi network or intracellular vesicles. 15. A method for producing a cell according to one of claims 1 to 14, from stem cells, monocytes, DCs, CD34 + stem cells, CD34 + progenitor stem cells and / or B cells of a patient to be treated with a bone marrow transplant antigen presenting cells
to generate, which are subject to treatment with binding molecules against B7, CD83, CD40, CTLA4, Fas, the TRAIL receptor on T cells or combinations thereof, and the DC in vitro with allogeneic stem cells or with allogeneic T cells or with allogeneic lymphocytes of a foreign stem cell transplant donor in order to switch off the alloreactive T cells, which interact intensively with the dendritic cells via complex adhesion systems and TCR / MHC complexes, by blocking the costimulation by the dendritic cells and / or switching them into the programmed ones To force cell death (apoptosis) and / or to differentiate them into regulatory T cells,
and / or to use fully or partially immature dendritic cells and to incubate them in vitro with allogeneic stem cells or with allogeneic T cells or with allogeneic lymphocytes from a foreign stem cell transplant donor in order to isolate the alloreactive T cells, which have complex adhesion systems and TCR / MHC complexes interact intensively with the dendritic cells, by switching off the lack of costimulation in immature DCs and / or forcing them into programmed cell death (apoptosis) and / or differentiating them into regulatory T cells,
and / or the said cells - to transfect with at least one gene for a Fas binding molecule and to incubate these in vitro with allogeneic stem cells or with allogeneic T cells or with allogeneic lymphocytes from a foreign stem cell transplant donor in order to incubate the alloreactive T cells, which enter into intensive interaction with the dendritic cells via complex adhesion systems and TCR / MHC complexes, by forcing the FasL expressed on the plasma membrane by the dendritic cells into programmed cell death (apoptosis),
and / or to transfect said cells with at least one gene for the (e.g. human) tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor binding molecule and to transfect them in vitro with allogeneic stem cells or with allogeneic T - Incubate cells or with allogeneic lymphocytes from a foreign stem cell transplant donor to the alloreactive T cells, which enter into intensive interaction with the dendritic cells via complex adhesion systems and TCR / MHC complexes, by means of the TRAIL expressed by the dendritic cells on the plasma membrane Receptor binding molecule to force programmed cell death (apoptosis)
and / or the said cells by adding aspirin, 1a, 25 dihydroxyvitamin D3, 1a, 25 (OH) 2-16-ene-23-yne-26,27-hexafluoro-19-nor-vitamin D3, vitamin D3, glucocorticoids To keep dendritic cells in a state which limits the immunostimulatory properties of the dendritic cells and to incubate them in vitro with allogeneic stem cells or with allogeneic T cells or with allogeneic lymphocytes from a foreign stem cell transplant donor in order to incubate the alloreactive T cells which have complex adhesion systems and TCR / MHC complexes enter into intensive interaction with the dendritic cells, switch off through the reduced costimulation and / or force them into programmed cell death (apoptosis) and / or differentiate them into regulatory T cells,
and / or said cells are transfected with at least one gene for interleukin 10 (IL-10) which limits the immunostimulatory properties of the dendritic cells and these in vitro with allogeneic stem cells or with allogeneic T cells or with allogeneic lymphocytes from a foreign stem cell transplant donor incubate in order to switch off the alloreactive T cells, which enter into intensive interaction with the dendritic cells via complex adhesion systems and TCR / MHC complexes, and / or to force them into programmed cell death (apoptosis) and / or to induce regulatory T- Differentiate cells
and / or the said cells are mixed with interleukin 10, which limits the immunostimulatory properties of the dendritic cells and incubates them in vitro with allogeneic stem cells or with allogeneic T cells or with allogeneic lymphocytes from a foreign stem cell transplant donor in order to incubate the alloreactive T cells which interact intensively with the dendritic lines via complex adhesion systems and TCR / MHC complexes, switch them off and / or force them into programmed cell death (apoptosis) and / or differentiate them into regulatory T cells,
and / or to transfect said cells with at least one gene for CTLA4 binding molecules and to incubate them in vitro with allogeneic stem cells or with allogeneic T cells or with allogeneic lymphocytes from a foreign stem cell transplant donor in order to incubate the alloreactive T cells complex adhesion systems and TCR / MHC complexes enter into intensive interaction with the dendritic cells by switching off the CTLA4 binding molecule expressed by the dendritic cells on the plasma membrane and / or forcing them into programmed cell death (apoptosis) and / or forcing them to regulate T -Differentiate cells,
and / or to transfect said cells with at least one gene for CD83 binding molecules and / or for CD40 binding molecules and / or for B7 (CD80 / CD86) binding molecules and these in vitro with allogeneic stem cells or with allogeneic T cells or with incubate allogeneic lymphocytes from a foreign stem cell transplant donor in order to allow the alloreactive T cells, which interact intensively with the dendritic cells via complex adhesion systems and TCR / MHC complexes, by the dendritic cells in the endoplasmic reticulum and / or Golgi and / or or on the plasma membrane and / or extracellularly expressed CD83 and / or CD40 binding molecule and / or B7 binding molecule which binds the CD83 and / or CD40 and / or B7 of the dendritic cells, and / or switch them off in the programmed cell death ( To force apoptosis) and / or to differentiate them into regulatory T cells,
the non-alloreactive allologic T cells positively selected by one of these procedures and / or any sequence of these procedures are infused into the patient with the allologic stem cells, preferably into the bone marrow, in order to obtain a graft-versus-leukemia effect (GvL). 16. The method of claim 15, wherein said cells ex vivo Treatment with viruses, viral vectors, bacterial vectors, Plasmids generated by viral gene transfer, electroporation techniques, Iontophoresis, ballistic methods and / or other techniques for Introducing molecules into eukaryotic cells. 17. The method of claim 15 and / or 16, wherein said cell by treatment with viruses, viral vectors, bacterial vectors, Plasmids by viral gene transfer, electroporation techniques, Iontophoresis, ballistic methods and / or other techniques for Molecular introduction into a cell with increased production of Fas binding molecule and / or TRAIL receptor binding molecule and / or CD83 binders, CD40 binders, B7 (CD80 / CD86) - Binding molecule, CTLA4 binding molecule, IL-10 is transfected, whereby T- Cells which have allologic antigens, e.g. B. on MHC molecules are presented, bind to the cell representing the antigen, turned off. 18. The method according to at least one of claims 15 to 17, wherein Molecules such as antibodies, proteins, peptides, peptidomimetics, CTLA4, CTLA4 derivatives such as CTLA4Ig, CD28, CD40L and / or components and / or combinations of these molecules, e.g. B. 87-1, B7-2, CD83, Bind CD40, which one in the presence of an alloantigen presentation stimulation and / or co-stimulation of T cells taking place disabled who brought into contact with the cell of the invention become. 19. The method according to at least one of claims 15 to 16, wherein the Molecules (Fas binding molecule, TRAIL receptor binding molecule, CD83- Binding molecules, CD40 binding molecules, B7 (CD80 / CD86) binding molecules, CTLA4 binding molecule, IL-10 gene) according to claim 12 by vehicles such as Liposomes, hydrogels, cyclodextrins, nanocapsules, nanoparticles, bioadhesive microspheres and / or by electroporation techniques, Iontophoresis, ballistic methods and / or other techniques for Molecule transfer into the cell according to the invention become. 20. The method according to at least one of claims 15 to 19, wherein Nucleic acids through viruses, viral vectors, bacterial vectors, Plasmids by viral gene transfer, electroporation techniques, Iontophoresis, ballistic methods and / or other techniques for Introducing molecules into the cells mentioned. 21. Pre-cell selected from the group consisting of stem cells, monocytes, DCs, CD34 + stem cells, CD34 + progenitor stem cells and / or 8 cells, characterized in that an inhibitor of hypusin biosynthesis, such as. B. GC7 (N ¹ -guanyl-1,7-diaminoheptane) is used to hinder the production of functional eIF-5A, which in turn hampers CD83 biosynthesis. 22. Medicament containing at least one cell according to the invention or according to at least one of claims 1 to 14. 23. Medicament according to claim 22, wherein at least one according to the invention Cell is formulated for ex vivo application. 24. Use of at least one cell according to the invention after at least one of claims 1 to 14 for the manufacture of a medicament for Treatment of immune reactions against allologic tissue features. 25. Use according to claim 24, wherein the to be treated Immune responses associated with allologic tissue characteristics, their Gene sequences and / or partial sequences, in particular Major histocompatibility complexes, MHC I, MHC II, Rhesus factor, Minor histocompatibility antigens stands. 26. Use according to claim 1 to 25, wherein the binding molecules in one preferred execution can be networked by what others Binding molecules, such as B. antibodies, can happen, which in turn the Binding molecules against CD83, CD80, CD86, CD40, CTLA4, Fas, TRAIL- Bind receptors. 27. Use according to claim 1 to 26, wherein the ex vivo selected Cells are infused into the patient and then the patient in vivo Treatment with IL-2 is subject. 28. Use according to claim 1 to 26, wherein the ex vivo selected Cells ex vivo with IL-2 or other stimulants such as phytohemaglutinin (PHA) and then infused into the patient.