DE4411956A1 - Agents for influencing hyperactive immunological effector cells - Google Patents

Abstract

The following are claimed: (A) agent for influencing hyperactive immunological effector cells comprising: (a) a calcium antagonist; and (b) an agent which reduces the intracellular cAMP/cGMP ratio. (B) agent for influencing hyperactive immunological effector cells comprising: (a) an agent which eliminates the hyperactive effector cells; and (b) alloreactive cells with a preprogrammed death.

Description

Immunotherapy for neoplastic and autoimmune diseases as well as bacterial and (retroviral) infections (a) Unblocking the hyperactivated state of immunocomp cells and / or (b) by elimination or inactivity tion of hyperactivated effector cells ("microimmunosurgery gie "). Using the same principle for improvement of conventional vaccines as well as for the prevention of Rejection reaction in organ transplants.

(a) Unblocking hyper- or persistently activated immunocompetent cells

The real problem with number that has hardly been noticed so far range diseases such as tumor, autoimmune diseases, bak serial or (retro) viral infections (incl. HIV infections) and in CFS ("chronic fatigue syndrome") the hyper-, non-hypo-activated state of immunocompetent cells. Persistent activation of some subclones will make one local or systemic suppression of other subclones and hereby the lack of activation (hypoergy or anergy) for the disease-relevant antigens (pathogens). The ones mentioned above, which are fundamentally different at first glance Diseases have one element in common, namely one ahead going, the disease-inducing phase of the protracting ten immunosuppression, which in the case of tumor disease immunological surveillance of the (spontaneously) transformed body cells impaired and at Autoimmune diseases deblocking and clonal post-expan sion of auto-aggressive T and B subclones.  

To get the immune competent cells back for disease-relevant To make (neo) antigen signals susceptible, this cell len unblocked first, or as in part 2 of this application be executed, deactivated or eliminated.

According to the invention, this combination is achieved by the combination nation of (a1) the intracellular cAMP-reducing or lowering the intracellular cAMP / cGMP quotient Substances and mixtures, plus (a2) the "voltage-operated" and / or "receptor-operated" Ca2 + channels blocking substances and mixtures of substances.

• (a1) The first goal, i.e. H. the reduction of the cAMP level or the cAMP / cGMP quotient, succeeds according to the invention Antagonists of all those cell receptors that are via the Gs protein coupled with the membrane-associated adenylate cyclase (A.C.) are. This effect is intensified, especially the decrease in cAMP and the cGMP increase, i. H. Decrease in the cAMP / cGMP quotient by simultaneous administration of agonists of all Gp, Gi or Go protein-coupled receptors and / or cGMP-increase ten, Cai-reducing nitro compounds (e.g .: isosorbide Mono- and dinitrate, glycerol trinitrate / nitroglycerin, Erythritol tetranitrate, pentaerythritol tetranitrate, amyl nitrite, Molsidomine).

The antagonists are particularly suitable according to the invention those Gs-coupled cell receptors, their normal, physiolo (endogenous) agonists (ligands) simultaneously on Gp-, Bind Gi- or Go-coupled cell receptors; by ousting Delivery of these endogenous ligands from their Gs-coupled cell receptors increasingly interact with the correspondent rendering Gp- or Gi- or Go-coupled receptor and achieve 2 effects simultaneously, the decrease in cAMP and the increase in cGMP in the cytosol of the immune-competent target cell. Examples of such endogenous agonists are catecholamines (adrenaline / epinephrine and norepinephrine / norepinephrine), histamine and adenosine. So  lead z. B. the antagonists of the β-adrenoceptor (on immuno zytes, e.g. B. T cells and monocytes / macrophages) the catecho lamine, primarily adrenaline, from beta to alpha adrenoceptor. Similarly, antagonists of the H2 histamine receptor endogenous ligand histamine from cAMP-enhancing H2 receptor to redirect cAMP-reducing or cGMP-increasing H1 receptor tet. In the case of the endogenous agonist adenosine, this causes Blocking of the A2 subtype of the P1 adenosine receptor (by A2 receptor antagonists) the enhanced interaction of Adenosine with the cAMP suppressing A1 receptor.

The blocking of Ca2 + channels mentioned under point (a2) can according to the invention by "classic" Ca2 + antagonists (Ca2 + channel blocker) of all subtypes (e.g. phenylalkylamines, Dihydropyridines, benzothiazepines, piperazines, quinoxalines, Quinazoline u. a., such as bepridil and perhexiline). Alternatively or additionally, it can be carried out according to the invention simultaneous partial inhibition (blocking) of alpha plus beta adrenoceptors and / or of H2 plus H1 histamine recipe tors and / or A2 plus A1 adenosine receptors (with corre low-dose antagonists) and / or 5HT (serotonin) receptors and / or receptors of various Inflammation mediators (e.g. bradykinin, kinin cascade, comple ment cascade, especially C5a, C4a, C3a, PAF etc.). Examples of patented combinations are listed in Appendix I. It should be mentioned that the in Annex I substances and mixtures invented appropriately with subdosed nitro compounds (incl. Molsido min), Ca overload blockers (e.g. cinnarizine) and others Ca antagonists and with BRM (immunomodulators) and / or Cytokines can be combined. Especially interesting Because of the low side effects, the combination of Molsidomin and Nicergolin (an alpha blocker), with and without Ca overload blocker (e.g. cinnarizine as a representative of the Piperazines).  

Instead of the combination (a1) of cAMP-reducing plus (a2) intracellular Ca2 + controlling (reducing) sub According to the invention, punches (preparations) can also be made under Point (a1) and substances discussed under point (a2) and Mixtures separated, d. H. as individual substances or individual mixtures of substances (either only (a1) or only (a2)) therapeutic be used.

The use of substances is also to be protected by patent and mixtures of substances that, in addition to the Ca channels, Can reversibly inhibit channels; the principle of action is that Increasing the resting potential of immune-competent cells, wel ches is reduced in the hyperactivated state of the same. Some Ca antagonists, such as Cinna, belong to these substances ricin, flunarizine, fendiline, bepridil, tiapamil and z. T. Verapamil and Gallopamil. On the other hand, subdosed are anti arrhythmics (class I to IV) of interest, including spe specifically the combination of class I B with class 111 because of the balanced balance of K-Efluxes (class I B) and K- Influxes (class III) with reversible inhibition in the same direction of the Na channel. Among these substances are the adrenozep Tor blockers Sotalol and Propranolol are of particular interest. The combination of two should also be emphasized: cinnarizine and Propranolol, which is clinically tested by us.

All are covered by the patent protection of the present application Preparations and combinations of preparations, their use in Cardiovascular diseases already (e.g. BGA or FDA) are admitted or are about to be admitted, their novel Application ("second indication") for regulation and modulation lation of immunocytes (immunocompetent cells, such as T-, NK- or K / ADCC, B cells, monocytes / macrophages) and hereby in the treatment of everyone with hyperactivated Diseases associated with immunocytes (e.g. tumor, Autoimmune diseases, infections, chronic fatigue syndrome / CFS, etc.), but only after basic animal experiments  and the applicant's first clinical investigations has been. The essence of the invention remains here Finding that the decrease in intracellular cAMP Level or the cAMP / cGMP quotient with the blocking the "voltage-operated" and / or "receptor-operated" Ca2 + - Combine channels. In the special case the nitrover bonds, including the sydnonimine derivatives (e.g. molsedomin), both effects (cGMP increase, Cai decrease) are already achieved by the monopreparation.

The second important finding concerns necessity the general reduction of non-specific and speci signals, causing the anergy of hyper or false activated effector cells (for the crane listed above kungen) and these effector cells (T cells, Macrophages / monocytes, NK cells) for new, disease-related gen signals become accessible again. The applicant designates net this reduction of unspecific ("unproductive" or "background" signals) as "filtering" out "/" cutting off ") of signals, achievable, as mentioned, by sub-dosed antagonists of e.g. B. β- plus alpha- Adrenoceptors, etc.

Further improvements in both the novel therapy of diseases mentioned above as well as in the efficiency of Conventional vaccines are according to the invention Methylxanthine, intracellular pH (pHi) corrective (increasing) substances, redox potential or GSH / GSSG or NAD (P) H / NAD (P) + - Quotient improving and ion home to educate stasis, especially K + balance correcting preparations len. These preparations are in detail in one of the previous ones gene patent applications (applicant: P. Leskovar) and are therefore not dealt with here.  

(b) inactivation / elimination of hyper- or persistently activated immunocompetent cells

The principle of this in vivo inactivation or depletion of hyperactivated ("incorrectly programmed") effector cells is the so-called "microimmune surgery", one from the applicant introduced technology, which in the future will be a gene therapy parallel or competing with or complementary to it Could represent treatment.

This "microimmune surgery" is already one of the most advanced filed patent applications (applicant: P. Leskovar) in detail have been described; here is only the basic principle that goes far selective inactivation or elimination of the sick unit inducing or maintaining the lymphocyte clone by combining (b1) panT or T subclass specific monoclonal antibodies (Mabs) or the derived immunotoxins (i.e. Mab plus cytotoxin), plus (b2) alloreactive T cells from the healthy donor, be discussed.

This inventive combination of humoral (Mab) and cellular (allogeneic T-cell) technology can increase efficiency the Mab-mediated depletion of pathogenic immunocyte Subclones are increased significantly, like our animal experiments have clearly shown. Both in tumor patients as well in patients with (chronic) infections, including HIV infection and those with the "new" CFS (chronic fatigue syndrome) it is noticeable that the FACS analysis z. T. greatly increased values for CD8 positive (Ts) and / or for HLA-DR (MHC II) positive T- Has cells that appear before or during the onset of the disease rise even more.

By combining Mabs (against CD3 or CD8 antigens) plus allogeneic donor PBM / PBL or donor T cells, the Cell death beforehand through a special in vitro pretreatment  lung (subject of previous registration, applicant: P. Leskovar) must be "pre-programmed" / "pre-determined", can (according to the laws of MLR / MLC, CML and PLT) the he mentioned CD8 and HLA-DR positive pathological (Hyperactivated) effector cells selectively inactivate in vivo ren or eliminate.

In this way, 94-100% survival rates of tumor-bearing mice are achieved (own investigation gene).

Note 1: The special, in vitro pretreatment of the allo gene donor PBM / PBL or donor T cells ("donor effector cells ") for preprogramming cell death is a plus step procedure, consisting of the following substeps:

• (1) Synchronization of the "donor effector cells" by (a) Cell incubation in serum-free medium followed by the cell culture in the serum-containing medium, or (alternatively) (b) by Cell incubation first in the absence of essential amino acids (e.g. isoleucine) and then eat in the presence of them tial amino acids, or (alternatively) (c) by cell incubation tion in the presence of synchronizing cytostatics, such as Vinchristine, hydroxyurea or bleomycin.
• (2) Treatment of the "donor effector cells" by (a) bifunk cationically alkylating agents, d. H. the DNA cross-linking Substances (e.g. mitomycin C) and / or (b) through inhibitors the enzyme ribonucleotide reductase (e.g. hydroxyurea), which block DNA synthesis, RNA and protein but do not interfere with synthesis.
• (3) Incubation of the "donor effector cells" in the presence of Inhibitors of DNA repair (DNA repair system) (e.g. Hydroxyurea).  
• (4) Thorough cell washing, e.g. B. with PBS or RPMI 1640
• (5) Infusion of the pretreated "donor effector cells" in the recipients (e.g. tumor patients).

An alternative method provides for the incubation of "donor Effector cells "(a) with radiolabeled DNA building blocks (Purine and pyrimidine bases) and / or (b) with radioisotope hal amino acids.

Another alternative method is the irradiation development of the "donor effector cells", followed by their incubation tion in the presence of inhibitors of DNA repair phases (e.g. Hydroxyurea).

In the special case of autoimmune diseases, the targets are len of the "preprogrammed" alloreactive donor T cells also HLA-DR (MHC II) positive autoaggressive T cells (predominantly T4, partly T8 cells).

The procedure consists of in vivo depletion of T cells (with anti-panT (CD3) -Mabs) or their T8 or T4 subclasses (with anti-CD8 or anti-CD4 Mabs). For cost reasons "Pure" Mabs or immunotoxins through a Mab-saving combination with cyclophosphamide (or other cytostatics) who replaced the.

The alloreactive donor T cells or donor PBMs / PBLs (Peripheral blood lymphocytes) eliminate the MHC II positive as well as the blast-like pathological subclones, without this To induce GvHD because (because of the "preprogrammed" Cell death) die prematurely.

The technique described above can still be improved if, after exposure to the specially pretreated Donor T or PBMs / PBLs cells on the pathologically active  fourth recipient lymphocyte (see above) autologous peripheral blood cells that were previously ex vivo against the donor PBMs / PBLs have been reinfused into the patient.

Note 2: The latest animal experiments have shown that the "Microimmune surgery" is so efficient that (a) the donor Effector cells cytolysis of without preactivation enable pathological leukocyte subclones of the patient and (b) that they have no previous in vivo Ts-Deple tation (by subpopulation (Ts) and / or panT (CD3) spec fish Mabs) are effective, although the combination of the cellu and the humoral attack is still the most efficient is most. In all experiments, however, it is shown that the in vivo used Mabs by effector cells with pre-programmed Cell death experience an enormous increase in effectiveness; this applies according to the invention both for the use described above a combination of this specially pretreated effector cells with different Mabs in tumor patients, as well for the Mabs already used clinically in the organ transplantation (anti CD3-Mabs) and in the treatment of Autoimmune diseases (anti CD4-Mabs).

Another way (a) of bridging the critical immunocompetent phase z. B. after excision of the primary tumor or after the bone marrow transplant, and (b) the Prevention of GvHR (if GvLR exists at the same time) according to the invention consists in the following process:

• (a) The patients, e.g. B. those with solid tumors first with anti CD3-Mab (or with the appropriate immunotoxin) or with the Mab-saving combination of cytostatic (e.g. cyclophosphamide) plus Mab "conditioned".
• (b) The CD8: HLA-DR / DQ double posi is then in vivo active suppressor fraction with the help of "microimmune surgery" eliminated, and  
• (c) by the patient's own (autologous) T cells or PBMs / PBLs the donor effector cells are depleted in vivo, whereby the ratio between the autologous T cells or PBMs / PBLs (Point (c)) on the one hand and between the corresponding leuko sub-populations of healthy donors (point (b)) 3: 1 must be up to 10: 1. In this case, cell death Programming u. U. omitted.

Note: Both the donor effector cells (point (b)) and the autologous effector cells (point (c)) can, too but not be all pre-activated.

Note 3: In conclusion from our detailed tier it is recommended to try the parental if possible Use PBMs / PBLs as donor effector cells.

Note 4: By making the alloreactive more present Donor effector cells against recipient lymphocytes Another advantage can be achieved: The pre-sensitive lized donor effector cells are blastogenic pretransfor mated and can, similar to the effector cells of the sekun the MLC approach and that of the PLT (primed lymphocyte typing) approach, a day or two earlier than the non-before sensitized comparison clones can be activated in vivo. This gives them the crucial advantage that she after her infusion in the patient of pathological (Hyper) activated, MHC II-positive subpopulations elimi kidneys before the resistance against this is therapeutically established set donor effectors can be built. For this Basically, the number of donor effects to be transfused gates reduced and the cell death preprogramming u. U. ent fall.  

(c) Improving organ transplantation (kidney, heart / lung, liver allograft)

The acute rejection response, often leading to loss of the allo leads graft can be essential according to the invention improve if the classic method based on (a) a generalized, side effect-rich immunosuppression (Azathioprine, prednisone, (methyl) prednisolone, cyclosporin A) and / or (b) on in vivo T cell depletion by anti-CD3 Mabs or ALG or ATG, through "microimmune surgery" or through the cell death preprogrammed effector cells either added or z. T. would be replaced.

(d) Improvement of conventional vaccines

The same principle and the same techniques (deblocking and / or inactivation / elimination of hyperactivated Effector cells) are used by the applicant to improve con conventional antibacterial and anti (retro) viral vaccine anti-HIV vaccines recommended; the target cells here are the CD8: MHC II double positive suppressor effect gate cells.

The principle is to increase the absolute number of blasto gene-pre-transformed, pathogen-specific Th (helper T- Cells), Tc / CTL (cytotoxic T cells) and / or B (Plasma) cells by (a) deblocking and / or (b) by Inactivation / elimination of pathogen-specific Ts (Suppressor T cells). These Ts block an im early Process of vaccination started generation of pathogenic specific Th, Tc / CTL and B memory cells. By (a) Deblocking and / or (b) inactivating / eliminating the CD8: HLA-DR / DQ-double positive Ts cells becomes the clonal Expansion of "positive" memory cells (Th, Tc, B) strongly increased and thereby the infection protection of the "classic" Vaccines improved significantly.

• (a) The Ts cells are unblocked (a1) by intra cellular cAMP concentration reducing antagonists of Gs-coupled receptors (e.g. β-adrenoceptor, H2-histamine receptor, A2 / P1 adenosine receptor) and / or by agonists of the Gp, Gi and Go coupled receptors (e.g. alpha- Adrenoceptor, HI-histamine receptor, A1 / P1 adenosine receptor) and / or (a2) by blocking "voltage-operated" and / or "receptor-operated" Ca2 + channels (details in previous outgoing registration, applicant: P. Leskovar).
• (b) Inactivating / Eliminating CD8: HLA-DR / DQ- double positive Ts cells are made by alloreactive, cell pre-programmed effector cells, as in the present Registration described (see above).
• (c) Another method of improving the Vaccination-induced, pathogen-specific "immunologi memory "is the elimination of pathogen-specific fish Ts cells by treating the vaccine with Subset (CD8 / Ts) - and / or panT (CD3) -specific Mabs or ent speaking immunotoxins.
• (d) Another way of determining the number of pathogen-speci fishing to increase Th, Tc and B cells is the delay Antibody formation by Mabs (and by immunotoxins), directed against (d1) B cells, (d2) Th (T4) cells, (d3) B- plus Th (T4) cells, (d4) monocytes / macrophages ("suppressor- Monocytes "), and / or (d5) B cells plus suppressor mono cytes. (Details were given in one of the previous patents applications (applicant: P. Leskovar).

Note: Here, too, "pure" Mabs can be mab-in economical mixture of cytostatics (e.g. cyclophosphamide) plus Mab to be replaced.

• (e) Support and partial replacement of glucocorticoids (e.g. cortisone) by low-dose antagonists of the Gi (Gp, Go)-coupled receptors and / or through low dosed agonists of the Gs-coupled receptors.

The glucocorti characterized by strong side effects coide can according to the invention by subdosed blockers of Gi-, Gp- or Go-coupled receptors and / or by low rig dosed ligands of the Gs-coupled receptors supports or be partially replaced. In addition, the Effect of these substances and mixtures of substances through a combination can be enhanced with subdosed Ca antagonists.

The indication of these new combination products ent speaks that of the "classic" glucocorticoids (Cortico steroids). Again, the antagonists are particularly suitable those Gi (Gp, Go) -coupled receptors that address the Share endogenous ligands with a Gs-coupled receptor (Examples: catecholamines, histamine, adenosine).

Note: Leave with this kind of combination preparation other, clinically (e.g. in organ transplantation tion) immunosuppressive agents used (Cyclosporin A, FK 506, Support rapamycin, azathyoprin, cyclophosphamide, etc.) or replace partially.

By a balanced combination of the individual subdoses Agonists and antagonists, e.g. B. by simultaneous partial (reversible) inhibition of alpha- and beta-adreno application can be achieved with low side effects become.

Important note:
Because the hyperactivated state of effector cells (T cells, monocytes / macrophages, etc.) is an important element in the pathogenesis (a) of the tumor (b) of autoimmune diseases (c) of arteriosclerotic vascular changes (d) of infectious diseases (including HIV Infections), apply under point (a) ("Unblocking hyper- or persistently activated immune competent cells") and under point (b) ("Deactivating / eliminating hyper- or per-activated activated immune competent cells") benen method according to the invention for all these diseases.

Reducing background signals, i. H. "Filter out" of unspecific (unproductive) transmembrane signals, about the susceptibility of immunocompetent cells for speci fish to increase or enable immune-relevant signals.

• 1. Combination of subdosed β- (β1- plus β2-) and sub dosed alpha- (alphal- plus alpha2-) adrenoceptor- Blockers (antagonists) (objective: prevention of hypo or the anergic state of hyperactivated immune compe cells by reducing the level of non-specific background signals).
• 1.1. Combination of preparations based on pindolol (e.g. Durapindol / -15 / -retard (26.039), or Pinbetol / forte (26.067)) plus preparations based on phenoxybenzamine (e.g. Dibenzyran 1/5/10 (81.091)).

Note: Pindolol is a β1 plus β2 sympatholytic, Phenoxybenzamine, on the other hand, is an alpha 1 plus alpha 2 blocker.

Recommended dosage: 1 × 15 mg / d or 3 × 5 mg / d durapindole plus 1 × 5 mg / d or 2-3 × 1 mg / d dibenzyran.

• 2. Combination of subdosed beta (beta1 plus beta2) adrenozep tor blockers with subdosed alphal receptor antagonists, which additionally the H1-histamine and the 5HT (serotonin) - Block receptor (objective: as in point 1).  
• 2.1. Combination of preparations based on pindolol (e.g. Durapindol / -15 / -retard (26.039), or Pinbetol / forte (26.067)) plus preparations based on indoramine · HCl (e.g. Wydora / 50 (16.039)).

Note: Indoramine · HCl is an antagonist of the alpha1- Adrenoceptor, the H1 histamine receptor and the 5HT (Serotonin) receptor.

Recommended dosage: Durapindol (see above); Indoramine 1 x 25 mg / d.

• 3. Combination of subdosed β- (β1- plus β2-) adrenozep tor antagonists with subdosed alpha - (alphal- or alpha2-) receptor blockers (objective: as in point 1 and 2).
• 3.1. Combination of preparations based on 3.1.1. Alprenolol · HCl (e.g. aptin (26.002)), 3.1.2. Bupranolol HCl (e.g. Betadrenol 50 / -100 (26.017)), 3.1.3. Penbutololsul fat (e.g. betapressin (26.019)), 3.1.4. Bisoprolol fumarate (e.g. Concor5 / 10 (26.025)) or 3.1.5. CarteololHCl (e.g. Endak5 / 10 (26.046))
  plus preparations based on 3.1.1. Urapidil (e.g. Ebrantil 30/60/90 (16.032)), 3.1.2. Doxazosin mesilate (e.g. Cardular 1mg / -2mg / -4mg (16.029) or Diblocin 1mg / -2mg / -4mg (16.030)) or 3.1.3. Terazosin (e.g. Heitrin 1/2/5 (16.035)).

Recommended doses: Aptin-Duriles 1 × 200 mg / d; Betadrenol 1-2 x 50 mg / d; Betapressin 0.5-1 x 40 mg / d; Concor 1 × 5 mg or 1 × 10 mg / d; Endak 5 mg / d; Ebrantil 30mg / d; Cardular 1 mg / d; Diblocin 1 mg / d; Heitrin 0.5-1 mg / d;

• 4. Combination of Subdosed H2 and H1 Histamine Receptor Antagonists (objective: as above).
• 4.1. Combination of preparations based on cymetidine (e.g. Sigacimet 200 / -400 / -800 (59.102) or Tagamet 200 / - 400 / -800 (59.105) or H2-Blocker-ratiopharm 200/400/800/1000 ( 59.096)
  plus preparations based on 4.1.1. Oxatomide · H20 (e.g. Barpet (07004)), 4.1.2. Brompheniramine hydrogen maleate (e.g. Dimegan (07.005)), 4.1.3. Dimetind maleate (e.g. Fenistil (07.006)) or 4.1.4. Terfenadine (e.g. Hisfedin (07.009)) Recommended doses: Sigacimet 1 × 200 mg / d; Tagamet 1 x 200 mg / d; H2 blocker ratiopharm 1 × 200 mg / d; Barpet 1 x 30 mg / d; Dimegan 1 x 12 mg / d; Fenistil 1 x 1 mg / d; Hisfedin 0.5-1 x 60 mg / d.
• 5. Combination of subdosed antagonists of the A2 plus A1 P1-purinergic (adenosine) receptor (objective: as above).
• 5.1. Combination of preparations based on methyl xanthines (theophylline) (e.g. Aerobin mite (27.102) or Contiphyllin prolonged-release tablets (27.113) or euphyllin N tablets (27.125))
  plus preparations based on ipratropium bromide (e.g. Atrovent capsules (27,048) or Itrop film-coated tablets (09028)).

Recommended dosage: Aerobin 0.5-1 × 200 mg / d; Contiphylline Prolonged-release tablets 0.5-1 x 300 mg / d; Euphyllin N tablets 1 × 73 mg / d; Atrovent capsules 0.5-1 × 200 µg / d; Itrop film-coated tablets 0.5-1 × 10 mg / d Note: Combinations are also of interest with preparations based on cromoglicic acid di sodium salt and ketotifen hydrofumarate.

Important note: Subdosed antagonists under point 1, 2, 3 and 4 can be combined. In such a case it is Dosage to 5-50% of those listed under points 1, 2, 3 and 4 Reduce dose.  

The heavily subdosed antagonists in items 1, 2, 3 and 4 can with conventional Ca antagonists and / or with sub dosed agonists of Gp and Gi coupled receptors be combined.

Claims (7)

1. comprising means for influencing hyperactivated immunological effector cells

• (I) an agent eliminating the hyperactivated effector cells
• (II) all-reactive cells with predetermined cell death.

2. Composition according to claim 1, characterized indicates that component (I) eliminates T cells means. 3. Means according to claim 1, characterized records that component (I) against CD8 and / or CD3 directed antibodies. 4. Agent according to one of claims 1 to 3, characterized in that Component (I) additionally a cytostatic, in particular whose cyclophosphamide contains. 5. Agent according to one of claims 1 to 4, characterized in that Component (II) allogeneic, the pathological Ts cells and / or inactivating hyperactivated macrophages Cells whose DNA has been changed in a controlled manner. 6. Use a combination of a hyperactivated Effector cells eliminating agents and alloreactive Cells with predetermined cell death for the production of a Anti-cancer drug, viral disease genes and autoimmune diseases.   7. Method of treating cancer, viral diseases and autoimmune diseases that include hyperacti fourth immunological effector cells eliminated or in restores the normal state and thereby your own Immune defense to restore the condition before sick empowered to start.