JP2001516721A - Regulation of the immune response - Google Patents

Abstract

(57) Abstract: A method of affecting or regulating the stimulation or suppression of an immune cell product in an animal in response to an immune response to an external or endogenous immune stimulator, comprising the general formula (I) R ₁ − during CO-NR ₂ R ₃ (wherein, R ₁ is selected from H and lower (i.e. C ₁ -C ₃₎ group consisting of alkyl and C ₂ -C ₃ alkenyl group, R ₂ and R ₃ or equal to or And R ₂ and R ₃ are each selected from the group consisting of H, lower (ie, C ₁ -C ₃ ) alkyl and C ₂ -C ₃ alkenyl groups, which groups are optionally halogenated or hydroxyl may be of, or in combination with each other, - (CH _{2) n} - group (n is any number from 2 to 5), or _{- (CH 2) 2 -O- (} CH 2) 2 Which may form a group) Xie and methods of non-toxic compound selected from the group of prodrugs comprising administering an amount effective immunoregulatory to the animal. The method is useful for treating various diseases associated with an inappropriate immune response, the present invention relates to the use of a compound of formula (I) in the manufacture of a medicament for use in treating such diseases, and A pharmaceutical preparation containing it is provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] The present invention relates to the treatment of conditions associated with an inappropriate immune response in the human body. More specifically, the present invention is directed to the treatment of conditions in which an inappropriate immune response is associated with inappropriate immune cell metabolic activity, the activity of which is determined by a protein tyrosine kinase, hereinafter referred to as "PTK". In a tyrosine kinase cascade that plays a role, or in immune cells, is mediated by a cyclin-dependent kinase, hereinafter referred to as "CDK";
Or at least for the treatment of a condition believed to be relevant. Therefore,
The present invention relates to the treatment of various diseases associated with an inappropriate immune response in an animal, a term intended to include the human body herein, and drugs for use in the treatment.

[0002] The immune cells in the immune system of background animal of the invention are well known to play an important role. A variety of such cells have been identified. Among these, T lymphocytes known as T cells and B lymphocytes known as B cells have been recognized for their important role in the immune response of animals to foreign body infection. In addition, other cells capable of producing immune mediators have immune function.
The normal or appropriate response of such cells to an exogenous stimulus, such as a viral or bacterial infection of the animal body, or to an endogenous immune stimulus, such as a tumorigenic transformation, is the metabolic pathway of the cell in the tissue And the production of cytokines, lymphokines, chemokines, growth factors and cytotoxic cells, and usually also causes the proliferation of such immune cells. In addition, immunological mediators perform or supplement the function of neutralizing infectious agents, or toxins released by them, and are part of the body's process of fighting or curing innate infections. Department. These pathways include biochemical and signaling systems that are further mentioned below.

[0003] Although the reasons have not been fully elucidated at this time, it is well known that the immune system response is abnormal, often resulting in the expression of products deemed inappropriate by immune cells and their secretion. I have. Such abnormalities may, but need not, be associated with abnormal proliferation of such cells. Such abnormalities in immune cell activity may be manifested simply by the secretion of inappropriate amounts of immune cell products, without necessarily increasing the proliferative activity of such cells.

[0004] Improper immune responses have been linked to various diseases affecting the human and animal body. The present invention is directed to the treatment of such conditions as described below. In the conditions in question, the development of inappropriate immune responses, including the presence of cytotoxic cells and / or inappropriate amounts of immune cell products required to combat a particular infection or condition, What is believed to be an attack by the immune system on specific organs of the body itself, rather than an attack directed at metabolites such as exogenous or endogenous antigens or factors or toxins produced thereby, or It even causes a nonspecific immune attack on the whole. The target organs for such inappropriate aggression are diverse and include skin, muscle, skeletal structures,
Including internal organs, including joints, blood, brain and nervous system, intestines, kidneys, lungs, liver, and even sensory organs including eyes.

[0005] In some conditions or syndromes related to the present invention, primary or triggering factors or stimuli for the immune response have been identified. However, characteristics of such a condition or syndrome are that causative factors or stimuli, such as, for example, viral or microbial infections or other forms of antigens, cause the body's own defense mechanisms, ie, the immune system, or pharmaceutical intervention, or a combination thereof. The immune response can survive even after being eliminated by. In other cases, the causal factor is unknown or at least unknown at present. All of these states
It is considered an immune-mediated disease.

[0006] In order to clearly understand the nature and effect of the present invention, it is necessary to briefly explain the latest knowledge on the nature of immune response activity in the body. The biological function of immune cells, specifically T lymphocytes, is specific to the T lymphocyte surface and relies on signaling through T cell receptors present only on that surface. T cell receptor is a complex group of surface molecules including CD ₄ or CD ₈ surface molecules. CD _4, CD _8, and the surface molecule certain other has the ability to transmit a signal from the exterior surface of the cell membrane to the interior environment, the cytoplasm of ie the cells in the cell. These signals are transmitted via an enzymatic pathway known as the tyrosine kinase cascade.
Activated tyrosine kinases phosphorylate certain proteins, leading to the expression of new signal intermediates. In this cascade, an enzyme known as protein tyrosine kinase (PTK) plays an important role. This enzyme is a protein characterized by a free sulfhydryl group. The tyrosine kinase cascade ultimately ends with the expression of specific genes in T cells. Each of these genes encodes various immunological mediators, including cytokines, and structural proteins required for cell growth. As noted above, the disease mediated by the immune response to which the present invention pertains is associated with the uncontrolled expression of immunological mediators by immune cells and the activity of unregulated cytotoxic cells.

DISCUSSION OF THE PRIOR ART Dimethylformamide or DMF is a nonionic liquid that is volatile at room temperature and is well known for use as an industrial solvent. In particular, it is used in the production of various products for human consumption, including the production of pharmaceuticals. Its toxicity has been well studied. It is known to be non-toxic at concentrations several times higher than those associated with the present invention. The toxicity in the presence of high concentrations of DMF in the human body is due to the depletion of glutathione in hepatocytes and the necrosis of hepatocytes. Cryopreservation Technologies CC is
PCT application PCT published June 26, 1997 as O97 / 22248
/ US96 / 19697 alleged that dimethylformamide and related compounds can be used in the treatment of viral and / or microbial infections. The publication discloses that in HIV-positive patients, DMF can be administered transdermally to patients.
An example was given in which an attempt was made to obtain a blood concentration of DMF targeted at 00 ppm, but the concentration actually reported was different from this target. It further reports that the viral load in patients decreased from 120,000 to 500 / ml after such treatment with DMF for less than three weeks. It also reports improvement in acne and rubella symptoms in patients treated with DMF and having DMF blood levels of 50-100 ppm. The disclosure relates to the use of DMF as antiviral and antimicrobial agents, the immune response modulating properties of the compounds of the invention, and the use of such compounds in the treatment of immune cell related disorders, or No mention is made of the use of such compounds in the manufacture of a medicament for use in treating such conditions.

OBJECTS OF THE INVENTION It is an object of the present invention to provide a method of modulating an immune response in an animal or human body, and a method of treating a disease associated with an inappropriate immune response in an animal, including the human body.

Description of the Invention Surprisingly, in contrast to the prior art knowledge on the toxicity and antiviral and antibacterial properties of DMF, such products are used at subtoxic doses and have immunological functions. That the immune response metabolic processes in cells can be modulated by influencing the processes that stimulate or suppress the expression or secretion of immunological mediators by these cells without destroying the cells by administering DMF to the body. I found it.

The present invention provides compounds of the general formula (I): R ₁ —CO—NR ₂ R ₃ (I) wherein R ₁ is H and lower (ie C ₁ -C ₃ ) alkyl and C ₂ -C 3 ₃ is selected from the group consisting of alkenyl groups, R ₂ and R ₃ are the same or different, each R ₂ and R _3, H, lower (i.e. C ₁ -C ₃₎ alkyl and C ₂ -C ₃ alkenyl Selected from the group consisting of
These groups may be halogenated or hydroxylated, optionally or in combination with each other, - (CH _{2) n} - group (n is any number from 2 to 5), or - (CH compounds and metabolites and are selected from the group of compounds consisting of a prodrug compound of _{2) 2} -O- (CH ₂₎ may form a ₂ group), an amount effective in immunomodulation nontoxic There is provided a method of affecting an immune response in an animal comprising the step of administering to the animal.

The immune response affected by the above method may be an immune response of immune cells forming part of the body's immune system. The immune cells may be T lymphocytes and or B lymphocytes. The method can be performed to reduce the expression or secretion of immune cell products in the body.

According to another aspect of the present invention, the general chemical formula (I): R ₁ —CO—NR ₂ R ₃ (I) wherein R ₁ is H and lower (ie C ₁ -C ₃₎ ) is selected from the group consisting of alkyl and C ₂ -C ₃ alkenyl group, R ₂ and R ₃ are the same or different, each R ₂ and R _3, H, lower (i.e. C ₁ -C ₃₎ alkyl And C ₂ -C ₃ alkenyl groups,
These groups may be halogenated or hydroxylated, optionally or in combination with each other, - (CH _{2) n} - group (n is any number from 2 to 5), or - (CH ₂ ) administering to the animal a non-toxic, therapeutically effective amount of a compound selected from the group consisting of: a compound which may form a _2- O- (CH ₂ ) ₂ group) and its metabolites and prodrugs A method of treating an animal afflicted with a disease associated with an inappropriate immune response in an animal is provided.

According to another aspect of the present invention, the present invention provides a compound of the general formula (I) R ₁ -CO-NR ₂ R ₃ (I) wherein R ₁ is H and lower (ie C _1- C ₃₎ is selected from alkyl and C ₂ -C ₃ group consisting of alkenyl groups, R ₂ and R ₃ are the same or different, R ₂ and R ₃ each, H, lower (i.e. C ₁ -C ₃ ) is selected from the group consisting of alkyl and C ₂ -C ₃ alkenyl group,
These groups may be halogenated or hydroxylated, optionally or in combination with each other, - (CH _{2) n} - group (n is any number from 2 to 5), or - (CH ₂ ) a compound selected from the group consisting of a compound which may form a _2- O- (CH ₂ ) ₂ group) and its metabolites and prodrugs, wherein the compound has It relates to the use in the manufacture of a medicament for use in a method of treating an animal afflicted with a related disease.

Further, according to the present invention, the present invention provides a compound represented by the general chemical formula (I): R ₁ —CO—NR ₂ R ₃ (I) wherein R ₁ is H and lower (ie, C ₁ -C ₃₎ is selected from the group consisting of alkyl and C ₂ -C ₃ alkenyl group, R ₂ and R ₃ are the same or different, R ₂ and R ₃ each, H, lower (i.e. C ₁ -C ₃₎ is selected from the group consisting of alkyl and C ₂ -C ₃ alkenyl group,
These groups may be halogenated or hydroxylated, optionally or in combination with each other, - (CH _{2) n} - group (n is any number from 2 to 5), or - (CH _{2) 2} -O- (CH ₂₎ compounds of may be formed ₂ group) and its metabolites and a compound selected from the group of compounds consisting of prodrug into an pharmaceutically acceptable dosage forms A pharmaceutical composition for use in treating an animal afflicted with a disease associated with an inappropriate immune response in an animal comprising the same.

In all treatments related to aspects of the invention, the condition to be treated can be any one of the following: Systemic lupus erythematosus (SLE) scleroderma (systemic sclerosis) vasculitis syndrome (including Wegener thrombosis and giant cell arteritis of any form) dermatomyositis asthma adult respiratory distress syndrome (ARDS) systemic inflammatory response syndrome ( SIRS) inflammatory bowel disease chronic hepatitis rheumatoid arthritis rheumatic fever myasthenia gravis multiple sclerosis psoriasis eczema multiple myeloma Reiter's syndrome glomerulonephritis rheumatic polymyalgia tonic spondylitis nodular polyarteritis allergic Rhinitis diabetes optic neuritis acute transverse myelitis head injury spinal cord injury vasospasm after subarachnoid hemorrhage.

In all the above aspects of the invention, particularly preferred compounds are dimethylformamide and its metabolites ie N-methylformamide, N-methyl-isocyanite and its carbamates, and N-acetyl-S- Prodrugs of (N-methylcarbamoyl) cysteine and such metabolites.

Further, according to the present invention, the method provides a DMF plasma concentration of 0.001% and 0.1%.
%, Most preferably between 0.01% and 0.05%, by administering to the patient to be treated an amount of DMF sufficient to maintain it. Similarly, the medicament according to the invention may be such as to achieve and maintain a DMF plasma concentration of between 0.001% and 0.1%, most preferably between 0.01% and 0.05%. It is compatible with the use for administering DMF to a patient in a rate amount.

Also, in all aspects of the invention, the compounds can be administered by any route of administration, such as oral, nasal, rectal, intravenous, intramuscular, subcutaneous or transdermal. The preferred route of administration of the present invention is transdermal. However, administration via transdermal patches is preferred.

As shown in the examples below, mixed lymphocytes were exposed to 1 to 10 μg of non-specific stimulator of lymphocytes such as PHA per 200 μL. Simultaneous exposure of these lymphocytes to very low concentrations of DMF is indicated by the fact that these cells have a reduced ability to reduce the patented (US Pat. No. 5,501,959) redox indicator. As shown, reduced metabolic activity has been demonstrated. This inhibition of metabolic activity is directly related to the fact that the therapeutic concentration for effecting metabolic activity and thereby inhibiting proliferation is lower than the concentration that causes cellular metabolism and thus activation of proliferation. Is not the result of typical cytotoxicity.

By contacting immunoreactive cells in need of modulation with therapeutic concentrations of DMF or any metabolite, it is possible to reduce the metabolic activity of cells having immune function. By reducing the metabolic activity of T lymphocytes, certain T lymphocyte-specific antigens, a major histocompatibility complex molecular combination, and their responsiveness to antigens are severely inhibited. Must be. Underlying the clinical application of DMF for regulating immune cell mediated diseases proposed by the present invention is
Antigen-specific inhibition of T lymphocyte response.

According to the present invention, to transdermally administer DMF to a patient in need of treatment, D
It has been proposed to use a versatile transdermal administration system that can deliver a variety of drugs, including MF and related compounds described above, for treatment.

The parameters of the patch design that may be important include: 1. Patches determine the amount of active ingredient (drug) absorbed over a period of time,
Must be of the specified dimensions. 2. Drug administration should not be time dependent. 3. Drug concentrations should be variable depending on the patient's profile. 4. Patches must be stable and repeatedly deliver therapeutic concentrations of the drug (drug) to be administered. 5. Since the rate of drug (drug) administration depends on the skin, the release of the drug from the membrane must be the same or very close to the rate of absorption by the skin. 6. Patches and drugs must have a relatively long shelf life.

To fulfill the above need, patches were designed with the following features. 1. High density nylon support material. 2. A safe boundary made of PTFE nylon (Teflon). 3. Nylon or PTFE with low density. 4. Hydrophilic or hydrophobic NYLON or PTFE membranes (depending on which drug is administered). 5. A membrane with a pore size of 0.05-0.45 microns, depending on which drug is administered. 6. Diatomaceous earth (SiO ₂ ) adsorbent material. 7. Stabilizers (salting agents for reducing evaporation as well as for uniform weight distribution throughout the membrane). 8. Suitable skin adhesive that does not react with drugs. 9. Anti-irritant-Vitamin E (this agent can be applied before, during, or after application of the drug to protect the skin from side effects).

More specifically, a patch was created as follows.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

Coating Technique Indirect administration of a drug such as DMF can be accomplished by applying a known amount of the active agent to the adsorbent silicon dioxide by syringe after applying the patch to the skin. The following advantages can be obtained by using this technique. 1. Controlled drug delivery to patches from ampoules / containers. 2. The dosage of the therapeutic agent can be predetermined according to the patient's profile. 3. By making the drug concentration dependent, the treatment time and area of skin exposure are constant during treatment. 4. Patches and medications can be applied with confidence without overdosing the patient. 5. Patch and drug administration is easy and the patient can peel off after administration. 6. Patches are extremely stable, have an unlimited shelf life, and drugs administered from ampoules have an expiration date of at least 2 years unless otherwise specified.

[0026] Example of the invention now will clarify the present invention with reference to the following examples, not intended to limit the scope of the present invention to the illustrated embodiments.

Example 1 Peripheral human lymphocytes were separated from whole blood of healthy volunteers by using the density gradient separation technique well described and known in immunology research papers. Briefly, this technique dilutes peripheral whole blood 1: 2 with a cell culture medium such as phosphate buffered saline or RPM1640. Next, Histopaque
) Layer a density gradient, such as 1077 (Sigma Cat # 1077), underneath the diluted peripheral blood, taking care to create sharp boundaries. Then, a density gradient of 6
Centrifuge at 00 g for 20-25 minutes. After centrifugation, a clear buffy coat layer containing mainly lymphocytes is readily visible. Then, the layer is removed, the light tan coating is transferred to another tube, and washed three times in PBS or cell culture medium. After each washing step, the cells are centrifuged at 400 g for 9 minutes. After the third wash, collect lymphocytes from the pellet. Count the number of cells and dilute to the desired cell concentration.

Various DMF concentrations were prepared by using complete cell culture medium as the diluent. The following concentrations were prepared: 1%, 0.1%, 0.05%, 0.01% and 0.001%. Separated lymphocytes were diluted to the required concentration using complete cell medium.

The complete cell culture medium used in the above step contained RPMI 1640 consisting of 20-25 mM HEPES, 1 mM L-glutamine, 2 × 10 ⁻⁵ mM dimercapto-ethanol and 10% heat-inactivated fetal bovine serum.

[0030] The prepared lymphocytes were placed in 96-well cell culture plates at a concentration of 150,000 cells per well. PHA (phytohemagglutinin) was added to each test well at a concentration of 1-10 μg per 200 μL. At the same time, DMF was added to each test well at a predetermined concentration, and the culture wells were incubated at 37 ° C. in a 5% CO ₂ , 95% O ₂ atmosphere for 1 to 4 days.

A redox indicator sold under the trademark AlamarBlue was added to each culture well at a volume: volume ratio of 10%. The culture was incubated with AlamarBlue for 18 hours and the absorbance was measured at 570 nm using 630 nm as a control. The results can be summarized as follows.

Cultures obtained by exposing peripheral lymphocytes of healthy volunteers to PHA and DMF at a concentration of 1% for 24 hours produce Al reduced by cultures in normal PHA growth wells.
102% of the amount of amarBlue was reduced. However, cultures that only added DMF at a concentration of 0.05% reduced only 52% of the amount of AlamarBlue reduced by cultures containing lymphocytes stimulated by PHA. This indicates a marked inhibition of metabolic activity in the culture wells and is very closely correlated with the level of cell growth in the specific well.

As shown by AlamarBlue reduction of unstimulated lymphocytes, when compared to unstimulated lymphocytes exposed to low concentrations of DMF for metabolic activity, 0.05% DM
A 40% reduction in AlamarBlue reduction was observed for lymphocytes exposed to the F concentration (see FIGS. 1 and 2 which show representative results of many replicate experiments).

Example 2 A series of experiments were further performed to clarify the putative action mechanism of DMF in causing suppression of lymphocyte metabolic activity. In these experiments, lymphocytes of healthy volunteers were separated using the technique described in Example 1. After separation of the lymphocytes, they were exposed to various concentrations of DMF for various lengths of incubation time. The DMF concentrations used were 0.1%, 0.01%, and 0.001%, and the incubation times were 5, 15, 30, 75, 120 and 180 minutes.
Tyrosine kinase activity was measured using a commercially available tyrosine kinase quantification kit available from Boehringer Mannheim (catalog number 1534505). The results were as shown in the graphs of FIGS. Exposure to 0.01% DMF for more than 3 hours resulted in 71% inhibition of tyrosine kinase activity in test lymphocytes. The graph points out that the lower the absorbance reading, the higher the inhibition of tyrosine kinase activity. The general shape of these graphs remained the same regardless of the time at which the color reaction developed. These results indicate that a certain concentration of DMF exposed to lymphocytes for a certain period of time
Support the hypothesis that serving to inhibit tyrosine kinase activity underlies the present invention. The reduction in tyrosine kinase activity observed in test lymphocytes may be the result of stimulating certain tyrosine phosphatases. These graphs shown here are representative of many of the graphs obtained.

Example 3 The PTK inhibitory activity of DMF and its two metabolites was measured using the cervical cancer cell line H
For two cell lines, ELA and the liver cancer cell line HEP3B, Boeh
This was further clarified by comparison with the commercially available PTK inhibitor Piceatanol, sold by Ringer Mannheim as # 15353405. The following results were obtained. The inhibitor was used as a 10% DMSO solution.

The test was performed under the following conditions, and the following results were obtained. Slunk: 0.043 Function: Control (Cntrl) Endogenous phosphatase: 20.3% Endogenous phosphorylation: 0.14 (0.208) Mean inhibitory activity HELA inhibitor: 0.076 (0.132) (Pilleatranol + 10% DMSO) 66% 75 % 29.5% Untreated cells 0.115 (0.176) 100% 0% 2% Metabolite I 0.099 (0.167) 86% 95% 9.5% 0.2% Metabolite II 0.074 (0.140) 64% 80% 28.5% 2% Metabolite II 0.055 (0.091) 48% 55% 48.5% 0.2% DMF 0.073 (0.146) 63% 83% 27% 2% DMF 0.042 (0.082) 37% 47% 58% HEP3B inhibitor: 0.055 (0.111) 60% 60% 40% ( Pilleattanol + 10% DMSO) 66% 75% 29.5% Untreated cells 0.091 (0.186) 100% 0% 2% Metabolite I 0.090 (0.150) 99% 81% 10% 0.2% Metabolite II 0.036 (0.060) 40% 32% 64% 2% Metabolite II 0.095 (0.095) 60% 51% 44.5% 0.2% DMF 0.080 (0.123) 88% 66% 33.3% 2% DMF 0.040 (0.064 ) 44% 34% 61% IC50 1.7-17 μM established. An IC50 of 1.7-17 μM was established. Code metabolite I-N-methylformamide Metabolite II-N-methylisocyanate DMF-dimethylformamide

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61P 27/16 A61P 27/16 29/00 29/00 101 101 37/02 37/02 37/08 37 / 08 43/00 111 43/00 111 123 123 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL , PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, B , CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, HR, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK , SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (72) Inventor Du Prize, Gabriel, Johannes South Africa. 0186 Pretoria, Villiera, Kirkenberg Avenue 322 (72) Inventor Silac, Volker, Reinhart South Africa. Pretoria, Liedfontein, Twenty-Eighth Avenue-872 (72) Inventor Atfield, Derrick, Cecil South Africa. 0157 Centurion, Pierre von Reinefeld, Frodo Crescent 41 (72) Inventor Van den Bogarden, Johannes, Bayers South Africa. 0181 Pretoria, Groencroaf, France Ederstreet 76 F term (reference) 4C206 AA01 HA12 HA18 ZA02 ZA33 ZA34 ZA59 ZA66 ZA81 ZA89 ZB07 ZB15 ZB26 ZC35

Claims (12)

[Claims] 1. A compound of the general formula (I): R ₁ —CO—NR ₂ R ₃ (I) wherein R ₁ is H and lower (ie C ₁ -C ₃ ) alkyl and C ₂ -C ₃ alkenyl. R ₂ and R ₃ are the same or different and R ₂ and R ₃ are each selected from H, lower (ie, C ₁ -C ₃ ) alkyl and C ₂ -C ₃ alkenyl groups. Selected from the group consisting of
These groups may be halogenated or hydroxylated, optionally or in combination with each other, - (CH _{2) n} - group (n is any number from 2 to 5), or - (CH compounds and metabolites and are selected from the group of compounds consisting of a prodrug compound of _{2) 2} -O- (CH ₂₎ may form a ₂ group), an amount effective in immunomodulation nontoxic A method of affecting an immune response in an animal, comprising administering to the animal. 2. The method according to claim 1, wherein the immune response affected by said method is an immune response of immune cells forming part of the body's immune system. 3. The method according to claim 2, wherein the cells are selected from the group consisting of T lymphocytes and B lymphocytes. 4. The method of claim 1, wherein the method is performed to reduce the expression and secretion of immune cell products in the body. 5. A compound of the general formula (I): R ₁ —CO—NR ₂ R ₃ (I) wherein R ₁ is H and lower (ie C ₁ -C ₃ ) alkyl and C ₂ -C ₃ alkenyl. R ₂ and R ₃ are the same or different and R ₂ and R ₃ are each selected from H, lower (ie, C ₁ -C ₃ ) alkyl and C ₂ -C ₃ alkenyl groups. Selected from the group consisting of
These groups may be halogenated or hydroxylated, optionally or in combination with each other, - (CH _{2) n} - group (n is any number from 2 to 5), or - (CH ₂ ) administering to the animal a non-toxic, therapeutically effective amount of a compound selected from the group consisting of: a compound which may form a _2- O- (CH ₂ ) ₂ group) and its metabolites and prodrugs A method of treating an animal afflicted with a disease associated with an inappropriate immune response in the animal, comprising the step of: 6. A compound of the general formula (I) R ₁ —CO—NR ₂ R ₃ (I) wherein R ₁ is H and lower (ie C ₁ -C ₃ ) alkyl and C ₂ -C ₃ alkenyl groups. Wherein R ₂ and R ₃ are the same or different, and R ₂ and R ₃ are each comprised of H, lower (ie, C ₁ -C ₃ ) alkyl and C ₂ -C ₃ alkenyl groups Selected from the group,
These groups may be halogenated or hydroxylated, optionally or in combination with each other, - (CH _{2) n} - group (n is any number from 2 to 5), or - (CH ₂ ) a compound selected from the group consisting of a compound which may form a _2- O- (CH ₂ ) ₂ group) and its metabolites and prodrugs, wherein the compound has Use in the manufacture of a medicament for use in a method of treating an animal suffering from a related disease. 7. A compound of the general formula (I): R ₁ —CO—NR ₂ R ₃ (I) wherein R ₁ is H and lower (ie C ₁ -C ₃ ) alkyl and C ₂ -C ₃ alkenyl. R ₂ and R ₃ are the same or different and R ₂ and R ₃ are each selected from H, lower (ie, C ₁ -C ₃ ) alkyl and C ₂ -C ₃ alkenyl groups. Selected from the group consisting of
These groups may be halogenated or hydroxylated, optionally or in combination with each other, - (CH _{2) n} - group (n is any number from 2 to 5), or - (CH _{2) 2} -O- (CH ₂₎ compounds of may be formed ₂ group) and its metabolites and a compound selected from the group of compounds consisting of prodrug into an pharmaceutically acceptable dosage forms A pharmaceutical composition for use in the treatment of an animal afflicted with a disease associated with an inappropriate immune response in an animal, comprising: 8. The disease is systemic lupus erythematosus (SLE) scleroderma (systemic sclerosis) vasculitis syndrome (including Wagener thrombosis and giant cell arteritis of any type) dermatomyositis asthma adult respiratory distress syndrome ( ARDS) Systemic inflammatory response syndrome (SIRS) Inflammatory bowel disease Chronic hepatitis Chronic rheumatoid arthritis Rheumatic fever Myasthenia gravis Multiple sclerosis Psoriasis Eczema Multiple myeloma Reiter syndrome Glomerulonephritis Rheumatic polymyalgia Tonic spondylitis 7. The method according to claim 5, wherein the method according to claim 5 is selected from the group consisting of polyarteritis nodosa, allergic rhinitis, diabetes, optic neuritis, acute transverse myelitis, head trauma, spinal cord injury, subarachnoid hemorrhage and vasospasm. Or the composition according to claim 7. 9. The method, use or composition according to claim 1, wherein the compound is dimethylformamide. 10. The method of claim 9, wherein the DMF is administered to the patient to be treated in an amount and at a rate sufficient to maintain a DMF plasma concentration of between 0.001% and 0.1%. Method. 11. The method, use or composition according to claim 9 or the method according to claim 10, wherein the drug is administered or adapted to be transdermally administered. 12. The method, use or composition of claim 11, wherein DMF is administered or adapted to be administered by a transdermal patch substantially as described herein. .