RU2211698C2 - Modulation of immune response due to ribavirin - Google Patents

Abstract

FIELD: medicine, immunology. SUBSTANCE: the present innovation deals with ways of immunomodulation with the help of nucleotides. For this purpose, response of immune system to the stimulus should be modified due to representing nucleoside at concentration to affect B7 molecular marker being the opposite one against stimulus' impact. Stimuli under consideration include allergens, neoplasm, virus, bacteria, parasitic invasion and autoimmune reaction. The most important molecular markers for this purpose are considered to be B7-1 and B7-2. Predominant nucleosides are ribavirin and its analogs. The method in question enables to obtain higher immunocorrecting action at different diseases. EFFECT: higher efficiency of modulation. 14 cl, 2 tbl

Description

 The scope of the present invention is immunology.

BACKGROUND OF THE INVENTION
In addition to the commonly used physiological and phenotypic diagnostic parameters, diseases can sometimes be correlated with molecular markers, such as polidy, mutations in specific genes, the manifestation of certain cell surface markers, and so on. Many of these markers act as disease-specific prognostic indicators or signs and can thus be used as diagnostic tools to accurately determine the physiological state.

 In recent years, many attempts have been made to correlate relatively complex diseases, such as an autoimmune reaction, asthma, cancer, and so on, with specific molecular markers. Several studies have identified the direct or indirect involvement of costimulatory molecules B7-1 and B7-2 in modulating the immune system in diseases. However, despite numerous detailed data on the different levels of expression of B7-1 and B7-2 in diseases resulting from such studies, a comprehensive and complete picture has not been created (Hepatology 25, No. 5, 1997, pp. 1108-1114 : Expression of costimulatory molecules B7-1 and B7-2 and human hepatocellular carcinoma; J. Cancer. Res. Clin. Oncol. 124, 7, 1998, pp. 383-388: Expression of costimulatory molecules B7-1 and B7-2 on human gastric carcinoma; J. Neuroimmunol. 84, 2, 1998, p. 179-187: Costimulatory CD80 (B7-1) and CD86 (B7-2) on cerebrospinal fluid cells in multiple sclerosis; J. Neuroimmunol. 91, No . 1-2, 1998, pp. 198-203: B7-1 (CD80), B7-2 (CD86), interleukin-12 and transforming growth factor-beta mRNA expression in CSF and peripheral blood mononuclear cells from multiple sclerosis patients) .

 In many cases, clearly contradictory correlations between B7-1, B7-2 and specific diseases were observed (see Table 1). In some types of cancer, for example, B7-1 is present in relatively high quantities, and B7-2 is present in relatively small quantities. For other types of cancer, 87-1 and B7-2 have a completely inverse correlation (J. Cancer Res. Clin. Oncol. 124, 7, 1998, p. 383-388: Expression of costimulatory molecules B7-1 and B7-2 on human gastric carcinoma; Br. J. Haematol. 102, No.5, 1998, p. 1257-1262: The expression of costimulatory molecules and their relationship to the prognosis of human acute myeloid leukemia: poor prognosis of B7-2 positive leukemia; Int J. Mol. Med. 2, 2, 1998, p. 167-171: Lack of B7-1 and B7-2 on head and neck cancer cells and possible significance for gene therapy).

 Expression of B7-1 and B7-2 also shows only a contradictory correlation with models of known cytokines (see Table 2). For example, a correlation was established between the increased expression of B7-1 with both positive and negative regulation of the Type 1 response, and a correlation was established between B2-7 with both positive and negative regulation of the Type 1 response. The same can be said about correlations of B7-1 and B7-2 with a type 2 response (see Table 1) (Am. J. Respir. Cell Mol. Biol. 17, No.2, 1997, p.235-242: Differential regulation of human, antigen-specific Type 1 and Type 2 responses by the B-7 homologues CD80 and CD86; J. Immunol. 156, No.8, 1996, p.2387-2391: Costimulation of IL-4 production by murine B7-1 and B7 -2 molecules.).

 Further, it is not yet clear which drugs or even categories of drugs would be effective in modulating the activity of B7-1 or B7-2, and even if such drugs were identified, it remains unclear how to use such costimulatory molecules to modulate the immune system. Considering all these unknowns in aggregate, there remains a significant need to create methods and compositions for modulating one or more than one B7 marker, especially as a means of influencing the response of the immune system to a given stimulus.

Short description of tables
Tab. 1 is a table comparing specific diseases and their correlation with the expression of B7-1 and B7-2.

 Tab. 2 is a table comparing various types of diseases with expression of type 1, type 2, B7-1 and B7-2.

SUMMARY OF THE INVENTION
This invention provides methods and compositions by which the response of the immune system to a stimulus is modified. In general, the response is modified by introducing into the system a nucleoside at a concentration selected so as to have an effect opposite to the stimulus on the B7 marker.

 In one aspect of preferred embodiments, the stimuli are selected from the groups consisting of allergens, neoplasm, virus, bacteria, invasion, and autoimmune response. Particularly interesting molecular markers are B7-1 and B7-2. In another aspect of preferred embodiments, the nucleoside is analogues of ribavirin, and in particularly preferred embodiments, the nucleoside is ribavirin. In yet another aspect of preferred embodiments, a sufficient amount of nucleoside is provided to achieve a concentration range between about 0.2: M and about 5: M, respectively, in a fluid containing cells expressing the B7 marker.

 In yet another aspect of preferred embodiments, the stimulus is correlated with an increase in type 2 response, and nucleoside use is correlated with a decrease in type 2 response.

Detailed Description of Specific Embodiments
The inventor has found that there is a striking relationship between certain nucleosides, especially ribavirin and its analogs, and the expression of one or more than one B7 marker. Further studies revealed another unexpected connection - that the use of such nucleosides can be used to beneficially influence the outcome of a disease or other stimulus. In particular, a method was found to modulate the response of the immune system to a stimulus, in which: (a) the stimulus is correlated with exposure to the B7 marker; (b) correlate the use of nucleoside within the concentration range with modulation of the B7 molecular marker, which is the opposite of this effect; and (c) present the nucleoside to the immune system within this concentration range.

 As used herein, the term “nucleoside” refers to a compound consisting of any pentose or modified pentose moiety attached to a specific position of the heterocycle or to the natural position of purine (9-position) or pyrimidine (1-position), or to an equivalent position in the analogue, including in particular, the D- and L-forms of nitrogen bicyclic and monocyclic heterocycles. The term "D-nucleosides" refers to nucleoside compounds that have a D-ribose sugar moiety (eg, adenosine). The term "L-nucleosides" refers to nucleoside compounds that have an L-ribose sugar moiety. The term "nucleotide" means nucleosides in which phosphate esters replace the 5 'position of the nucleoside.

 The term "pharmaceutically acceptable salts" refers to any salt derived from inorganic or organic acids or bases.

 The term "neoplasm" refers to any type of autonomous pathological tissue growth that may or may not become malignant, including any kind of tumors and cancers.

 The terms “treating” or “treating” a disease refer to the execution of a protocol, which may include administering one or more drugs to a patient to alleviate the signs or symptoms of the disease. Thus, “treatment” or “therapy” does not require the complete removal of signs or symptoms, does not require recovery, and specifically includes protocols that have only a marginal effect (such as the placebo effect) on the patient.

 As used herein, the term "immune system" refers to any combination of immunocompetent cells that collectively identify and attack foreign objects and that dynamically respond to new pathogens or other stimuli. Examples of the immune system are human or other mammalian immune systems, which include the spleen, thymus B lymphocytes, T lymphocytes and antibodies. The immune system, as defined here, must have a cellular component, but may or may not have a humoral component. When the humoral component is incorporated into the immune system, this humoral component may include soluble molecules secreted from immunocompetent cells, including antibodies or interleukins. Examples of soluble molecules are IgG, IgM, IgE or IL2, IL4, IL 10 (interleukin 2, 4, 10).

 According to this definition, whole blood, as well as blood depleted in fibrinogen, platelets and red blood cells, contains the immune system, as it contains immunocompetent cells that are able to dynamically respond to new pathogens. Other immune systems are cell culture media containing immunocompetent cells. In contrast, a buffered antibody solution is not considered an immune system, since it does not contain many immunocompetent cells. In other embodiments, the human or other animals comprise immune systems, as defined herein.

 The term “stimulus” is used herein to mean any component or event that triggers an immune system response. Incentives can be grouped into three categories: proprietary, non-proprietary, and modified proprietary stimuli. Inherent type stimuli include cells or molecules, the immune system and these stimuli originating from the same organism, intrinsic proteins or autologous proteins and fragments thereof. Examples include human blood cells, undifferentiated cells, antibodies, or coagulating factors of the same person. Non-proprietary stimuli include cells, viruses or molecules, the immune system and this stimulus being derived from different organisms, or the stimulus is xenogenic. Examples include organs or cells from an non-identical donor, bacteria, viruses, or any type of molecule typical of other species, including endotoxins, enzymes, or structural proteins. The stimuli of the altered intrinsic type include cells or molecules, the immune system and this stimulus coming from the same organism, but the stimulus is subjected to modifications, degradation or neoplastic changes. Examples of such modifications include modifying the profile of a B7 marker or representing antigen cells. Examples of degradation changes include apoptotic cells or necrotic tissue. Examples of neoplastic changes include cancer induction.

 The terms “immune response” and “immune response” are used herein to mean any response of the immune system to a stimulus. Of particular interest in this application are the immune responses, which include modulation of the B7 marker. Such modulation may include any combination of increasing or decreasing expression of B7-1 and B7-2. Thus, all the answers presented in table. 1 and 2 are examples of the considered responses of the immune system.

 Other considered immune system responses include the involvement of cellular components in specific cellular interactions or changes in genetic activity. Cell-specific interactions can be cell-cell interactions or cell-stimulus interactions. Examples of cell-cell interactions are T helper cells in contact with T cells, or T helper cells in contact with macrophages. Examples of cell-stimulus interactions are antigen-presenting cells that incorporate the stimulus, process this stimulus and expose the processed stimulus on the cell surface, or B cells that expose stimulus-specific antibodies on their cell surface and bind the stimulus to the antibody. Changes in genetic activity may be rearrangements in genomic DNA or selective activation of genes. Examples of rearrangements in genomic DNA are splicing events leading to the "maturation of affinity" of antibodies against the stimulus, or splicing events leading to class switching between different classes of antibodies. Examples of selective gene activation are an increase or decrease in the transcription or translation of genes encoding interleukins or B7-1 or B7-2.

 As used herein, the production of a B7 exposure, which is the “reverse” effect associated with a stimulus, means that this B7 exposure produced by one nucleoside is at least marginal in the opposite direction to that associated with only one stimulus. Thus, if the stimulus is associated with reduced expression of B7-1, the reverse B7 effect will be an effect in which B7-1 will be at least marginally elevated. Similarly, if the stimulus is associated with increased expression of B7-2, the reverse B7 effect will be an effect in which B7-2 will be at least marginally reduced.

 As used herein, the term “presentation of the nucleoside immune system” means that the nucleoside is in contact with a component of the immune system to a degree sufficient to produce an immune system response. In preferred embodiments, this means adding a nucleoside to the body. In other embodiments, this means adding a nucleoside to a vessel or other container for the immune system.

 It should be understood that the definition of the term “presentation to the immune system of a nucleoside” is broad enough to include any combination of m-vivo, in-vitro or ex-vivo contact. In vivo may include injection, ingestion, transdermal delivery, or inhalation. Examples of various injections are intramuscular, intravenous or subcutaneous injection. Examples of various forms for oral administration are tablets, syrups or powders. Using occlusive dressings, ointments, or electrophoretic methods, transdermal delivery can be achieved. Inhalation can be carried out by evaporation or spray methods.

 In-vitro contacting can be achieved either by dispensing a solution containing the nucleoside into the immune system in a suitable vessel, or by dissolving the nucleoside in a solution, which may or may not be part of the immune system. Dosing examples include automatic or manual pipetting, dripping, pouring, or injection of a solution containing a nucleoside into the immune system. Alternatively, the nucleoside may also be dissolved in the fluid by stirring, mixing or pouring ribavirin into the fluid. This fluid may contain the immune system or may be a carrier solution, including buffers, isotonic solutions, and blood. This carrier can then be dosed into the immune system.

 Ex-vivo contacting can be achieved in several stages, in which (1) a part of the immune system is taken from the source, (2) the nucleoside is introduced into the immune system and (3) the immune system is returned at least partially to the source. The selection of part of the immune system can be performed by removing part of the immune system from an in-vivo or in-vitro source. Examples of in vivo sources are vertebrates, including humans, and invertebrates. Seizures can be carried out using venipuncture, ocular hemorrhage or injections.

 Examples of in-vitro sources are cell cultures containing the immune system, processed or canned blood. The removal can be carried out using any means for transferring fluids, for example, automatic or manual pipetting, aspiration, dripping and so on. The return of the immune system to the source can be carried out using any means for transferring fluids. In the case of an in vitro source, this can be automatic or manual pipetting, aspiration, dripping, and in the case of an in vivo source, intravenous injection.

 The nucleosides considered are ribavirin (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) and its analogs. For clarity, ribavirin analogs mean any ribavirin derivative in which (1) one or more hydroxyl groups is replaced by a non-hydroxyl group having less than 25 atoms, including H, lower alkyl, lower aryl, lower aralkyl, lower alkyl alkenyl, halogen and so on, and independently, one or more hydrogen is replaced by a non-hydrogen moiety having less than 25 atoms, including OH, lower alkyl, lower aryl, lower aralkyl, lower alkylalkenyl, halogen, and so on.

 Ribavirin, an analogue of ribavirin, or another nucleoside is preferably formulated in a buffered aqueous solution. In alternative embodiments, however, the nucleoside may be formulated in numerous other liquid or solid forms. Liquid forms may be solutions containing pure solvents, including water, DMSO (dimethyl sulfoxide) or ethanol. Liquid forms may also contain solutions, including solvent mixtures with other solvents, or dissolved solids, including water-ethanol mixtures, water-DMSO mixtures, and buffers. Further, liquid forms of nucleosides can be mixed, for example, with consistency modifying agents to form gels, creams or ointments. Examples are amphiphilic molecules, waxes, or gelatin. Solid forms may contain solids, which may or may not be active ingredients. Examples of active ingredients are buffers, ion exchange resins, including MOPS ((3- (N-morpholino) propanesulfonic acid), phosphates or citrates. Examples of inactive ingredients include starch, cellulose or silica. Further, solid forms may be in various drugs, including tablets, capsules, powders, and so on.

 In preferred embodiments, a sufficient amount of nucleoside is taken to achieve a concentration range between about 0.2: M and about 5: M, respectively, in a fluid containing cells expressing the B7 marker. Less preferred embodiments encompass other concentrations in the range of 0.1 μM to about 10 μM.

 In another aspect of the preferred embodiments, the stimulus is correlated with an enhancement of a type 2 response, and the use of a nucleoside is correlated with an attenuation of a type 2 response. A type 2 response can be understood as follows.

 The mammalian immune systems contain two main classes of lymphocytes: B-lymphocytes (B-cells), which come from bone marrow, and T-lymphocytes (T-cells), which come from thymus, B-cells are mainly responsible for humoral immunity ( there is antibody production), while T cells are mainly responsible for cell mediated immunity. T cells are generally divided into two subclasses, helper T cells and cytotoxic T cells. Helper T cells activate other lymphocytes, including B cells and cytotoxic T cells, and macrophages, by releasing soluble protein mediators called cytokines, which are involved in cell-mediated immunity. As used herein, lymphokines are a subset of cytokines.

 In general, it is also believed that helper T cells are also divided into two subclasses, type 1 and type 2. Cells of type 1 (also known as Th1 cells) produce interleukin 2 (IL-2), tumor necrosis factor (TNF-α) and interferon gamma (IFN-γ) and are mainly responsible for cell-mediated immunity, such as delayed-type hypersensitivity and antiviral immunity. In contrast, type 2 cells (also known as Th2 cells) produce IL-4, IL-5, IL-6, IL-9, IL-10 and IL-13 interleukins, and are involved in promoting humoral immune responses, such as responses obtained in response to allergens, for example, isotype switching of IgE and IgG4 antibodies (Mosmann, 1989, Annu. Rev. Immunol., 7: 145-173).

 As used herein, the terms “responses” of type 1 and type 2 include the entire spectrum of effects resulting from the induction of type 1 and type 2 lymphocytes, respectively. Among other things, such responses include variation in the production of the corresponding cytokines through transcription, translation, secretion, and possibly other mechanisms, increased proliferation of the corresponding lymphocytes, and other effects associated with increased production of cytokines, including effects on motility.

 As described in US Pat. No. 5,767,097 (Tarn, June 1998), the disclosure of which is incorporated herein by reference, any type 1 and type 2 response can be selectively suppressed, while the other is either induced or relatively unaffected, and any of the type responses 1 or type 2 can be selectively induced, while the other is either suppressed or relatively unaffected. As set forth in PCT / US98 / 00634, which is undergoing PCT review, which is incorporated herein by reference, some nucleosides, such as ribavirin, are effective in selectively modulating Type 1 and Type 2 responses relative to each other. The determination of which nucleosides are effective in lowering the type 2 response is easily carried out experimentally.

 It is believed that the methods described herein can be used to treat a wide range of diseases, virtually any disease that responds favorably to such treatment. Among other things, it is specifically believed that such combinations can be used to treat an allergen (allergy), neoplasm (cancer), bacteria viruses (viral infection) (bacterial infection), invasion or an autoimmune disease.

 Infections contemplated for treatment with the nucleosides of the present invention include respiratory syncytial virus (RSV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex type 1 and type 2, genital herpes, herpes keratitis , herpetic encephalitis, herpes zoster, human immunodeficiency virus (HIV), influenza A virus, xanthan virus (hemorrhagic fever), human papillomavirus (HPV), measles and fungus. In particular, it is believed that the combinations claimed herein will be useful in the treatment of chronic viral and bacterial infections, including HIV, tuberculosis, leprosy, and so on.

 The invasions contemplated for treatment with the nucleosides of the present invention include intracellular protozoan invasions, as well as helminth and other parasitic invasions. Again, in particular, it is believed that the combinations claimed herein will be useful in the treatment of chronic infestations.

 Neoplasms proposed for treatment include neoplasms caused by a virus, and the effect may include inhibiting the transformation of virus-infected cells into a neoplastic state, inhibiting the spread of viruses from transformed cells to other normal cells, and / or stopping the growth of virus-transformed cells.

 Allergies suspected for treatment include all IgE and IgG allergies, hyper-IgE syndrome, and dermatological conditions such as atopic dermatitis. It is also believed that the claimed methods can be used to treat graft rejection (graft versus host disease) and implant reactions.

 Autoimmune diseases can be classified as non-organ-specific or organ-specific. Inorganic autoimmune diseases include rheumatoid arthritis, gout and gouty arthritis, systemic lupus erythematosus (SLE), Sjogren's syndrome, scleroderma, polymyositis and dermomyositis, ankylosing spondylitis and rheumatic fever. Organ-specific autoimmune diseases are known for almost any organ, including insulin-dependent diabetes, thyroid diseases (Graves' disease and Hashimoto's thyroiditis), Addison’s disease and some diseases of the kidneys and lungs, including allergies and asthma, multiple sclerosis, severe pseudoparalytic myasthenia, uveitis, hepatitis and cirrhosis, celiac disease, inflammatory bowel disease, and some types of male and female infertility. Autoimmune processes may also be stimulated by viral infections, including the HIV virus, may result from transplant rejection, and may accompany some tumors, or be accelerated by certain chemicals.

Synthesis
The synthesis of ribavirin is well known, and the synthesis of analogues of ribavirin becomes apparent from the materials of applications PCT / US97 / 18387 and PCT / US97 / 00600, a description of both is incorporated herein by reference.

Introduction
It is contemplated that nucleosides in accordance with the present invention are administered as part of any suitable pharmaceutical preparation and by any suitable protocol. Preferred dosages and protocols are obviously best set based on experiments with specific patients. Such experiments should not be extensive, and it is contemplated that nucleosides are administered to humans in the range between about 100 mg / day and about 5000 mg / day. It is believed, in particular, that ribavirin or another nucleoside should be delivered to humans and other systems at parameters that create a concentration of nucleoside in a fluid containing cells expressing B7 between about 0.2: M and about 5: M, respectively.

Of course, when the treatment relates to the disease, the specialist understands that the therapeutically effective amount will vary depending on the infection or the condition to be treated, its severity, the treatment regimen used, the pharmacokinetics of the agent used, as well as the patient (animal or human) to be treated. Thus, effective dosages can vary from 1 mg / kg body weight or less to 25 mg / kg body weight or more. In general, it is believed that a therapeutically effective amount of a “second” drug varies from a little less than about 1 mg / kg to about 25 mg / kg of a patient, depending on the nucleoside used, the condition being treated or the infection and the route of administration. This dosage range usually provides effective levels of active nucleoside concentration in the blood, ranging from about 0.04 to about 100 μg / cm ^{3 of} blood in a patient. It is understood, however, that a suitable patient-specific regimen will be developed by administering a small amount, and then increasing the amount until either side effects become excessively unfavorable or the desired effect is achieved.

 Nucleosides of the present invention can be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, epigastric injection or infusion methods), by inhalation aerosol, or rectally, topically, etc., and in unit dose formulations containing conventional non-toxic pharmaceutically acceptable carriers adjuvants and excipients.

 It is believed that the nucleosides of the present invention can be formulated in admixture with a pharmaceutically acceptable carrier. For example, the nucleosides of the present invention can be administered orally as pharmacologically acceptable salts. Since the nucleosides of the present invention are usually water soluble, they can be administered intravenously in physiological saline (for example, buffered to a pH of from about 7.2 to 7.5). Conventional buffers such as phosphates, bicarbonates or citrates may be used for this purpose. Of course, one skilled in the art can modify the preparations within the scope of this specification to obtain numerous preparations for a particular route of administration without imparting instability to the compositions of the present invention or reducing their therapeutic activity. In particular, the modification of the presented nucleosides to make them more soluble in water or another carrier, for example, can be easily carried out by small modifications (salt formation, esterification, etc.), which are well known in the art. It is also well known to specialists how to modify the route of administration and the dosage regimen of specific nucleosides to change the pharmacokinetics of the nucleosides in question to obtain the maximum beneficial effect in patients.

 In certain pharmaceutical dosage forms, a prodrug is administered as a nucleoside, especially including acylated (acetylated or other) derivatives, pyridine esters and various salt forms of the present nucleosides. One skilled in the art knows how to rapidly modify the presented nucleosides into prodrug forms to facilitate the delivery of active nucleosides to the target site within the host or patient. The specialist should take advantage of the favorable pharmacokinetic parameters of the prodrug forms, when applicable, upon delivery of the nucleosides of interest to the target site within the host organism to achieve the maximum nucleoside effect.

 In addition, the nucleosides in question can be administered individually or together, and wherein the separate administration can be carried out in any order. The amounts of active ingredients and pharmaceutically active agents and relative modes of administration are chosen so as to achieve the desired combined therapeutic effect.

 The route of administration of the nucleosides in question can vary from continuous (drip intravenous infusion) to several oral administrations per day (for example, four times a day) and may include, among other routes of administration, oral, local, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include a penetration enhancer), buccal and suppository administration.

 In the treatment of the present invention, a therapeutically effective amount of a nucleoside is preferably uniformly mixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical mixing techniques to obtain a dose. The carrier may take a wide range of forms depending on the form of the preparation desired for administration, for example, oral or parenteral. In preparing the pharmaceutical compositions in oral dosage form, any conventional pharmaceutical medium may be used. Thus, for liquid oral preparations, such as suspensions, elixirs and solutions, suitable carriers and additives, including water, glycols, oils, alcohols, flavoring agents, preservatives, colorants and the like, can be used. For solid oral preparations such as powders, tablets, capsules, and for solid preparations such as suppositories, suitable carriers and additives, including starches, a sugar carrier such as dextrose, mannitol, lactose and related carriers, diluents, granulating agents, can be used. lubricants, binders, disintegrants and the like. If desired, tablets or capsules may be enteric coated or formulated as a sustained release preparation using standard methods.

 The parenteral drug carrier usually contains sterile water or an aqueous solution of sodium chloride, although other ingredients, including dispersion promoting ingredients, may be included. Of course, in cases where sterile water should be used and maintained sterile, the compositions and carriers should also be sterilized. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.

 It should also be understood that, in general, the most preferred uses of the present invention are those in which the active nucleosides are relatively less cytotoxic to non-target host cells and relatively more active against the target. In this regard, it may also be useful that L-nucleosides may have increased stability with respect to D-nucleosides, which may lead to improved pharmacokinetics. This result can be achieved due to the fact that L-nucleosides may not be recognized by enzymes and thus may have a longer half-life.

 Thus, methods are described in which ribavirin or other nucleosides are used to modulate the B7 molecular marker favorably. While specific embodiments are described herein, the scope of the invention is not limited by anything other than an interpretation of the claims.

Claims (15)

 1. A method of modulating the response of the immune system to the stimulus, in which the relationship between the stimulus and the effect on the B7 marker is established, the relationship between the use of a nucleoside within the concentration range and the modulation of the B7 molecular marker, which is inverse to this effect, is established and the nucleoside is presented to the immune system within this range of concentrations.  2. The method of claim 1, wherein the stimulus is an allergen.  3. The method of claim 1, wherein the stimulus is a neoplasm.  4. The method of claim 1, wherein the stimulus is a virus.  5. The method of claim 1, wherein the stimulus is a bacterium.  6. The method of claim 1, wherein the stimulus is parasitic invasion.  7. The method of claim 1, wherein the stimulus is an autoimmune reaction.  8. The method according to any one of paragraphs. 1-7, where the molecular marker is a B7-1.  9. The method according to any one of paragraphs. 1-8, where the molecular marker is a B7-2.  10. The method according to any one of paragraphs. 1-8, where the nucleoside is ribavirin.  11. The method according to any one of paragraphs. 1-8, where the nucleoside is an analogue of ribavirin.  12. The method of claim 1, wherein the stimulus is selected from the group consisting of an allergen, microbe, neoplasm, parasitic invasion, and autoimmune reaction, the molecular marker is B7-1, and the nucleoside is ribavirin.  13. The method of claim 1, wherein the stimulus is selected from the group consisting of a microbe allergen, a parasitic invasion neoplasm, and an autoimmune reaction, the molecular marker is B7-2, and the nucleoside is ribavirin.  14. The method of claim 1, wherein the stimulus is selected from the group consisting of an allergen, microbe, neoplasm, parasitic invasion, and autoimmune reaction, the molecular marker is B7-1, and the nucleoside is not ribavirin.  15. The method according to any one of paragraphs. 1-8, in which the stimulus is additionally correlated with an increase in type 2 response, and the use of nucleoside is correlated with a decrease in type 2 response.

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