KR20020023939A - Modulation of immune response by ribavirin - Google Patents

Abstract

The present invention relates to the immune system's response to the test administration modified by providing the nucleoside to the immune system at a concentration selected to have an effect on the B7 marker against the effect of the test administration. Examinations considered include allergens, neoplasms, viruses, bacteria, invasion and autoimmune reactions. Of particular interest are molecular markers B7-1 and B7-2. Preferred nucleosides are ribavirin and ribavirin analogs provided in particular in fluids containing cells expressing B7 markers within concentrations of about 0.2 μM to about 5 μM, respectively.

Description

MODULATION OF IMMUNE RESPONSE BY RIBAVIRIN

In addition to the commonly used physiological phenotypic diagnostic parameters, diseases can often be correlated with molecular markers such as polydyes, mutations in specific genes, display of distinct cell surface markers, and the like. Many of these markers serve as disease specific predictors or indicators and thus can be used as diagnostic tools for clearly defined physiological diseases.

In recent years, many attempts have been made to correlate relatively complex diseases such as autoimmunity, asthma, cancer and the like with specific molecular markers. Some studies have found direct or indirect associations of costimulatory molecules B7-1 and B7-2 in regulating the immune system in disease. However, despite the detailed investigation of B7-1 and B7-2 of various expression levels in the diseases obtained through the above studies, comprehensive and integrated findings have not been described in detail. Hepatology 25, No. 5 , 1997 p1108-1114: Expression of costimulatory molecules B7-1 and B7-2 and human hepatocellular carcinoma; J. Cancer Res. Clin. Oncol. 124, No. 7, 1998 p383-388: Expression of costimulatory molecules B7-1 and B7-2 on human gastric carcinoma; J. Neuroimmunol. 84, No. 2, 1998 p179-187: Costimulatory CD80 (B7-1) and CD86 (B7-2) on cerebrospinal fluid cells in multiple sclerosis; J Neuroimmunol 91, No 1-2, 1998, p198-203: 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 instances, apparently contradictory correlations were observed between B7-1, B7-2 and certain diseases. (See Figure 1). For example, in some types of cancer, B7-1 is present in relatively high amounts and B7-2 is present in relatively low amounts. In other types of cancer, B7-1 and B7-2 have the exact opposite correlation. See J. Cancer Res. Clin. Oncol. 124, No. 7 1998 p383-388: Expression of costimulatory molecules B7-1 and B7-2 on human gastric carcinoma; Br. J. Haematol 102, No. 5, 1998 p1257-1262: 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, No. 2, 1998 p167-171: Lack of B7-1 and B7-2 on head and neck cancer cells and possible significance for gene therapy].

In addition, B7-1 and B7-2 expression shows only a correlation opposite to known cytokine patterns. See FIG. 2. For example, enhanced expression of B7-1 is correlated with both up and down regulation of the type 1 response, and B7-2 is also correlated with both up and down regulation of the type 1 response. The same can be said of the correlation between the type 2 response and B7-1 and B7-2. (See FIG. 1) [See Am. J. Respir. Cell. Mol. Biol. 17, No. 2, 1997 p235-242: 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 p2387-2391: Costimulation of IL-4 production by murine B7-1 and B7-2 molecules.].

In addition, it is unclear whether drugs or even drugs will be effective in modulating B7-1 or B7-2 activity, and even if these drugs are identified, it remains unclear how beneficially these costimulatory molecules are used to modulate the immune system. Remains. Putting all these unknowns together, there is still a significant need to provide methods and compositions for modulating one or more B7 markers, particularly as a means of influencing the immune system's response to a given trial.

Brief description of the drawings

1 is a table that correlates specific correlations between specific diseases and their expression with B7-1 and B7-2 expression.

2 is a table correlating various types of disease with type 1, type 2, B7-1 and B7-2 expression.

Summary of the Invention

The present invention provides methods and compositions for altering the response of the immune system to challenge administration. In general, this response is altered by providing nucleosides to the immune system at a concentration selected to affect the B7 marker against the effect of the challenge.

In one aspect of the preferred embodiments, the test administration is selected from the group consisting of allergens, neoplasms, viruses, bacteria, invasive and autoimmune responses. Of particular interest are molecular markers B7-1 and B7-2. In another aspect of the preferred embodiment, the nucleoside is a ribavirin analog and in a particularly preferred embodiment the nucleoside is ribavirin. In another aspect of the preferred embodiments, enough nucleosides are provided to achieve concentrations of from about 0.2 μM to about 5 μM each in a fluid containing cells expressing the B7 marker.

In another aspect of the preferred embodiment, the trial administration correlates with an increase in the type 2 response and the application of nucleosides is correlated with a decrease in the type 2 response.

The present invention relates to immunology.

Detailed Description of the Specific Embodiment

We have found a surprising association between the expression of certain nucleosides, particularly ribavirin and analogs thereof, and one or more B7 markers. Further discoveries have revealed another unexpected linkage-the application of nucleosides can be used to advantageously influence overcoming a disease or other trial. In particular, methods of modulating the response of the immune system to challenge administrations include (a) correlating challenge administrations with effects on B7 markers; (b) correlating the application of nucleosides in the concentration range with the regulation of B7 molecular markers against said effect; (c) providing the immune system with nucleosides in the concentration range.

As used herein, the term "nucleoside" includes, in particular, both the D- and L-forms of nitrogenous bicyclic and monocyclic heterocycles, including specific positions of the heterocycle or purine (9-position). Or a compound consisting of an pentose sugar or a modified pentose moiety that is bound to the equivalent position of the present position or analog of pyrimidine (1-position). The term “D-nucleoside” refers to a nucleoside compound having a D-ribose sugar moiety (eg, adenosine). The term "L-nucleoside" refers to a nucleoside compound having an L-ribose sugar moiety. The term "nucleotide" refers to a nucleotide having a phosphate ester substituted on the 5 'position of the nucleoside.

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

The term “neoplasm” broadly refers to any type of tissue that grows autonomously and may or may not be malignant, including all manner of tumors and cancers.

The term “treating” or “treatment” for a disease refers to implementing a protocol that may include administering one or more drugs to a patient in an effort to alleviate the signs or symptoms of the disease. Thus, “treating” or “treatment” does not require complete relief of the signs or symptoms, does not require soothing, and specifically includes protocols that have only minimal effects (such as placebo effects) on the patient. do.

As used herein, the term “immune system” refers to any collection of immuno-receptive cells that collectively identify and attack foreign objects and dramatically respond to new pathogens or other trials. Examples of the immune system are the spleen, thymus B-lymphocytes, T-lymphocytes and human or other mammalian immune systems that contain antibodies. As defined herein, the immune system must have cellular components, but may or may not have a humoral component. When the humoral component is included in the immune system, the humoral component may comprise soluble molecules secreted from immunoreceptive cells, including antibodies or interleukins. Examples of soluble molecules are IgG, IgM, IgE or IL2, IL4, IL10.

Under this definition, blood depleted of fibrinogen, plasma and erythrocytes, as well as whole blood, is thought to include the immune system because it has immunoreceptive cells that can respond dramatically to new pathogens. Another immune system is cell culture medium containing immunosoluble cells. In contrast, a buffered solution of an antibody is not considered an immune system because it does not have a plurality of immunosoluble cells. In other embodiments, both humans or other animals have an immune system as defined herein.

As used herein, the term "test administration" refers to any component or event that causes a response by the immune system. Test administration can be divided into three categories: magnetic, non-magnetic and altered self-administration. Self-type challenge administrations include cells or molecules, wherein the immune system and challenge administration are from the same organism, magnetic protein or similar protein and fragments thereof. Examples include human blood cells, undifferentiated cells, antibodies or coagulation factors from the same person. Non-magnetic type test doses include cells, viruses or molecules, wherein the immune system and test dose are from different organisms, or the test dose is heterologous. Examples include organs or cells derived from any type of molecule typical for other species, including unequal donors, bacteria, viruses, or endotoxins, enzymes or structural proteins. Altered self-type dosing includes cells or molecules in which the immune system and the test administration are from the same organism, but where the test administration has undergone modification, degradation or oncological changes. Examples of such modifications include modification of the profile of the B7 marker on antigen presenting cells. Examples of degradative changes include cells or necrotic tissues that are in apoptosis. Examples of oncological changes include induction of cancer.

As used herein, the terms "immune response" and "immune response" refer to any response of the immune system to test administration. Of particular interest in this application are immune responses involving the regulation of B7 markers. Such regulation may include any combination of increases or decreases in B7-1 and B7-2 expression. Thus, all of the responses shown in the tables of FIGS. 1 and 2 are examples of immune system responses discussed.

Other discussed immune system responses include changes in cellular components or genetic activity in cell specific interactions. The cell specific interaction may be a cell-cell interaction or a cell-study interaction. Examples of cell-cell interactions are T-cells in contact with T-helper cells or T-helper cells in contact with macrophages. Examples of cell-study interactions include antigen-presenting cells incorporating the challenge, displaying the challenge treated and displaying the treated challenge on the cell surface, or displaying the challenge specific antibody on the B cell surface. And B-cells that combine test administration with The change in genetic activity may be rearrangement of the genome DNA, or selective activation of the gene. Examples of rearrangement of genome DNA are splicing events that result in affinity maturation of the antibody for challenge or splicing events that cause class transitions between different classes of antibodies. An example of selective activation of a gene is an increase or decrease in the transcription or translation of an interleukin or gene encoding B7-1 or B7-2.

As used herein, generating a B7 effect 'opposite' to a pattern associated with a test administration means that the B7 effect generated by nucleosides alone is at least minimally opposite to the effect associated with the test administration alone. Thus, when trial administration is associated with reduced B7-1 expression, the B7 adverse effect will be one at least to raise B7-1 to a minimum. Similarly, when a trial is associated with increased B7-2 expression, the B7 adverse effect will be one in reducing B7-2 at least to a minimum.

As used herein, the term "using the nucleoside to provide an immune system" means that the nucleoside is in sufficient contact with some components of the immune system to produce an immune system response. In a preferred embodiment this means adding nucleosides to the body. In other embodiments, this means adding nucleosides to a container, or other container of the immune system.

The definition of the term “using a nucleoside to provide an immune system” should be understood to be extensive enough to encompass any combination of in vivo, in vitro or ex vivo contact. In vivo may include infusion, ingestion, percutaneous delivery or inhalation. Examples of various infusions are intramuscular, intravenous or subcutaneous infusions. Examples of various forms of ingestion include tablets, syrups or powders. Sealed bandages, ointments or electrophoretic methods can perform percutaneous delivery. Inhalation may include vaporization or spray methods.

In vitro contact can be accomplished by dispensing the nucleoside containing the solution to the immune system in a suitable container, or dissolving the nucleoside in a solution that may or may not be part of the immune system. Examples for dispensing include pipetting, dropping, pouring or injecting nucleosides containing solutions into the immune system, either automatically or manually. Nucleosides may also be dissolved in the fluid by stirring, mixing or pouring ribavirin in the fluid. Such a fluid may comprise an immune system or may be a buffer solution, an isotonic solution, a carrier solution containing blood. Such carriers can then be distributed to the immune system.

In vitro contact can be in several steps, including (1) collecting a portion of the immune system from a source, (2) administering a nucleoside to the immune system, and (3) returning the immune system at least partially to a source Can be achieved. Collecting portions of the immune system may be performed by recovering portions of the immune system from in vivo or in vitro sources. Examples of in vivo sources include vertebrates, including humans, and non-vertebral animals. The recovering step may be performed by venipuncture, ocular bleeding or pinprick. An example of an in vitro source is a cell culture containing the immune system, treated or stored blood. The recovering step may be performed by any means for delivering the fluid, such as by automatic or manual pipetting, aspiration, dropping, or the like. Returning the immune system to a source can be performed by any means for delivering a fluid. This is possible when pipetting, aspirating, dropping, or injecting a source intravenously in vivo, either automatically or manually, in vitro.

Nucleosides contemplated are ribavirin (1-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide), and analogs thereof. To clarify the substance, ribavirin analogues may be selected from (1) non-having at least one hydroxyl group having less than 25 atoms, including H, lower alkyl, lower aryl, lower aralkyl, lower alkyl alkenyl, halogen, and the like. Substituted by hydroxyl moieties, and independently one or more hydrogens are substituted by non-hydrogen moieties having less than 25 atoms, including OH, lower alkyl, lower aryl, lower aralkyl, lower alkyl alkenyl, halogen, and the like. By any derivatized ribavirin substituted.

Ribavirin, ribavirin analogs or other nucleosides are preferably formulated in a buffered aqueous solution. However, in alternative embodiments, nucleosides may be formulated in many different liquid or solid forms. The liquid form may be a solution comprising a pure solvent containing water, DMSO or ethanol. The liquid form may also include a mixture of a solvent with another solvent or a solution having a dissolved solid containing a water-ethanol mixture, a water-DMSO mixture, a buffer. In addition, the liquid form of the nucleoside may be mixed with, for example, a hardness-modifying material to form a gel, cream or ointment. Examples are amphipathic molecules, waxes or gelatins. Solid forms may include solids which may or may not be active ingredients. Examples for active ingredients are buffers, ion-exchange resins including MOPS, phosphates or citrate. Examples of active ingredients include starch, cellulose or silica. Solid forms can also be a variety of preparations, including tablets, capsules, powders, and the like.

In a preferred embodiment, sufficient nucleosides are provided to achieve a concentration of about 0.2 μM to about 5 μM, respectively, in a fluid containing cells expressing the B7 marker. In less preferred embodiments other concentrations of 0.1 μM to about 10 μM are considered.

In another aspect of the preferred embodiment, the trial administration correlates with an increase in the type 2 response and the application of nucleosides is correlated with a decrease in the type 2 response. Type 2 reactions can be understood as follows.

The mammalian immune system includes two major classes of lymphocytes: B lymphocytes (B cells) (derived from bone marrow); And T lymphocytes (T cells) (derived from the thymus). B cells are primarily responsible for humoral immunity (ie, antibody production), while T cells are primarily responsible for cell-mediated immunity. T cells are generally thought to be divided into two subclasses, helper T cells and cytotoxic T cells. Helper T cells activate B lymphocytes and other lymphocytes, including cytotoxic T cells, and macrophages by releasing soluble protein mediators called cytokines associated with cell-mediated immunity.

It is also thought that helper T cells are generally divided into two subclasses, type 1 and type 2. Type 1 cells (also known as Th1 cells) produce interleukin 2 (IL-2), tumor necrosis factor (TNFα) and interferon gamma (IFNγ), and cell-mediated immunity such as delayed type hypersensitivity and antiviral immunity. Mainly in charge of. In contrast, type 2 cells (also known as Th2 cells) produce interleukins (IL4, IL-5, IL-6, IL-9, IL-10 and IL-13) and allergens such as IgE And humoral immunity as seen in response to IgG4 antibody isotype switching (Mosmann, 1989, Annu Rev Immunol , 7: 145-173).

As used herein, the terms type 1 and type 2 “response” are meant to encompass the entirety of the effects of induction of type 1 and type 2 lymphocytes, respectively. Among others, these reactions may be associated with other effects associated with increased production of cytokines, including the production of corresponding cytokines, increased proliferation of corresponding lymphocytes, and motility effects through transcription, translation, secretion, and possibly other mechanisms. It includes a change in the field.

As described in Tam's US Patent No. 5767097 (June 1998), which is incorporated herein by reference, the Type 1 and Type 2 reactions are selectively made while the remainder is induced or remains relatively unaffected. It can be suppressed and a Type 1 or Type 2 response can be selectively induced while the rest is suppressed or remains relatively unaffected. In addition, as described in PCT co-application PCT / US98 / 00634, which is incorporated herein by reference, certain nucleosides, such as ribavirin, are effective in selectively regulating Type 1 and Type 2 responses to each other. Determination of which nucleosides are effective in reducing type 2 response is readily determined by experiment.

We have considered the methods described herein that can be used to treat a wide variety of diseases and any diseases that actually respond favorably to the treatment. Among other things, the above combinations that can be used to treat allergens (allergies), neoplasms (cancers), viruses (virus infections), bacteria (bacterial infections), invasive or autoimmune diseases have been specifically considered.

Infections contemplated to be treated using the nucleosides of the present invention include respiratory synstium virus (RSV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex types 1 and 2, genital herpes , Herpes keratitis, herpes encephalitis, herpes zoster, human immunodeficiency virus (HIV), influenza A virus, larynx virus (bleeding fever), human papilloma virus (HPV), measles and fungi. Particularly contemplated are the combinations claimed herein useful for treating chronic viral and bacterial infections, including HIV, tuberculosis, leprosy, and the like.

Invasions contemplated to be treated with the nucleosides of the invention include intracellular protozoa invasion as well as rotifers and other parasitic invasion. Particularly contemplated are the combinations claimed herein useful for treating chronic invasion.

Neoplasms contemplated to be treated include neoplasms caused by viruses, the effect of which is to inhibit the transformation of virus-infected cells into an neoplastic state, from which the virus from the transformed cells to other normal cells Inhibit spreading and / or retard the growth of cells transformed with the virus.

Allergies contemplated to be treated include both IgE and IgG allergies, excessive IgE syndrome, and skin diseases such as atopic dermatitis. Also discussed are claimed methods that can be used to treat transplant rejection, (plant versus host disease), and transplant response.

Autoimmune diseases can be classified as organ nonspecific or organ specific. Tracheal nonspecific autoimmune diseases include rheumatoid arthritis, gout and gouty arthritis, systemic lupus erythematosus (SLE), Sjogren's syndrome, scleroderma, polymyositis and dermatitis, spondylitis and rheumatic fever. Organ specific autoimmune diseases include insulin-dependent diabetes, thyroid disease (Grace's and Hashimoto's thyroiditis), Addison's disease, and some kidney and lung diseases including allergies and asthma, multiple sclerosis, myasthenia gravis, uveitis, psoriasis, hepatitis and cirrhosis Virtually all organs are known, including forms, chronic digestive disorders, inflammatory bowel disease, and some types of male and female infertility. Autoimmune processes can also be stimulated by viral infections, including the HIV virus, can result from transplant rejection, can involve certain tumors, or be facilitated by exposure to certain chemicals.

synthesis

The synthesis of ribavirin is well known and the synthesis of ribavirin analogs has been considered in accordance with the teachings of PCT applications PCT / US97 / 18387 and PCT / US97 / 00600, the details of both documents being incorporated herein by reference.

administration

Nucleosides according to the present invention to be administered in any suitable pharmaceutical formulation under any suitable protocol were contemplated. Preferred dosages and protocols were considered to be best established through experiments with specific patients. The experiment does not need to be extended and considers nucleosides administered to humans from about 100 mg / day to about 5,000 mg / day. In humans and other systems, it has been specifically contemplated that ribavirin or other nucleosides will be provided under parameters that produce concentrations of nucleosides in fluids containing cells expressing B2 from about 0.2 μM to about 5 μM, respectively.

Of course, when considering the treatment of a disease, one skilled in the art will recognize that a therapeutically effective amount will depend on the infection and disease being treated, its severity, the treatment regime used, the pharmacodynamics of the agent used, as well as the patient (animal or human) being treated. Will recognize. Thus, the effective amount can range from less than 1 mg / kg body weight to more than 25 mg / kg body weight. Generally, a therapeutically effective amount of a “second” drug is determined to be about 1 mg./kg of patient, depending on the nucleoside used, the disease or treatment being treated, and the route of administration. Consideration ranged from slightly below to about 25 mg./kg. Such dosage ranges generally produce effective blood level concentrations of active nucleosides from about 0.04 to about 100 μg / cc of the patient's blood. However, appropriate patient specific regimes have been considered that are developed by administering a small amount to make the side effects excessively disadvantageous or increase the amount until the intended effect is achieved.

The administration of nucleosides according to the invention can be administered orally, parenterally (including subcutaneous, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, locally, and the like. And dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.

Nucleosides according to the present invention that can be formulated in admixture with pharmaceutically acceptable carriers are contemplated. For example, the nucleosides of the present invention may be administered orally as pharmaceutically acceptable salts. Since the nucleosides of the invention are mostly water soluble, they can be administered intravenously with physiological saline (eg, buffered to a pH of about 7.2 to 7.5). Conventional buffers such as phosphate, bicarbonate or citrate can be used for this purpose. Of course, those skilled in the art can modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without making the compositions of the present invention unstable or impairing their therapeutic activity. In particular, such modifications, for example, to make the nucleotides more soluble in water or other vehicles, can be readily performed by small modifications (salt formulations, esterifications, etc.) well known in the art. It is also well known in the art to modify the route of administration and method of administration of certain nucleosides to maintain the pharmacokinetics of the nucleosides discussed to maximize the beneficial effects in the patient.

For certain pharmaceutical dosage forms, prodrug forms of administered nucleosides are particularly preferred, including acylated (acylated or otherwise) derivatives, pyridine esters and various salt forms of the nucleosides of the invention. Those skilled in the art will know how to readily modify the nucleoside to prodrug form to facilitate delivery of the active nucleoside to the target site in the host organism or patient. Those skilled in the art will also use advantageous pharmacodynamic parameters in the form of prodrugs, where applicable, in the delivery of the considered nucleoside to the target site in the host organism or patient to maximize the intended effect of the nucleoside.

In addition, the nucleosides contemplated may be administered separately or together and may be performed in any order if administered separately. Relative timing for the amount and administration of the active ingredient (s) and pharmaceutical active agent (s) will be selected to achieve the desired combined therapeutic effect.

The route of administration of nucleosides discussed may range from continuous administration (intravenous drip) to several oral administrations per day (eg QID), among other routes of administration, oral, topical, non-transnational, intramuscular, intravenous Internal, subcutaneous, percutaneous (which may include penetration enhancers), buccal and suppository administration.

In the treatment according to the invention, the therapeutically effective amount of nucreoside is preferably intimately mixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical preparation techniques to produce a dosage. The carrier can be in a wide variety of forms depending on the form of preparation desired for administration, such as oral or parenteral administration. In preparing pharmaceutical compositions in oral dosage form, any conventional pharmaceutical medium may be used. Thus, for oral preparations of liquids such as suspensions, elixirs and solutions, suitable carriers and additives can be used including water, glycols, oils, alcohols, spices, preservatives, colorants and the like. For solid oral preparations such as powders, tablets, capsules, and solid preparations such as suppositories, sugar carriers and related carriers such as starch, dextrose, mannitol, lactose, diluents, granules, lubricants, binders, powders Appropriate carriers and additives may be used, including release and the like. If desired, tablets or capsules may be enteric coated or sustained release by standard techniques.

In parenteral formulations, the carrier typically includes sterile water or aqueous sodium chloride solution, but may include other ingredients, including ingredients that aid in dispersion. Of course, if sterile water is used and kept sterile, the composition and carrier should be sterile. Injectable suspensions may also be prepared, in which case suitable liquid carriers, suspending agents and the like may be used.

It will also be generally understood that the most preferred uses according to the invention are those which are relatively less cytotoxic to non-target host cells and relatively more active against targets. In this regard, it may be advantageous that L-nucleosides may increase stability beyond D-nucleosides, which may lead to better pharmacodynamics. This result can be achieved because L-nucleosides cannot be recognized by the enzyme, and thus may have longer half-lives.

Thus, the methods have been described as using ribavirin or other nucleosides to advantageously regulate B7 molecular markers. While specific embodiments have been described herein, the scope of the invention is limited only by the interpretation of the appended claims.

Claims (16)

Correlate trials with effects on B7 markers; The application of nucleosides within a certain concentration range correlates with the regulation of B7 molecular markers against this effect; A method of modulating the response of the immune system to challenge administration, comprising providing the immune system with nucleosides within the concentration range. The method of claim 1, wherein the trial administration comprises an allergen. The method of claim 1, wherein the trial administration comprises neoplasia. The method of claim 1, wherein the trial administration comprises a virus. The method of claim 1, wherein the test administration comprises bacteria. The method of claim 1, wherein the trial administration comprises invasion. The method of claim 1, wherein the trial administration comprises an autoimmune response. 9. The method of claim 1, wherein the molecular marker is B7-1. 10. 9. The method of claim 1, wherein the molecular marker is B7-2. 10. 9. The method of claim 1, wherein the nucleoside is ribavirin. 10. The method of claim 1, wherein the nucleoside is a ribavirin analogue. The method of claim 1, wherein the trial administration is selected from the group consisting of allergens, microorganisms, neoplasms, invasive and autoimmune reactions, the molecular marker is B7-1 and the nucleoside is ribavirin. The method of claim 1, wherein the trial administration is selected from the group consisting of allergens, microorganisms, neoplasms, invasive and autoimmune reactions, the molecular marker is B7-2 and the nucleoside is ribavirin. The method of claim 1, wherein the trial administration is selected from the group consisting of allergens, microorganisms, neoplasms, invasive and autoimmune reactions, the molecular marker is B7-1 and the nucleoside is not ribavirin . The method of claim 12, wherein the concentration range is about 0.2 μM to about 5 μM, respectively, in a fluid containing cells expressing the B7 marker. 9. The method of claim 1, further comprising correlating the test administration with an increase in the type 2 response and correlating the application of the nucleoside with a decrease in the type 2 response. 10. How to.