SI20802A - Modulation of immune response by ribavirin - Google Patents

Abstract

The response of an immune system to a challenge is modified by presenting the system with a nucleoside in a concentration selected to have an effect on a B7 marker that is inverse from the effect of the challenge. Contemplated challenges include allergens, neoplasm, virus, bacteria, infestation, and autoimmune reaction. Molecular markers of particular interest are B7-1 and B7-2. Preferred nucleosides are Ribavirin and Ribavirin analogs, especially provided within a concentration range between about 0.2 :M and about 5 :M, respectively, in a fluid containing cells expressing the B7 marker.

Description

MODULATION OF IMMUNE RESPONSE WITH RDBAVIRINE

Field of Invention

The field of invention is immunology.

BACKGROUND OF THE INVENTION

In addition to commonly used physiological and phenotypic diagnostic parameters, diseases can sometimes be correlated with molecular markers such as polydia, mutations of specific genes, display of specific cell surface markers, etc. Many of these markers act as predictors or indicators of a specific disease and can thus be used as a diagnostic tool for a well-defined physiological condition.

In recent years, several attempts have been made to correlate relatively complex diseases such as autoimmunity, asthma, cancer, etc. with specific molecular markers. Several studies have identified the direct or indirect involvement of B7-1 and B7-2 co-stimulatory molecules in modulating the immune system in diseases. However, despite the many insights gained from such studies, the insight into the different expression levels of B7-1 and B7-2 in diseases has not produced a comprehensible and unified picture. (Hepatology 25, No.5, 1997 pl 108-1114: Expression of costimulatory molecules B7-1 and B7-2 and human hepatocellular carcinoma; J. Cancer Res. Ciin. 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 pl79-187: Costimulatory CD80 (B7-1) and CD86 (B72) on cerebrospinal fluid celeriac in multiple sclerosis J- Neuroimmunol 91, No 1-2, 1998, p 198-203: B7-1 (CD80), B7-2 (CD86), interleukin-12 and transforming growth factorbeta mRNA expression in CSF and peripheral blood mononuclear multiple sclerosis patients).

In many cases, apparently inconsistent correlations between B7-1, B7-2 and specific diseases were observed. See Table 1. For some cancers, for example, B7-1 is present in relatively high amounts and B7-2 is present in relatively low amounts. For other cancers, B7-1 and B7-2 have the exact opposite correlation. J. Cancer Res. Ciin. Oncol. 124, No.7 1998 p383-388: Expression of costimulatory molecules B7-1 and B7-2 on human gastric carcinoma; No. J. Haematol 102, No.5, 1998 pl257- 1262: 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 pl67-171: Lack of B7-1 and B7-2 on head and neck cancer intolerance and possible significance for gene therapy).

Table 1

Correlation of specific diseases with B7-1 and B7-2 expression

A type of cancer B7-1 B7-2 Hepatcytic carcinoma Down Down Gastric cancer (primary) Up Up Gastric cancer (metastatic) Down Up Head & neck (primary & populated) Down Down Acute myeloid leukemia Down Up An autoimmune disease Multiple sclerosis Up Up Asthma Neutral Up Inflammatory bowel syndrome Up Up

Expression of B7-1 and B7-2 also shows only an inconsistent correlation with known cytokine patterns. See Table 2. For example, increased expression of B7-1 was correlated with both upstream and downstream regulation of the type 1 response, and B7-2 correlated with both upstream and downstream regulation of the type 1 response. The same can be argued for the correlation with B7-1 and B7-2 with type 2 response (see Table 1) (Am. J. Respir. Whole. Mol. Biol. 17, No. 2.1997 p235-242: DifFerential regulation of human, antigenspecific Type 1 and Type 2 responses by B7 homologues CD80 and CD86; J. Immunol. 156, No. 8.196 p2387-2391: Costimulation of IL-4 production by murine B7-1 and B7-2 molecules.).

Table 2

Correlation of various types of diseases with type 1, type 2 and expression of B7-1 and B7-2

Type / answer Type 1 Type 2 B7-1 B7-2 Autoimmune Illness Up (AIDS specific for organ) Up (systemic AIDS) Up Up / down Cancer Down Up Up / down Up / down Bacterial infection Up Up Up Up Viral infection Up Up Up Up

Furthermore, it is unclear which drug, or even the drug category, would be effective in modulating B7-1 or B7-2 activity and, even if such drugs were identified, it remains unclear how useful it is to use these co-stimulatory molecules to modulate immune system. Combining all these unknowns, there is still a considerable need to provide procedures and compositions for modulating one or more B7 markers, especially as a means of influencing the immune system's response to a given challenge.

A brief description of the tables

Table 1 correlates specific diseases and their correlation with B7-1 and B7-2 expression. Table 2 correlates the various types of diseases with the expression of B7-1 and B7-2 and type 1 and type 2.

Summary of the Invention

The present invention provides methods and compositions for modifying the immune system's response to challenges. Generally, we modify the answer by adding to the system a nucleoside at a concentration chosen to have such an effect on the B7 marker, which is opposite to the challenge effect.

In one aspect of the preferred embodiments, the challenges are selected from groups such as allergens, neoplasm, virus, bacterium, infection, and autoimmune reaction. Of particular interest are the molecular markers B7-1 and B7-2. In another aspect of the preferred embodiments, the nucleoside is an ribavirin analog, in a particularly preferred embodiment the nucleoside is ribavirin. According to a further aspect of the preferred embodiments, sufficient nucleoside is provided to achieve a concentration range between about 0.2 μΜ and about 5 μΜ in a liquid medium containing cells expressing B7 marker.

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

Detailed description of specific embodiments

The present inventor has discovered that there is a striking relationship between some nucleosides, in particular ribavirin and its analogues, and the expression of one or more B7 markers. Further discoveries have shown another, unexpected connection - that the application of such nucleosides can be used to favorably influence the outcome of the disease or another challenge. In particular, a method has been discovered to modulate the immune system's response to the challenge, the process comprising: (a) correlating the challenge with effect on the B7 marker; (b) correlating nucleoside application within a concentration range with modulation of the B7 molecular marker opposite to the effect; and (c) adding a nucleoside to the immune system within the concentration range.

The term "nucleoside" as used herein refers to a compound consisting of any part of the pentose or modified pentose that is attached to the specific position of the heterocycle or to the natural position of the purine (position 9) or pyrimidine (position 1) or the corresponding position analogs, in particular including both D- and L-forms of bicyclic and monocyclic nitrogen-containing heterocycles. The term "D-nucleosides" refers to compounds of nucleosides that have a part of the sugar of D-ribose (for example adenosine). The term " Linucleosides " refers to compounds of nucleosides that have a part of the sugar of L-ribose. The term "nucleotide" means nucleosides in which the phosphate esters are substituted at 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" refers broadly to any type of autonomic pathologic tissue growth that may or may not become malignant, including all types of tumors or cancers.

The term "treatment" or "treatment" of a disease refers to the execution of a protocol that may include administering one or more drugs to a patient in order to relieve the signs or symptoms of the disease. Thus, "treatment" or "treatment" do not require complete relief of signs or symptoms, but require treatment procedures, and specifically include protocols that have only a marginal effect (as a placebo effect) on the patient.

The term "immune system", as used herein, means any collection of immunocompetent cells that collectively identify and attack alien beings and that dynamically respond to new pathogens or other challenges. Examples of immune systems are human or other mammalian immune systems, which include the spleen, thymus B-lymphocytes, T-lymphocytes, and antibodies. The immune system as defined herein must have a cellular component, but it may or may not have a humoral component. Where a humoral component is incorporated into the immune system, it may contain soluble molecules secreted by immunocompetent cells, including antibodies and interleukins. Examples of soluble molecules are IgG, IgM, IgE or IL2, IL4, IL10.

By this definition, all blood, as well as blood that is stripped of fibrinogen, blood platelets and erythrocytes, can be considered immune, because it contains immunocompetent cells that can dynamically respond to new pathogens. Other immune systems are artificial media environments containing immunocompetent cells. In contrast, the antibody solution with the addition of buffer is not considered as an immune system because it does not contain a large number of immunocompetent cells. In other embodiments, everyone, human or animal, contains immune systems as defined herein.

The term "challenge" is used here to refer to any ingredient or event that elicits an immune system response. Challenges can be grouped into three categories: auto-live, non-auto-live and modified auto-live. Challenges of the auto-challenge type include cells or molecules where the immune system and the challenge from the same organism are auto-proteins or analog proteins and fragments thereof. Examples include human blood cells, undifferentiated cells, antibodies, or coagulation factors from the same person. Non-auto-invasive challenges include cells, viruses, or molecules where the immune system and challenge are from different organisms, or the challenge is xenogeneic. Examples include organs or cells of non-identical donoi, bacteria, viruses, or any molecule specific to other genres that include endotoxins, enzymes, or structural proteins. Challenges to the type of modified auto-invasion include cells or molecules where the immune system and challenge originate from the same organism, but the challenge is exposed to modifications, abnormal or neoplastic changes. Examples of such modifications include modifying the B7 marker profile on antigen-supplying cells. Examples

-7Ί abnormal changes include cells associated with apoptosis or necrotic tissue. Examples of neoplastic changes are cancer.

The terms "immune system response" and "immune response" are used herein to refer to any immune system response to a challenge. Immune responses involving modulation of the B7 marker are of particular interest in this application. Such modulation may comprise any combination of the rise and fall of B7-1 and B7-2 expression. Thus, all the answers given in Tables 1 and 2 are examples of the immune system responses considered.

Other relevant responses of the immune system include the involvement of cellular constituents in specific cell interactions or changes in genetic activity. Specific cell interactions may be cell-to-cell interactions or cell interactions with challenge. Examples of cell-to-cell interactions are T-cell contacts with helper T-cells or contacts of helper T-cells with macrophages. Examples of cellular interactions with the challenge are cells that supply the antigen and include the challenge, process the challenge and display the processed challenge on the cell surface, or B cells that display specific antibodies for the challenge on their surface and bind the challenge to the antibody. Changes in genetic activity may be rearrangements in genomic DNA or selective activation of genes. Examples of genomic DNA rearrangements are intertwining events that lead to class switching between different antibody classes. Examples of selective gene activation are increasing or decreasing the transcription or translation of gene coding for interleukins or B7-1 or B7-2.

As used herein, producing a B7 effect that is "opposite" to a challenge-related pattern is that the effect of B7 produced by the nucleoside itself is at least marginally opposite to the effect associated with the challenge itself. If such a challenge is associated with decreased expression of B7-1, then the opposite effect of B7 would be the one in which B7-1 is at least marginally elevated. Similarly, if the challenge is associated with increased expression of B72, the inverse effect of B7 would be the one in which B7-2 is at least marginally reduced.

As used herein, the term "administering a nucleoside to the immune system" means that the nucleoside comes into sufficient contact with certain components of the immune system to elicit a response from the immune system. In preferred embodiments, this means adding a nucleoside to the body. In other embodiments, this means adding a nucleoside to a container or other container with the immune system.

It should be borne in mind that the definition of the term "nucleoside delivery to the immune system" is sufficiently broad to include any combination of in-vivo, in-vitro or ex-vivo contacts. In-vivo may include injection, ingestion, administration through the skin or inhalation. Examples of miscellaneous injection are intramuscular injection, vascular injection, or subcutaneous injection. Examples of various forms of ingestion are tablets, syrups or powders. Patches, ointments or electrophoresis can deliver through the skin. Inhalation may include evaporation or dispersion procedures.

In vitro contact can be obtained either by administering a nucleoside-containing solution to the immune system in a suitable container or by dissolving the nucleoside in a solution that may or may not be part of the immune system. Examples for administration include automated or manual pipetting, dripping, pouring or injection of a nucleoside-containing solution into the immune system. Alternatively, the nucleoside may be dissolved in the fluid by shaking, stirring or pouring ribavirin into the fluid. This fluid may contain the immune system or the carrier solution containing the buffer, isotonic solutions, blood. This carrier can then be administered to the immune system.

Ex-vivo contact can be performed in several steps, comprising (1) obtaining a portion of the immune system from a source, (2) administering a nucleoside to the immune system, and (3) returning at least a portion of the immune system to the source. The acquisition of a portion of the immune system can be accomplished by retrieving a portion of the immune system from an in vivo or in vitro source. Examples of in-vivo sources are invertebrates, including humans, and invertebrates. Retraction can be done by puncture out, eye discharge or run-ins.

Examples of in-vitro sources include cell culture media containing the immune system, treated or stored blood. Recovery can be accomplished by any means of transferring fluid, for example by automatic or manual pipetting, suction, dripping, etc. The immune system can be restored to the source by any fluid transfer agent. In the case of an in-vitro source, this may be automatic or manual pipetting, suctioning, dripping or, in the case of an in-vivo source, injection into a vessel.

The nucleosides discussed are ribavirin (Ι-β-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) and its analogs. To clarify the matter, analogs mean any ribavirin derivatives in which (1) one or more hydroxyl groups is substituted by a non-hydroxyl moiety having less than 25 atoms and includes hydrogen, lower alkyl, lower aryl, lower aralkyl, lower alkyl alkenyl, halogen etc. and is one or more hydrogen independently substituted by a non-hydrogen moiety having less than 25 atoms and including OH, lower alkyl, lower aryl, lower aralkyl, lower alkyl alkenyl, halogen, etc.

Ribavirin, ribavirin analogues or other nucleosides are preferably formulated in aqueous solution with the addition of buffer. In alternative embodiments, nucleosides can be formulated in many other liquids or solid forms. Liquid forms may be solutions containing pure solvents, including water, DMSO or ethanol. Liquid forms may include solutions containing solvent mixtures with other solvents or dissolved solids, including water-ethanol mixtures, water-DMSO mixtures, buffers. Further, the liquid forms of nucleosides can be mixed, for example, with substances that alter the consistency to form gels, creams or ointments. Examples are amphiphilic molecules, waxes or gelatin. Solid forms may include solids, which may or may not be active ingredients. Examples of active ingredients are buffers, resin ion exchangers including MOPS, phosphates and nitrates. Examples of inactive ingredients include starch, cellulose or silica. Furthermore, solid forms may be present in various preparations including tablets, capsules, powders, etc.

-1010

In preferred embodiments, sufficient nucleoside is provided to obtain a concentration range between about 0.2 μΜ and, respectively, about 5 μΜ in a fluid containing cells expressing the B7 marker. The less preferred embodiments consider other concentrations within the range of 0.1 μΜ to about 10 μΜ.

In another aspect of the preferred embodiments, the outcome is correlated with an increase in the type 2 response, and the use of a nucleoside is correlated with a decrease in the type 2 response. The type 2 response can be understood as follows.

Mammalian immune systems contain two major classes of lymphocytes: B lymphocytes (B cells) that originate in the bone marrow and T lymphocytes (T cells) that originate in the thymus. B cells are largely responsible for humoral immunity (i.e., antibody production), while T cells are responsible for cell-mediated immunity. Generally, T cells are divided into two subclasses, helper T cells and T. cytotoxic cells. T helper cells activate other lymphocytes, including B cells and T cytotoxic cells, and macrophages by secreting soluble protein mediators, called cytokines that are involved in cell-mediated immunity. As used herein, lymphokines are a subtype of cytokines.

It is also commonly considered that helper T cells fall into two subclasses, type 1 and type 2. Type 1 cells (also known as Thl cells) produce interleukin 2 (IL-2), tumor necrosis factor (TNF V), and interferon gamma (IFN (), and are primarily responsible for cell-mediated immunity such as delayed-type hypersensitivity and antiviral immunity. In contrast, they produce type 2 cells (also known as Th2 cells) interleukins, IL4, IL-5, IL-6. , IL-9, IL-10 and IL-13 and are primarily involved in supporting humoral immune responses as seen in allergen responses, such as isotype switching of IgE and IgG4 antibodies (Mosmann, 1989, Annu Rev Immunol, 7: 145 -173).

-1111

As used herein, the terms "type 1 and type 2 responses" are understood to include the full range of effects obtained from the introduction of type 1 or type 2 lymphocytes, among others. Such responses include changes in the production of appropriate cytokines through transcription, translation, secretion and possible other mechanisms, increased reproduction of relevant lymphocytes, and other effects associated with increased cytokine production, including motility effects.

As described by US Patent no. 5767097 to Tam (June 1998), whose disclosure we include here as a reference, either Type 1 or Type 2 responses can be selectively suppressed, while the other is either induced or left relatively unscathed, and either Type 1 or Type 2 responses are either can be selectively induced while suppressing the other or leaving relatively unaffected.Also, as explained in the conflicting PCT applications No. PCI / US98 / 00634, the disclosures of which are incorporated herein by reference, some nucleosides as ribavirin are effective in selectively modulating type 1 responses and type 2 of each other. The determination of which nucleoside is effective in reducing the type 2 response is easily determined by experimentation.

It is contemplated that the procedures described herein may be used to treat a diverse array of diseases and indeed any disease that responds favorably to such treatment. Among other things, it is specifically intended that such combinations can be used to treat allergic (allergy), neoplasmic (cancer), viral (viral infection), bacterial (bacterial infection) disease, infection or autoimmune disease.

Infections that are suitable for the treatment of nucleosides of the present invention include respiratory syncytial virus (RSV), hepatitis B virus (HBV), hepatitis C virus (HCV), type 1 and type 2 herpes simplex, genital herpes, retinal inflammation, herpes encephalitis, herpes zoster, human immunodeficiency virus (HIV), influenza A virus, hantan virus (hemorrhagic fever), human papillomavirus (HPV), measles and fungi. In particular, we anticipate that the combinations identified herein will be useful for treatment

-1212 chronic viral and bacterial infections, including HlV, tuberculosis, leprosy, etc.

The infections that are suitable for treating the nucleosides of the present invention include intracellular infections with protozoa as well as intestinal worms and other parasite infections. It is again particularly noteworthy that the combinations considered here will be useful in the treatment of chronic infections.

Neoplasms that are considered for treatment include neoplasms caused by the virus, and the effect may include inhibiting the change of virus-infected cells into a neoplastic state by inhibiting the spread of viruses from the changed cells to normal cells and / or stopping cell growth, modified by the virus.

Treatment allergies include all IgE and IgG allergies, hyper IgE syndromes and dermatic conditions such as atopic dermatitis. In addition, it is recognized that the claims procedures can be used to treat graft rejection (graft versus host disease) and implant reactions.

Autoimmune diseases can be classified as either organ-specific or organ-specific. Non-organ specific autoimmune diseases include rheumatoid arthritis, gout and gout arthritis, systemic cutaneous tuberculosis erythematosus (SLE), Sjogren's syndrome, scleroderma, polymyositis and dermomyositis, ankylosing spondylitis and rheumatic fever. Organ-specific autoimmune diseases are actually known in every organ, including diabetes-dependent insulin, thyroid disease (Graves' disease and Hashimoto's thyroiditis), Addison's disease and some kidney and lung diseases including allergy and asthma, multiple sclerosis, myasthenia gravis, uveitis, psoriasis, with forms of hepatitis and cirrhosis, celiac disease, inflammatory bowel disease and certain types of male and female infertility. Autoimmune processes can promote viral infections including

-1313 HIV may result from transplant rejection and may accompany some tumors or be caused by exposure to certain chemicals.

Synthesis

The synthesis of ribavirin is well known, and for the synthesis of ribavirin analogues, PCT applications PCT7US97 / 18387 and PCT / US97 / 00600 are applicable, and disclosure of both is incorporated herein by reference.

Prescribing

For the nucleosides of the present invention, prescribing in any pharmaceutical formulation and according to any suitable record is appropriate. Preferred dosage and protocols are intended to be determined by experimentation with specific patients. Such experiments need not be extensive, and nucleosides are projected to be administered to humans at about 100 mg / day to about 5000 mg / day. In particular, it is contemplated that ribavirin or other nucleosides are provided according to parameters that produce a concentration of nucleoside in a fluid containing cells expressing B7 between about 0.2 μΜ and about 5 μΜ, respectively.

Of course, when it comes to treating a disease, one of ordinary skill in the art will recognize that a therapeutically effective amount will vary depending on the infection or the condition it is treating, its severity, the treatment regimen to be used, the pharmacokinetics used means as well as to the treated patient (animal or human). Effective dosages thus range between 1 mg / kg body weight or less and 25 mg / kg body weight or more. The therapeutically effective amount of the "other" drug is expected to range from slightly less than about 1 mg / kg to about 25 mg / kg of patient, depending on the nucleoside used, the condition being treated or the infection and route of administration. This dosage range typically produces an effective concentration level of active nucleoside, which ranges from about 0.04 to about 100 micrograms / ml of blood in

-1414 to the patient. However, it is anticipated that appropriate patient-specific regimens will be developed so that a small amount is administered and the amount is increased until the side effects become unduly harmful or the intended effect is achieved.

The administration of the nucleosides of the present invention can be performed orally, parenterally (including subcutaneous injections, injection into a vein or muscle, intrastemal injection or infusion techniques), inhalation from a nebulizer, or rectally, topically, etc. and in dosage formulations containing conventional, non-toxic, pharmaceutically acceptable carriers, devices and vehicles.

It is appreciated that the nucleosides of the present invention may be formulated in admixture with a pharmaceutically acceptable carrier. For example, nucleosides of the present invention may be administered orally as pharmaceutically acceptable salts. Since the nucleosides of the present invention are generally soluble in water, they can be administered intravenously in saline (for example by adding a buffer to a pH of about 7.2 to 7.5). For this purpose conventional buffers such as phosphates, bicarbonates or citrates can be used. Of course, one of ordinary skill in the art can modify the formulations within the specification instructions to provide a number of formulations for a particular route of administration without causing instability of the compositions of the present invention or compromising their therapeutic activity. Modification of the present nucleosides to make them more soluble in water or other solvents, for example, in particular, can be easily accomplished with minor modifications (salt formulation, esterification, etc.) that are suitable in the art. Modification of the route of administration and dosage regimen of a particular nucleoside is also appropriate in the conventional art in order to regulate the pharmacokinetics of the studied nucleoside for maximum beneficial effect for patients.

For some pharmaceutical dosage forms, the more preferred form of prodrug is the prescribed nucleoside, especially including acylated (acylated or other) derivatives, pyridine esters and various salt forms of the present nucleosides. One of ordinary skill in the art will recognize how to easily modify the present

-1515 nucleoside into prodrug forms to allow delivery of active nucleosides to the target position within the host organism or patient. One of ordinary skill in the art will also take advantage of the advantageous pharmacokinetic parameters of the prodrug forms, where applicable, in delivering the intended nucleosides to the target position within the host organism or patient to maximize the intended effect of the nucleoside.

In addition, the intended nucleosides can be administered separately or together, and when administered separately, this can be done in any order. The amounts of the active ingredient (s) and the pharmaceutically active agent (s) and associated timing of administration will be selected to achieve the desired combined therapeutic effect.

The routes of administration of the investigated nucleosides range from continuous (intravenous drip) to multiple doses per day (eg QID) and may include oral, topical, parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include increased penetration), oral administration, and administration of suppositories among other routes of administration.

In the treatments of the present invention, it is preferable to carefully mix a therapeutically effective amount of the nucleoside with a pharmaceutically acceptable carrier according to conventional pharmaceutical compositions manufacturing techniques to obtain a dose. The carrier may be of various forms depending on the desired form of preparation for administration, for example, orally or parenterally. Any of the conventional pharmaceutical environments may be used in the preparation of pharmaceutical compositions in the form of oral doses. Thus, it can be used for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives including water, glycols, oils, alcohols, fragrances, preservatives, colorants and the like. Suitable carriers and additives including starches, sugars, such as dextrose, mannitol, lactose and related carriers, diluents, granulating agents, can be used for solid oral preparations such as powders, tablets, capsules and for solid preparations such as suppositories. , lubricants, binders,

-1616 fragmentation agents and the like. If desired, tablets or capsules may be enteric coated or by prolonged elimination according to standard techniques.

For parenteral formulations, the carrier typically comprises sterile water or aqueous sodium chloride, although other ingredients may be included, including ingredients that aid dispersion. Of course, where we need to use sterile water and keep it sterile, we must also sterilize the compositions and supports. Injectable suspensions may also be prepared, in which case suitable liquid carriers, suspending agents and the like may be used.

In general, it can be appreciated that the most preferred uses of the present invention are the use where the active nucleosides are relatively less cytotoxic to non-target host cells and relatively more active against the target. Against this background, it may also be more advantageous that L-nucleosides are more stable than D-nucleosides, which could lead to better pharmacokinetics. This result may be true, because it is possible that L-nucleosides do not recognize enzymes and may therefore have longer half-lives.

Thus, we have disclosed methods using ribavirin or other nucleosides to advantageously modulate the B7 molecular marker. While specific embodiments have been disclosed herein, the purpose of the invention is not to be construed to be limited to the interpretation of the appended claims.

For ICN PHARMACEUTICALS, INC. [US / US];

3300 Hyland Avenue, Costa Mesa, CA 92626 (US):

Claims (10)

PATENT APPLICATIONS Use of a nucleoside for the preparation of a medicament for modulating the immune system response to a challenge, comprising correlating the challenge with effect on marker B7; correlating the application of a nucleoside within a concentration range with modulation of the B7 molecular marker opposite to the effect; and administering the nucleoside to the immune system within the concentration range. Use according to claim 1, wherein the challenge comprises an allergen, a neoplasm, a virus, a bacterium, an infection or an autoimmune reaction. Use according to any one of claims 1 - 2, wherein the molecular marker is B71 or B7-2. Use according to any one of claims 1 - 3, wherein the nucleoside is ribavirin. Use according to any one of claims 1-4, wherein the nucleoside is an ribavirin analogue. Use according to claim 1, wherein the challenge is selected from the group consisting of allergen, microbe, neoplasm, infection and autoimmune reaction, the molecular marker is B7-1 and the nucleoside is ribavirin. Use according to claim 1, wherein the challenge is selected from the group consisting of allergen, microbe, neoplasm, infection and autoimmune reaction, the molecular marker is B7-2 and the nucleoside is ribavirin. -1818 Use according to claim 1, wherein the challenge is selected from the group consisting of allergen, microbe, neoplasm, infection and autoimmune reaction, the molecular marker is B7-1 and the nucleoside is not ribavirin. Use according to any one of claims 6-8, wherein the concentration range ranges between about 0.2 μΜ and, respectively, about 5 μΜ in a fluid containing cells expressing B7 marker. Use according to any one of claims 1 - 3, further comprising correlating the increase of the type 2 response and correlating the application of the nucleoside with the decrease of the type response