AU2013205795A1 - Treatment of Demyelinating Disorders with Soluble Lymphotoxin-Beta-Receptor - Google Patents

Abstract

The invention relates to the treatment of demyelinating disorder, e.g. multiple sclerosis, using a soluble lymphotoxin receptor beta receptor (LTPR) as an inhibitor of the lymphotoxin pathway. Eo 0 ii! m= AUL4 00-

Description

TREATMENT OF DEMYELINATING DISORDERS BACKGROUND Lymphotoxin beta receptor (LT3R) is a member of the tumor necrosis factor receptor (TNFR) family. The receptor is expressed on the surface of cells in the 5 parenchyma and stroma of most lymphoid organs but is absent on T- and B lymphocytes. Signaling through LTpR by the LTa/B heterotrimer (LT) is important during lymphoid development. LTpR is also known to bind the ligand LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by I lymphocytes), 10 which has been implicated in T-cell driven events, both in the periphery and in the thymus. LT and LIGHT are expressed on the surface of activated lymphocytes. Blocking the LT pathway with a soluble decoy LTpR has been shown to be effective to treat autoimmune disease in various animal models. SUMMARY 15 The invention is based, in part, on the discovery that a soluble form of LTjpR (e.g., LTpR-Fc) can effectively promote remyelination in a subject. Accordingly, the invention provides methods, compositions (e.g., a soluble LTpR fusion protein, e.g., LTpR-Fc), devices, and kits useful for treating a demyelinating disorder (e.g., Multiple Sclerosis) in a subject, as well as for monitoring remyelination in the 20 subject. In one aspect, the invention features a method of treating a demyelinating disorder in a subject. The method includes the steps of: (i) administering to a subject a dose of a soluble LTpR (e.g., an LTpR fusion protein such as LTpR-Fc) sufficient to 25 promote remyelination; and optionally (ii) monitoring the subject for remyelination. Optionally, the method can also include the step of identifying a subject (e.g., a human (e.g., a human patient)) as one having, or at risk of developing, a demyelinating disorder. In some embodiments, the method can include the step of selecting a subject 30 (e.g., a human patient) on the grounds that the subject is in need of remyelination.

In some embodiments, the method can also include the step of classifying the subject (e.g., the human patient) as being in need of remyelination. In some embodiments, the method can further include the step of classifying the subject (e.g., the human patient) as having a preselected level of remyelination, e.g., no 5 remyelination or having some level of remyelination. Preferably, the patient is classified as having remyelination, e.g., the patient is classified as having a preselected level, e.g., a level selected from a set of graduated levels of remyelination, e.g., a minimal, intermediate, or larger amount of remyelination. The graduated level or amount of remyelination can also be expressed or assigned as a discreet value, e.g., a 10 scale of ascending values, e.g., 1-10, wherein a first score, e.g., a first score of "10," indicates more remyelination in a patient than one having a second, lower score, e.g., a second score of "9." The classification can be performed once or more than once. It may be desirable to classify a patient after a first preselected milestone, e.g., a preselected number of administrations, a predetermined period of treatment, or a 15 preselected level of an increase or diminution of one or more symptoms. Classification can, optionally, be performed again at a second or subsequent milestone, e.g., a milestone of the same type. In a related embodiment, a record of the classification (e.g., the preselected level of remyelination) of the subject is made, e.g., a computer readable record. 20 In some embodiments, the subject is treated with a soluble LTPR (e.g., an LTIpR fusion polypeptide such as LTpR-Fc). In some embodiments, the soluble LT3R is an LTpR -Fc fusion polypeptide having the amino acid sequence depicted in SEQ ID NO: 1 (see below). The subject can be any mammal including, for example, a mouse, a rabbit, a 25 guinea pig, a monkey, or a human (e.g., a human patient). The subject (e.g., a human patient) can be any subject having, or at risk of developing a demyelinating disorder. As used herein, a "demyelinating disorder" is any disease associated with the destruction or removal of myelin, the fatty sheath surrounding and insulating nerve fibers, from nerves. Demyelinating disorders include, for example, Multiple Sclerosis 30 (e.g., Relapsing/Remitting Multiple Sclerosis, Secondary Progressive Multiple Sclerosis, Progressive Relapsing Multiple Sclerosis, Primary Progressive Multiple Sclerosis, and Acute Fulminant Multiple Sclerosis), Central Pontine Myelinolysis, Acute Disseminated Encephalomyelitis, Progressive Multifocal Leukoencephalopathy; 2 Subacute Sclerosing Panencephalitis, Post-infectious Encephalomyelitis, Chronic Inflammatory Demyelinating Polyneuropathy, Guillain-Barre Syndrome, Progressive Multifocal Leucoencephalopathy, Devic's Disease, Balo's Concentric Sclerosis, and a leukodystrophy (e.g., Metachromatic Leukodystrophy, Krabb6 disease, 5 Adrenoleukodystrophy, Pelizaeus-Merzbacher disease, Canavan disease, Childhood Ataxia with Central Hypomyelination, Alexander disease, or Refsum disease). A human patient having a demyelinating disorder can have one or more symptoms of a demyelinating disorder such as, but not limited to, impaired vision, numbness, weakness in extremities, tremors or spasticity, heat intolerance, speech impairment, 10 incontinence, dizziness, or impaired proprioception (e.g., balance, coordination, sense of limb position). A human (e.g., a human patient) with a family history of a demyelinating disorder (e.g., a genetic predisposition for a demyelinating disorder), or who exhibits mild or infrequent symptoms of a demyelinating disorder described above can be, for the purposes of the method, considered at risk of developing a 15 demyelinating disorder (e.g., Multiple Sclerosis). In some embodiments, the soluble LTpR can be administered to the subject in an amount, frequency, and/or for a time sufficient to induce remyelination in the subject. In some embodiments, for the purpose of inducing remyelination in a subject, 20 the soluble LTpR (e.g., a LTpR fusion polypeptide such as LTpR-Fc) is administered to the subject once. In other embodiments, the soluble LTpR (e.g., a LTpR fusion polypeptide such as LTpR-Fc) is administered to the subject more than once, e.g., once every 3-10 days; at least twice and not more than once every 5-20 days; at least twice and not more than once every 28-31 days; weekly; biweekly; monthly; weekly over the 25 course of at least 4 weeks; biweekly over the course of at least 6 weeks; monthly over the course of at least 3 months; or monthly over the course of at least 6 months. In some embodiments, a suitable starting dose of soluble LTpR in trials to determine a dosage (e.g., the amount sufficient to induce remyelination in a subject) is 0.001 mg of soluble LTpR per kg body weight of the subject. 30 In some embodiments, a suitable dose or starting dose is determined by a number of subjective, patient-specific factors such as, but not limited to, sex, age, weight, physical health, or any other factor described herein. 3 In some embodiments, the soluble LT3R (e.g., an LTpR fusion polypeptide such as LTPR-Fc) is administered to a subject intravenously or parenterally (e.g., subcutaneously, intramuscularly, intranasally, or orally). In some embodiments, the soluble LT pR (e.g., an LT3R fusion polypeptide such 5 as LTjpR-Fc) can be administered to a subject as a monotherapy. In some embodiments, the soluble LT3R (e.g., an LT3R fusion polypeptide such as LTfpR-Fc) can be administered to a subject as a combination therapy with another treatment, e.g., another treatment for a demyelinating disorder (e.g., any of the demyelinating disorders described herein (e.g., Multiple Sclerosis)). For example, the 10 combination therapy can include administering to the subject (e.g., a human patient) one or more additional agents that provide a therapeutic benefit to the subject who has, or is at risk of developing, a demyelinating disorder. In some embodiments, the soluble LTpR and the one or more additional agents are administered at the same time. In other embodiments, the soluble LT3R is administered first in time and the one or 15 more additional agents are administered second in time. In some embodiments, the one or more additional agents are administered first in time and the soluble LTpR is administered second in time. The soluble LTIpR can replace or augment a previously or currently administered therapy. For example, upon treating with LTPR, administration of the one or more additional agents can cease or diminish, e.g., be administered at 20 lower levels. In other embodiments, administration of the previous therapy is maintained. In some embodiments, a previous therapy will be maintained until the level of LTpR reaches a level sufficient to provide a therapeutic effect. The two therapies can be administered in combination. In some embodiments, a human receiving a first therapy for a demyelinating 25 disorder (e.g., Multiple Sclerosis), e.g., Interferon Beta la (Avonex), Interferon Beta lb (Rebif), glatiramer acetate (Copaxone), mitoxantrone (Novantrone), azathiprine (Imuran), cyclophosphamide (Cytoxan or Neosar), cyclosporine (Sandimmune), methotrexate, Cladribine (Leustatin), methylprednisone (Depo-Medrol or Solu Medrol), prednisone (Deltasone), prednisolone (Delta-Cortef), dexamethasone (Medrol 30 or Decadron), adreno-corticotrophic hormone (ACTH), or Corticotropin (Acthar), can also be administered a soluble LTpR, e.g., LT3R-Fc. In some embodiments, when the human is administered the soluble LTpR, the first therapy is halted. In other 4 embodiments, the human is monitored for a first pre-selected result, e.g., an improvement in one or more symptoms of a demyelinating disorder (such as increased remyelination), e.g., any of the symptoms of demyelinating disorders described herein. In some embodiments, when the first pre-selected result is observed, treatment with the 5 soluble LTPR is decreased or halted. In some embodiments, the human is then monitored for a second pre-selected result after treatment with the soluble LTPR is halted, e.g., a worsening of a symptom of a demyelinating disorder. When the second pre-selected result is observed, administration of the soluble LTpR to the human is reinstated or increased, or administration of the first therapy is reinstated, or the human 10 is administered both a soluble LT3R, or an increased amount of soluble LTpR, and the first therapeutic regimen. In one embodiment, a human receiving a first therapy for a demyelinating disorder (e.g., Multiple Sclerosis or any other demyelinating disorder described herein), who is then treated with a soluble LT3R, e.g., an LTpR-Fc, continues to receive the first 15 therapy at the same or a reduced amount. In another embodiment, treatment with the first therapy overlaps for a time with treatment with the soluble LT$R, but treatment with the first therapy is subsequently halted. In some embodiments, the soluble LTPR can be administered to a subject receiving an anti-TNF therapy (e.g., Humira, Enbrel, or Remicade). In some 20 embodiments, the subject receiving the anti-TNF therapy has an autoimmune disorder such as, but not limited to, rheumatoid arthritis. Monitoring a subject (e.g., a human patient) for remyelination, as defined herein, means evaluating the subject for a change, e.g., an improvement in one or more parameters that are indicative of remyelination, e.g., one can monitor improvement in 25 one or more symptoms of a demyelinating disorder. Such symptoms include any of the symptoms of a demyelinating disorder described herein. Remyelination can also be monitored by methods which include direct determination of the state of myelin in the subject, e.g., one can measure white matter mass using magnetic resonance imaging (MRI) or measure the thickness of myelin fibers using a magnetic resonance 30 spectroscopy (MRS) brain scan. In some embodiments, the evaluation is performed at least 1 hour, e.g., at least 2, 4, 6, 8, 12, 24, or 48 hours, or at least 1 day, 2 days, 4 days, 10 days, 13 days, 20 days or more, or at least 1 week, 2 weeks, 4 weeks, 10 weeks, 5 13 weeks, 20 weeks or more, after an administration, preferably the first administration, of the soluble LTPR. The subject can be evaluated in one or more of the following periods: prior to beginning of treatment; during the treatment; or after one or more elements of the treatment have been administered. Evaluating can include evaluating 5 the need for further treatment, e.g., evaluating whether a dosage, frequency of administration, or duration of treatment should be altered. It can also include evaluating the need to add or drop a selected therapeutic modality, e.g., adding or dropping any of the treatments for demyelinating disorders described herein. For example, continued administration of the soluble LTpR could be done with one or more 10 additional treatment agents where necessary. In a preferred embodiment, if a preselected outcome of the evaluation is obtained, an additional step is taken, e.g., the subject is administered another treatment or another evaluation or test is performed. The level of remyelination can be used to make a determination on patient care, e.g., a selection or modification of a course of treatment or the decision of a third party to 15 reimburse for the treatment. In some embodiments, monitoring a subject (e.g., a human patient) for remyelination can also include monitoring for a reduction in the size or number of inflammatory lesions (i.e., scleroses) using, e.g., Magnetic Resonance Imaging (MRI) scans, Positron-Emission Tomography (PET) scans, Diffusion-Weighted imaging 20 (DW-I, or DW-MRI), Diffusion Tensor Imaging, Myelography, Magnetization Transfer. In some embodiments, monitoring a subject for remyelination can include the detection in cerebrospinal fluid of the presence of, e.g., (i) abnormal proteins such as tiny fragments of myelin, (ii) elevated levels of or specific types of lymphocytes, and/or (iii) abnormal levels of immunoglobulin (IgG) molecules, the fluid obtained from a 25 lumbar puncture (i.e., a spinal tap). In other embodiments, monitoring a subject for remyelination can include assessment of a change in the subject's neuropsychology (e.g., the status of various abilities such as memory, arithmetic, attention, judgment and reasoning). In some embodiments, the monitoring of a subject (e.g., a human patient) for remyelination can involve testing a patient's urine for a decrease in levels of myelin 30 basic protein-like material (MBPLM), which substance becomes elevated as axonal damage occurs during disease progression. In some embodiments, where the demyelinating disorder affects a subject's eyes or vision, the monitoring of a subject for remyelination can involve testing for improvements in, e.g., color blindness. 6 In one aspect, the disclosure features a method of evaluating a subject, to determine, e.g., if a subject is responding or not responding to a treatment for a demyelinating disorder, e.g., a therapy that increases remyelination in a subject such as 5 administering a soluble LTPR. The method includes providing a reference value (e.g., a pre-administration value) for the level or state of myelin in the subject, and optionally, administering to the subject a medicament that increases remyelination (e.g., a soluble LTpR, e.g., an LTpR fusion polypeptide such as LTpR-Fc). In embodiments where a medicament is administered, the method also includes providing a post-administration 10 value for the level or state of myelin in the subject (e.g., the level or state of myelin following administration of a remyelination therapy) and comparing the post administration value with the reference value, thereby evaluating the subject, e.g., determining if the subject is responding or not responding to the therapy. The post administration value (i.e., the value corresponding to the state or level of myelin in a 15 subject following a remyelination therapy) can be determined, e.g., by any of the assessment methods described herein. The reference value (i.e., the state or level of myelin in a subject prior to treatment with a remyelination therapy) can also be determined, e.g., by any of the assessment methods described herein. In some embodiments, the method includes assigning the subject to a class, and 20 optionally, recording the assignment, e.g., in a computer readable record. In some embodiments, the evaluation includes determining if the subject is responding. In other embodiments, the evaluation includes determining if the subject is not responding. In some embodiments, the evaluation includes providing information on which 25 to make a decision about the subject. In some embodiments, the method further includes the step of selecting the subject for a preselected treatment. In some embodiments, the method further includes the step of selecting a duration of treatment of demyelinating disorder (e.g., Multiple Sclerosis) in a subject. 30 In some embodiments, a determination that a subject is responding indicates that a shorter duration of treatment can/should/will be/is administered to the subject (e.g., shorter than the treatment which is recommended for a subject who is not 7 responding to a therapy, or a duration shorter than currently used with existing therapies for demyelinating disorders, and optionally, that indication is entered into a record. In some embodiments, a determination that a subject is responding indicates that a shorter duration of treatment is counter-indicated for the subject (e.g., a duration 5 shorter than currently used with existing treatments for demyelinating disorders, e.g., any of the treatments for demyelinating disorders described herein), and optionally, that indication is entered into a record. In some embodiments, providing a comparison of the post-administration value with a reference value includes: providing a determination of a post-administration 10 level of myelin in a subject at a first time point (e.g., wherein the first time point is 6, 7, 8, 9, 10, 11, 12, 13, 14 or more days (e.g., 3, 4, 5, 6, 8 or more weeks (e.g., 3, 4, 6, 12 or more months))) after the commencement of administration of the remyelination therapy (e.g., a soluble LTpR)); providing a determination of a reference value of the state or level of myelin in the subject at a second time point that is prior to the first time point 15 (e.g., wherein the second time point is prior to, or within about 1, 2, 3, 4, or 5 days of the commencement of, administration of a remyelination therapy (e.g., a soluble LTfpR, e.g., LTOR-Fc); and providing a comparison of the post administration level and reference-value of a subject's myelin, wherein increased levels of myelin in a subject (e.g., the levels differ by no more than about 60%, about 50%, about 40%, about 30%, 20 about 20%, about 10%, about 5%, about 2%, or about 1%) between the post administration level and reference value indicates that the subject is responding. In another aspect, the invention features a method of selecting a payment class for a course of treatment with a remyelination therapy (e.g., a soluble LT3R an LTpR 25 fusion polypeptide such as LTpR-Fc) for a patient having a demyelinating disorder, e.g., Multiple Sclerosis. The method includes providing (e.g., receiving) an evaluation of whether the patient is responding or not responding to a therapy for a demyelinating disorder; and performing at least one of (1) if the patient is responding (e.g., remyelination occurs in the patient), selecting a first payment class, and (2) if the 30 subject is not responding (e.g., no remyelination in the patient), selecting a second payment class. The therapy can include a soluble LT3R (e.g., an LTpR fusion polypeptide such as LTpR-Fc). The therapy can also include one or more of any of the 8 therapies for demyelinating disorders described herein. In some embodiments, the therapy is one that increases remyelination in a patient such as a soluble LT$R. In some embodiments, assignment of the patient is to the first payment class and the assignment authorizes payment for a course of treatment for a first duration. In 5 some embodiments, the patient is responding to a therapy for a demyelinating disorder and a treatment duration of less than 52, 48, 36, 24, 18, 12, 10, 8, 4 or 2 weeks is authorized. In some embodiments, assignment of the patient is to the second payment class and the assignment authorizes payment for a course of treatment for a second duration. 10 In some embodiments, the patient is not responding to a therapy for a demyelinating disorder and a treatment duration of more than 52, 48, 36, 24, 18, 12, 10, 8, 4 or 2 weeks is authorized. In some embodiments, the determination of whether a patient is responding to a therapy is made by evaluating the subject for a change, e.g., an improvement, in one or 15 more parameters that are indicative of remyelination, e.g., one can monitor improvement in one or more symptoms of a demyelinating disorder. Such symptoms include any of the symptoms of a demyelinating disorder described herein. Remyelination can also be monitored by methods which include direct determination of the state of myelin in the subject, e.g., one can measure white matter mass using 20 magnetic resonance imaging (MRI), measure the thickness of myelin fibers using a magnetic resonance spectroscopy (MRS) brain scan, or any other direct measures described herein. In another embodiment, the determination of whether a patient is responding to a therapy can also be evaluated by any other assessment or indicia described herein, 25 including, but not limited to, monitoring a patient for a reduction in the size or number of inflammatory lesions (i.e., scleroses) present in the patient; monitoring a patient's cerebrospinal fluid for a reduction in the presence or amount of, e.g., (i) abnormal proteins such as tiny fragments of myelin, (ii) elevated levels of or specific types of lymphocytes, and/or (iii) abnormal levels of immunoglobulin (IgG) molecules; 30 monitoring a patient for a positive change in neuropsychology (e.g., the status of various abilities such as memory, arithmetic, attention, judgment and reasoning); and/or monitoring a patient's urine for a decrease in levels of myelin basic protein-like material (MBPLM). 9 In some embodiments, at least a 5% (e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 60%, at least 70%) improvement in one or more symptoms of a demyelinating disorder or other above-described indicia following a remyelination therapy (e.g., a therapy that 5 induces remyelination in a subject, e.g., a therapy such as a soluble LT3R) is sufficient to classify the patient as responding to a therapy. In another aspect, the invention features a method of providing information on which to make a decision about a human subject (e.g., a patient), or making such a 10 decision. The method includes providing (e.g., receiving) an evaluation of a patient, wherein the evaluation was made by a method described herein, e.g., determining if a patient has, or is at risk of developing, a demyelinating disorder or is one in need of, or likely to benefit from, increased remyelination; providing a determination of a post administration state, level, or amount of myelin in a patient (e.g., the extent of 15 remyelination); thereby providing a post-administration value; providing a comparison of the post-administration level with a reference value (e.g., the level of myelin present in a patient prior to treatment); and thereby, providing information on which to make a decision about a patient, or making such a decision. In some embodiments, the method includes making the decision about the 20 patient. In some embodiments, the method also includes communicating the information to another party (e.g., by computer, compact disc, telephone, facsimile, email, or letter). In some embodiments, the method includes recording the information, e.g., in a computer readable record or in a patient's file. 25 In some embodiments, the decision includes selecting a patient for payment, making or authorizing payment for a first course of action if the subject is responding to a therapy for a demyelinating disorder (e.g., a therapy that increases remyelination in a patient) and a second course of action if the patient is not responding to a therapy for a demyelinating disorder. 30 In some embodiments, the decision includes selecting a first course of action if the post-administration value has a first predetermined relationship with a reference value (e.g., the post-administration value is higher than the reference value), and selecting a second course of action if the post administration value has a second 10 predetermined relationship with the reference value (e.g., the post-administration value is lower than the reference value). In some embodiments, the decision includes selecting a first course of action if the patient is responding and a second course of action if the subject is not responding 5 to a therapy for a demyelinating disorder (e.g., a therapy that increases remyelination in a patient). In some embodiments, the patient is responding and the course of action is authorization of a course of therapy. In some embodiments, the course of therapy is shorter than what is provided to an otherwise similar patient who is not responding, 10 e.g., the course of therapy is less than 52, 48, 36, 24, 18, 12, 10, 8, 4 or 2 weeks. In some embodiments, the patient is responding to a therapy and the course of action is assigning the patient to a first class. In some embodiments, assignment to the first class will enable payment for a treatment provided to the patient. In some embodiments, payment is by a first party to a second party. In some embodiments, the 15 first party is other than the patient. In some embodiments, the first party is selected from a third party payor, an insurance company, employer, employer sponsored health plan, HMO, or governmental entity. In some embodiments, the second party is selected from the subject, a healthcare provider, a treating physician, an HMO, a hospital, a governmental entity, or an entity which sells or supplies the drug. In some 20 embodiments, the first party is an insurance company and the second party is selected from the patient, a healthcare provider, a treating physician, an HMO, a hospital, a governmental entity, or an entity which sells or supplies the drug. In some embodiments, the first party is a governmental entity and the second party is selected from the patient, a healthcare provider, a treating physician, an HMO, a hospital, an 25 insurance company, or an entity which sells or supplies the drug. In some embodiments, the patient is not responding and the course of action is authorization of a course of therapy. In some embodiments, the course of therapy is longer than what is provided to an otherwise similar patient who is responding to a therapy for a demyelinating disorder (e.g., a therapy that increases remyelination in a 30 subject), e.g., the course of therapy is longer than 52, 48, 36, 24, 18, 12, 10, 8, 4 or 2 weeks. In some embodiments, the subject is not responding and the course of action is assigning the patient to a second class. In some embodiments, assignment to the second class will enable payment for a treatment provided to the patient, e.g., treatment 11 for a period which is longer than a preselected period (e.g., longer than the period of treatment for an enhanced responder). In some embodiments, payment is by a first party to a second party. In some embodiments, the first party is other than the patient. In some embodiments, the first party is selected from a third party payor, an insurance 5 company, employer, employer sponsored health plan, HMO, or governmental entity. In some embodiments, the second party is selected from the subject, a healthcare provider, a treating physician, an HMO, a hospital, a governmental entity, or an entity which sells or supplies the drug. In some embodiments, the first party is an insurance company and the second party is selected from the subject, a healthcare provider, a treating physician, 10 an HMO, a hospital, a governmental entity, or an entity which sells or supplies the drug. In some embodiments, the first party is a governmental entity and the second party is selected from the subject, a healthcare provider, a treating physician, an HMO, a hospital, an insurance company, or an entity which sells or supplies the drug. In some embodiments, the patient is one having, or at risk of developing, a 15 demyelinating disorder such as Multiple Sclerosis or any other demyelinating disorder described herein. In another aspect, the disclosure features a method of selecting a payment class for a course of treatment with a remyelination therapy for a subject having, or at risk of 20 developing, a demyelinating disorder and/or a subject in need of, or likely to benefit from, increased remyelination. The method includes identifying the subject as one responding to the therapy, and approving, making, authorizing, receiving, transmitting or otherwise allowing payment of a selected course of treatment, e.g., a shorter course of treatment (e.g., less than 52, 48, 36, 24, 18, 12, 10, 8, 4 or 2 weeks) than if the 25 subject has been identified as not responding to a therapy. In another aspect, the invention features a method of treating a demyelinating disorder in a human, which includes the steps of administering to a subject (e.g., a human (e.g., a human patient)) a dose of a soluble LTpR (e.g., a LTPR fusion 30 polypeptide such as LTpR-Fc), where said administration is sufficient such that remyelination occurs in the human. The method can optionally include the step of identifying a subject as one having, or at risk of developing, a demyelinating disorder. The method can also, optionally, include the step of monitoring the subject for 12 remyelination. The subject can be any subject described herein. The demyelinating disorder can be any demyelinating disorder described herein (e.g., Multiple Sclerosis). The soluble LTpR can be any of those described herein. Administration of the soluble LT pR to a subject can include any of the routes, doses, or schedules described herein 5 (e.g., see any of the administration methods described above). In some embodiments, the soluble LTpR (e.g., an LTpR fusion polypeptide such as LTPR-Fc) can be administered as a monotherapy or in combination with one or more additional therapies for a demyelinating disorder as described above. In some embodiments, the soluble LT3R can be administered to a subject receiving an anti-TNF therapy (e.g., Humira, 10 Enbrel, or Remicade). A subject can be identified as one having, or at risk of developing, a demyelinating disorder using any of the methods described herein. Monitoring a subject (e.g., a human patient) for remyelination can include any of the methods described herein. 15 In another aspect, the invention features a method of treating a demyelinating disorder in a human, which includes the steps of: (i) administering to a human a dose of a soluble LTIR sufficient to promote remyelination; and (ii) classifying the human as having a preselected level of remyelination. Optionally, the method can include the step of monitoring the human for remyelination. The method can also optionally 20 include the step of identifying a human as one having, or at risk of developing, a demyelinating disorder or as one in need of, or likely to benefit from, increased remyelination. The demyelinating disorder can be any demyelinating disorder described herein (e.g., Multiple Sclerosis). The soluble LTpR can be any of those described herein. Administration of the soluble LT$R to a subject can include any of 25 the routes, doses, or schedules described herein (e.g., see any of the administration methods described above). In some embodiments, the soluble LTQR (e.g., an LTpR fusion polypeptide such as LTsR-Fc) can be administered as a monotherapy or in combination with one or more additional therapies for a demyelinating disorder as described above. In some embodiments, the soluble LT3R can be administered to a 30 subject receiving an anti-TNF therapy (e.g., Humira, Enbrel, or Remicade). Monitoring a subject (e.g., a human patient) for remyelination can include any of the methods 13 described herein. Exemplary methods for classifying remyelination in a human (e.g., a patient) are described above. In another aspect, the invention also provides a method of promoting 5 remyelination. The method includes the steps of: (i) administering to a subject receiving an anti-TNF-therapy an effective dose of a soluble LT3R (e.g., an LTpR fusion polypeptide such as LTpR-Fc), and optionally, (ii) monitoring the human for remyelination. The method can also optionally include the step of identifying a subject as one having, or at risk of developing, a demyelinating disorder resulting from an anti 10 TNF therapy. The subject can be any subject described herein. Administration of the soluble LTpR to a subject can include any of the routes, doses, or schedules described herein (e.g., see any of the administration methods described above). In some embodiments, the soluble LT3R (e.g., an LTpR fusion polypeptide such as LTpR-Fc) can be administered as a monotherapy or in combination with one or more additional 15 therapies for a demyelinating disorder as described above. In some embodiments, the anti-TNF therapy that the subject is receiving is, e.g., Humira, Enbrel, or Remicade. A subject can be identified as one having, or at risk of developing, a demyelinating disorder using any of the methods described herein. Monitoring a subject (e.g., a human patient) for remyelination can include any of the methods described herein (see 20 the exemplary methods described above). In another aspect, the invention features a method of selecting a patient as one in need of, or who could benefit from, administration of a soluble LTpR. The method includes the step of determining if a patient is in need of, or could benefit from, 25 remyelination. The method can also include the step of treating the selected patient with a soluble form of LTpR. Methods for selecting the patient can include any of the methods exemplified herein including, for example, monitoring for one or more symptoms of a demyelinating disorder or any of the direct assessments of the state of myelin in a subject described above. The soluble LTpR can be any of those described 30 herein. The dose, frequency of administration (i.e., schedule), and duration of treatment can be any of those described herein. 14 In some embodiments of the method, the patient is a patient diagnosed with a demyelinating disorder. In other embodiments of the method, the patient is one presenting one or more symptoms associated with a demyelinating disorder such as any of the symptoms described herein. 5 In another aspect, the invention provides a method of selecting a dose, route of administration, frequency of administration, and/or duration of treatment of a soluble LTpR to a patient. The method includes the steps of (i) evaluating the patient for one or more patient-specific factors and (ii) selecting a dose, frequency of administration, 10 and/or duration of treatment based on the assessment of the one or more factors, and (iii) optionally, where appropriate, administering to the patient a soluble LTpR at a dose, frequency of administration, and/or duration of treatment determined in step (ii). The method can also include the step of selecting a patient as one having, or at risk of developing, a demyelinating disorder. Accordingly, the patient can be one having, or 15 likely to develop, a demyelinating disorder. The method can also include the step of monitoring the patient for remyelination following the treatment. The soluble LT3R can be any of those described herein. In some embodiments, the patient can be determined not to be in need of, or likely to benefit from, administration of a soluble LTr3R. 20 In another aspect, the invention provides a delivery device designed for intravenous, subcutaneous or intramuscular administration of a soluble LTpR (e.g., a LTpR fusion polypeptide such as LTpR-Fc) to a subject (e.g., a human (e.g., a human patient) having a demyelinating disorder, where the administration is sufficient such 25 that remyelination occurs in the subject. The delivery device can be any suitable delivery device described herein including, for example, a syringe. The demyelinating disorder can be any demyelinating disorder described herein (e.g., Multiple Sclerosis). The subject can be any of the subjects described herein. The soluble LTpR can be any of the soluble LTpR polypeptides described herein. 30 In some embodiments, the delivery device contains a unit dose of a soluble LTPR (e.g., LTpR-Fc), where the unit dose is sufficient to increase remyelination. 15 Doses of about 0.00 1 mg/kg of a soluble LTBR are expected to be suitable starting points for optimizing treatment doses. In some embodiments, the delivery device contains a lyophilized soluble LT3R (e.g., an LTPR fusion polypeptide such as LTPR-Fc). 5 In another aspect, the invention features a kit containing: (i) one or more unit doses of a soluble LT@R (e.g., a LTpR fusion polypeptide such as LTpR-Fc) and (ii) reagents and instructions for how to assay for remyelination. Instructions for how to assay for remyelination can include instructions for any of the methods for assessing remyelination described herein (see above). 10 In some embodiments, the kit is for the treatment of a demyelinating disorder (e.g., Multiple Sclerosis). In another aspect, the invention features a delivery device containing two compartments, where the first compartment contains a unit dose of lyophilized soluble 15 LTpR (e.g., an LTpR fusion polypeptide such as LTIR-Fc), wherein the unit dose is sufficient such that remyelination occurs in a subject (e.g., a human, e.g., a human patient); and the second compartment contains a liquid for reconstituting the soluble LT3R (e.g., an LTpR fusion polypeptide such as LTpR-Fc) prior to administration to the subject. The delivery device can be any suitable delivery device described herein 20 including, for example, a syringe. The subject can be any of the subjects described herein. The soluble LTPR can be any of the soluble LTIpR polypeptides described herein. The liquid can be any pharmaceutically acceptable diluent described herein, and can include, for example, a buffer (e.g., phosphate-buffered saline) or distilled and/or sterilized water. 25 In some embodiments, the delivery device contains a unit dose of a soluble LTpR (e.g., LTpR-Fc), such that administration of the reconstituted soluble LTPR (e.g., LTpR-Fc) to a subject will deliver to the subject at least about 0.001 mg of the soluble LTpR per kg body weight of the subject. In another aspect, the invention provides a method of instructing a patient 30 having a demyelinating disorder to treat the patient's demyelinating disorder, which includes the steps of: (i) providing the patient with at least two unit doses of a soluble LT3R (e.g., a LTpR-Fc); and (ii) instructing the patient to self-administer the unit doses 16 subcutaneously, one dose at a time, wherein the unit dose of LTpR-Fc is sufficient to induce remyelination in a patient. Optionally, the method can include the step of instructing the patient to self-monitor for remyelination. The demyelinating disorder can be any of those described herein such as Multiple Sclerosis. The soluble LTpR can 5 be any soluble LTpR polypeptide described herein such as the LTpR-Fc set forth in SEQ ID NO:1. Administration of one or more unit doses of a soluble LTpR (i.e., instructions for how to do so) can include any of the methods (e.g., schedules) described herein. A "soluble LTpR," as defined herein, is a polypeptide that includes a 10 lymphotoxin (LT)-binding fragment of the extracellular region of LT pR. For example, a soluble LT3R can include all or a fragment of the extracellular domain of human LTpR (e.g., it can include residues 40-200, 35-200, 40-210; 35-220, 32-225, or 28-225 of human LTpR as depicted by SEQ ID NO:2 below). 15 MLLPWATSAPGLAWGPLVLGLFGLLAASQPQAVPPYASENQTCRDQEKEYYE PQHRICCSRCPPGTYVSAKCSRIRDTVCATCAENSYNEHWNYLTICQLCRPCDP VMGLEEIAPCTSKRKTQCRCQPGMFCAAWALECTHCELLSDCPPGTEAELKDE VGKGNNHCVPCKAGHFQNTSSPSARCQPHTRCENQGLVEAAPGTAQSDTTCK NPLEPLPPEMSGTMLMLAVLLPLAFFLLLATVFSCIWKSHPSLCRKLGSLLKRR 20 PQGEGPNPVAGSWEPPKAHPYFPDLVQPLLPISGDVSPVSTGLPAAPVLEAGVP QQQSPLDLTREPQLEPGEQSQVAHGTNGIHVTGGSMTITGNIYIYNGPVLGGPP GPGDLPATPEPPYPIPEEGDPGPPGLSTPHQEDGKAWHLAETEHCGATPSNRGP RNQFITHD (SEQ ID NO:2). In some embodiments, a soluble LTpR includes the extracellular region of the LT3R 25 molecule as represented by residues 32-225 of SEQ ID NO:2 (depicted by SEQ ID NO:11 below). AVPPYASENQTCRDQEKEYYEPQHRICCSRCPPGTYVSAKCSRIRDTVCATCAE NSYNEHWNYLTICQLCRPCDPVMGLEEIAPCTSKRKTQCRCQPGMFCAAWAL ECTHCELLSDCPPGTEAELKDEVGKGNNHCVPCKAGHFQNTSSPSARCQPHTR 30 CENQGLVEAAPGTAQSDTTCKNPLEPLPPEMSGTM (SEQ ID NO: 11). In some embodiments, the full-length, immature LTpR R polypeptide is a full-length, immature LT3R polypeptide derived from any species (e.g., any mammal (e.g., a 17 mouse, rat, or monkey) that expresses a homolog of human LTpR polypeptide as set forth in SEQ ID NO:2. In a preferred embodiment, the LTIpR polypeptide is human LTPR. In some embodiments, the LTBR moiety is itself soluble. In some 5 embodiments, the LTBR is joined to a heterologous moiety that increases its solubility, e.g., an Fc region of an immunoglobulin molecule. In some embodiments, the heterologous moiety can be covalently joined to the LTBR moiety. In some embodiments, a soluble LTpR can be modified by covalent attachment of a second polypeptide moiety, e.g., a heterologous polypeptide (e.g., to make an 10 LTPR fusion protein) or a non-polypeptide moiety. In some cases, such moieties can improve a pharmacodynamic or pharmacokinetic parameter, such as solubility or half life. LTpR fusion proteins can include all or part of the constant region of an antibody (e.g., an Fc domain), transferrin, or albumin, such as human serum albumin (HSA) or bovine serum albumin (BSA). The fusion protein can include a tinker region between 15 the LTpR sequence and the non- LTpR protein domain. In some embodiments, a soluble LTpR is modified by covalent attachment to a polymer such as a polyethylene glycol (PEG). While not limited by any particular theory or mechanism, such soluble LTf3Rs can act as decoy receptors to reduce (block) LTpR activity. An exemplary soluble LTpR is an LTpR-Fc, e.g., the LTpR-Fc having the sequence of SEQ ID NO: 1 20 set forth below. MLLPWA TSAPGLA WGPL VLGLFGLLAAAVPPYASENOTC RDQEKEYYEPQHRICCSRCPPGTYVSAKCSRIRDTVCAT CAENSYNEHWNYLTICQLCRPCDPVMGLEEIAPCTSKRK TQCRCQPGMFCAAWALECTHCELLSDCPPGTEAELKDE 25 VGKGNNHCVPCKAGHFONTSSPSARCQPHTRCENQGLV EAAP GTAQS DTTC KNPLEPLPPEM S GTM VDKTHTCP PC PAPELLGGPS VFLFPPKPKDTLMISRTPE VTC V V VD VS HED PE VKFN WY VDG VE VHNAKTKPREE QYNS TYRVV SVL TVL HQDWLNGKEYKCKVSNKALPAPIEKTISKAK 30 GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIA V EWE S NGQPEN NYKTTPP VLD SD GS F FLYS KLTVD KS RWQQGNVFSCSVMHEALHNHYTQKSL SL SPG(Amino 18 acids in italics indicate signal sequence; underlined amino acids indicate sequence derived from the extracellular region of LTPR; and amino acids in bold indicate IgG Fc sequence. A valine linking the LT3R sequence with the IgG-Fc sequence is artificial, and derived neither from the LTpR or the IgG-Fc sequence. The underlined sequence 5 is a substantial part of the extracellular domain of LTpR and corresponds to amino acids 32 to 225 of SEQ ID NO:2 (see above)). "Polypeptide" and "protein" are used interchangeably and mean any peptide linked chain of amino acids, regardless of length or post-translational modification. The LTpR, heterologous polypeptides, or fusion proteins thereof, used in any of the 10 methods of the invention can contain or be human proteins or can be variants that have not more than 50 (e.g., not more than one, two, three, four, five, six, seven, eight, nine, ten, 12, 15, 20, 25, 30, 35, 40, or 50) conservative amino acid substitutions. Conservative substitutions typically include substitutions within the following groups: glycine and alanine; valine, isoleucine, and leucine; aspartic acid and glutamic acid; 15 asparagine, glutamine, seine and threonine; lysine, histidine and arginine; and phenylalanine and tyrosine. All that is required is that: (i) such variants of the soluble LTpR polypeptides have at least 25% (e.g., at least: 30%; 40%; 50%; 60%; 70%; 75%; 80%; 85%; 90%; 95%; 97%; 98%; 99%; 99.5%, or 100% or even greater) of the ability of the LTBR-Fc fusion protein (SEQ ID NO: 1) to induce remyelination in a subject. 20 A "polypeptide fragment," as used herein, refers to a segment of the polypeptide that is shorter than a full-length, immature polypeptide. A "functional fragment" of a polypeptide has at least 10% (e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 50%, at least 55%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, at least 99%, at least 25 99.5%, or 100% or more) of the activity of the mature, polypeptide. Fragments of a polypeptide include terminal as well as internal deletion variants of a polypeptide. Deletion variants can lack one, two, three, four, five, six, seven, eight, nine, ten, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acid segments (of two or more amino acids) or non-contiguous single amino acids. 30 Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Preferred methods and materials are describe below, although 19 methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting. 5 Definitions of the specific embodiments of the invention as claimed herein follow. According to a first embodiment of the invention, there is provided a composition comprising a lymphotoxin-p receptor (LTjR)-Ig fusion protein comprising a portion of an LTPR extracellular domain and a portion of an immunoglobulin constant region, wherein the portion of the LTPR extracellular domain consists of amino acids 32 to 225 of SEQ ID NO: 2. 10 According to a second embodiment of the invention, there is provided use of the composition of the first embodiment, wherein: the portion of the immunoglobulin constant region consists of the amino acid sequence set forth in bold in SEQ ID NO: 1; the portion of the LTPR extracellular domain and the portion of the immunoglobulin 15 constant region are linked by amino acid linker; the linker consists of a valine residue; said composition further comprises a pharmaceutically acceptable carrier; and said composition is formulated for subcutaneous administration, in the manufacture of a medicament for the treatment of multiple sclerosis. o According to a third embodiment of the invention, there is provided a method of treating multiple sclerosis comprising the administration of an effective amount of the composition of the first embodiment, wherein: the portion of the immunoglobulin constant region consists of the amino acid sequence set forth in bold in SEQ ID NO: 1; 25 the portion of the LTPR extracellular domain and the portion of the immunoglobulin constant region are linked by amino acid linker; the linker consists of a valine residue; said composition further comprises a pharmaceutically acceptable carrier; and said composition is formulated for subcutaneous administration. 30 Other embodiments of the invention as described herein are defined in the following paragraphs: 20 1. A method of treating a demyelinating disorder in a human, the method comprising (i) administering to a human a dose of a soluble LTPR sufficient to promote remyelination, and (ii) monitoring the human for remyelination. 5 2. The method of paragraph 1, wherein the soluble LTPR is administered to the human until remyelination is detected in the human. 3. The method of paragraph 1, wherein the dose is administered once every 3-10 days; at least twice and not more than once every 5-20 days; or at least twice and not more than once every 28-31 days. lo 4. The method of paragraph 1, wherein the dose is administered weekly. 5. The method of paragraph 1, wherein the dose is administered biweekly. 6. The method of paragraph 1, wherein the dose is administered monthly. 7. The method of paragraph 1, wherein the dose is administered weekly over the course of at least 4 weeks. 15 8. The method of paragraph 1, wherein the dose is administered biweekly over the course of at least 6 weeks. 9. The method of paragraph 1, wherein the dose is administered monthly over the course of at least 3 months. 10. The method of paragraph 1, wherein the soluble LTPR is human LTPR or an LT 20 binding fragment thereof. 11. The method of paragraph 10, wherein the soluble LTPR comprises an LT-binding fragment of the extracellular region of human LTPR (SEQ ID NO: 2) linked to an Fc region of an Ig. 12. The method of paragraph 11, wherein the soluble LTPR comprises the sequence set 25 forth in SEQ ID NO:1. 20a 13. The method of paragraph 1, wherein remyelination is monitored by Magnetic Resonance Imaging, Positron-Emission Tomography, Diffusion-Weighted Imaging, Diffusion Tensor Imaging, Myelography, Evoked Potential Testing, or Magnetization Transfer. 14. The method of paragraph 1, wherein remyelination is monitored by an improvement of a 5 symptom of a demyelinating disorder. 15. The method of paragraph 14, wherein the symptom is impaired vision, numbness, weakness in extremities, tremors, heat intolerance, speech impairment, incontinence, or impaired proprioception. 16. The method of paragraph 1, wherein the demyelinating disorder is Multiple Sclerosis. lo 17. The method of paragraph 1, wherein the demyelinating disorder is selected from the group consisting of Relapsing/Remitting Multiple Sclerosis, Secondary Progressive Multiple Sclerosis, Progressive Relapsing Multiple Sclerosis, Primary Progressive Multiple Sclerosis, and Acute Fulminant Multiple Sclerosis. 18. The method of paragraph 1, wherein the demyelinating disorder is selected from the 15 group consisting of Central Pontine Myelinolysis, Acute Disseminated Encephalomyelitis, Progressive Multifocal Leukoencephalopathy; Subacute Sclerosing Panencephalitis, Post infectious Encephalomyelitis, Chronic Inflammatory Demyelinating Polyneuropathy, Guillain Barre Syndrome, Progressive Multifocal Leucoencephalopathy, Devic's Disease, Balo's Concentric Sclerosis, and a leukodystrophy. 20 19. The method of paragraph 18, wherein the leukodystrophy is Metachromatic Leukodystrophy, Krabb6 disease, Adrenoleukodystrophy, Pelizaeus-Merzbacher disease, Canavan disease, Childhood Ataxia with Central Hypomyelination, Alexander disease, or Refsum disease. 20. A method of treating a demyelinating disorder in a human, the method comprising 25 administering to a human a dose of a soluble LTPR, wherein the unit dosage, frequency of administration, and duration of treatment is sufficient such that remyelination occurs in the human. 21. The method of paragraph 20, wherein the soluble LTPR is administered to the human until remyelination is detected in the human. 20b 22. The method of paragraph 20, wherein the dose is administered once every 3-10 days; at least twice and not more than once every 5-20 days; or at least twice and not more than once every 28-31 days. 23. The method of paragraph 20, wherein the dose is administered weekly. 5 24. The method of paragraph 20, wherein the dose is administered biweekly. 25. The method of paragraph 20, wherein the dose is administered monthly. 26. The method of paragraph 20, wherein the dose is administered weekly over the course of at least 4 weeks. 27. The method of paragraph 20, wherein the dose is administered biweekly over the course 10 of at least 6 weeks. 28. The method of paragraph 20, wherein the dose is administered monthly over the course of at least 3 months. 29. The method of paragraph 20, wherein the soluble LTPR is human LTPR or an LT binding fragment thereof. 15 30. The method of paragraph 29, wherein the LTBR comprises a substantial portion of the extracellular region of human LTPR (SEQ ID NO: 2) linked to an Fc region of an Ig. 31. The method of paragraph 30, wherein the soluble LTPR comprises the sequence set forth in SEQ ID NO:1. 32. The method of paragraph 20, wherein remyelination is monitored by Magnetic 20 Resonance Imaging, Positron-Emission Tomography, Diffusion-Weighted Imaging, Diffusion Tensor Imaging, Myelography, Evoked Potential Testing, or Magnetization Transfer. 33. The method of paragraph 20, wherein remyelination is monitored by an improvement of a symptom of a demyelinating disorder. 34. The method of paragraph 33, wherein the symptom is impaired vision, numbness, 25 weakness in extremities, tremors, heat intolerance, speech impairment, incontinence, or impaired proprioception. 20c 35. The method of paragraph 20, wherein the demyelinating disorder is Multiple Sclerosis. 36. The method of paragraph 20, wherein the demyelinating disorder is selected from the group consisting of Relapsing/Remitting Multiple Sclerosis, Secondary Progressive Multiple Sclerosis, Progressive Relapsing Multiple Sclerosis, Primary Progressive Multiple Sclerosis, 5 and Acute Fulminant Multiple Sclerosis. 37. The method of paragraph 20, wherein the demyelinating disorder is one selected from the group consisting of Central Pontine Myelinolysis, Acute Disseminated Encephalomyelitis, Progressive Multifocal Leukoencephalopathy; Subacute Sclerosing Panencephalitis, Post infectious Encephalomyelitis, Chronic Inflammatory Demyelinating Polyneuropathy, Guillain 10 Barre Syndrome, Progressive Multifocal Leucoencephalopathy, Devic's Disease, Balo's Concentric Sclerosis, and a leukodystrophy. 38. The method of paragraph 37, wherein the leukodystrophy is Metachromatic Leukodystrophy, Krabb6 disease, Adrenoleukodystrophy, Pelizaeus-Merzbacher disease, Canavan disease, Childhood Ataxia with Central Hypomyelination, Alexander disease, or 15 Refsum disease. 39. A method of treating a demyelinating disorder in a human, the method comprising (i) administering to a human a dose of a soluble LTPR sufficient to promote remyelination; and (ii) classifying the human as having a preselected level of remyelination. z0 40. The method of paragraph 39, wherein the preselected level of remyelination is no remyelination, an intermediate level of remyelination, or a high level of remyelination. 41. The method of paragraph 39, wherein the soluble LTPR is administered to the human until remyelination is detected in the human. 42. The method of paragraph 39, wherein the dose is administered once every 3-10 days; at 25 least twice and not more than once every 5-20 days; or at least twice and not more than once every 28-31 days. 43. The method of paragraph 39, wherein the dose is administered weekly. 44. The method of paragraph 39, wherein the dose is administered biweekly. 20d 45. The method of paragraph 39, wherein the dose is administered monthly. 46. The method of paragraph 39, wherein the dose is administered weekly over the course of at least 4 weeks. 47. The method of paragraph 39, wherein the dose is administered biweekly over the course 5 of at least 6 weeks. 48. The method of paragraph 39, wherein the dose is administered monthly over the course of at least 3 months. 49. The method of paragraph 39, wherein the soluble LTPR is human LTPR or an LT binding fragment thereof. lo 50. The method of paragraph 49, wherein the soluble LTBR comprises a substantial portion of the extracellular region of human LTPR (SEQ ID NO: 2) linked to an Fc region of an Ig. 51. The method of paragraph 50, wherein the soluble LTPR comprises the sequence set forth in SEQ ID NO:1. 52. The method of paragraph 39, wherein remyelination is monitored by Magnetic 15 Resonance Imaging, Positron-Emission Tomography, Diffusion-Weighted Imaging, Diffusion Tensor Imaging, Myelography, Evoked Potential Testing, or Magnetization Transfer. 53. The method of paragraph 39, wherein remyelination is monitored by an improvement of a symptom of a demyelinating disorder. 54. The method of paragraph 53, wherein the symptom is impaired vision, numbness, 20 weakness in extremities, tremors, heat intolerance, speech impairment, incontinence, or impaired proprioception. 55. The method of paragraph 39, wherein the demyelinating disorder is Multiple Sclerosis. 56. The method of paragraph 39, wherein the demyelinating disorder is selected from the group consisting of Relapsing/Remitting Multiple Sclerosis, Secondary Progressive Multiple 25 Sclerosis, Progressive Relapsing Multiple Sclerosis, Primary Progressive Multiple Sclerosis, and Acute Fulminant Multiple Sclerosis. 20e 57. The method of paragraph 39, wherein the demyelinating disorder is one selected from the group consisting of Central Pontine Myelinolysis, Acute Disseminated Encephalomyelitis, Progressive Multifocal Leukoencephalopathy; Subacute Sclerosing Panencephalitis, Post infectious Encephalomyelitis, Chronic Inflammatory Demyelinating Polyneuropathy, Guillain 5 Barre Syndrome, Progressive Multifocal Leucoencephalopathy, Devic's Disease, Balo's Concentric Sclerosis, and a leukodystrophy. 58. The method of paragraph 57, wherein the leukodystrophy is Metachromatic Leukodystrophy, Krabb6 disease, Adrenoleukodystrophy, Pelizaeus-Merzbacher disease, Canavan disease, Childhood Ataxia with Central Hypomyelination, Alexander disease, or [0 Refsum disease. 59. A method of promoting remyelination, the method comprising: (i) administering to a human receiving an anti-TNF-therapy a dose of a soluble LTjR sufficient to promote remyelination in the human, and (ii) monitoring the human for remyelination. 15 60. The method of paragraph 59, wherein the human has an autoimmune disease. 61. The method of paragraph 60, wherein the autoimmune disease is rheumatoid arthritis. 62. The method of paragraph 59, wherein the anti-TNF therapy is Humira, Enbrel, or Remicade. 63. The method of paragraph 59, wherein the soluble LTR is administered to the human o until remyelination is detected in the human. 64. The method of paragraph 59, wherein the soluble LTR is human LTR or a LT binding fragment thereof. 65. The method of paragraph 59, wherein the dose is administered once every 3-10 days; at least twice and not more than once every 5-20 days; or at least twice and not more than once 25 every 28-31 days. 66. The method of paragraph 59, wherein the dose is administered weekly. 67. The method of paragraph 59, wherein the dose is administered biweekly. 68. The method of paragraph 59, wherein the dose is administered monthly. 20f 69. The method of paragraph 59, wherein the dose is administered weekly over the course of at least 4 weeks. 70. The method of paragraph 59, wherein the dose is administered biweekly over the course of at least 6 weeks. 5 71. The method of paragraph 59, wherein the dose is administered monthly over the course of at least 3 months. 72. The method of paragraph 64, wherein the soluble LTPR comprises a substantial portion of the extracellular region of human LTPR (SEQ ID NO: 2) linked to an Fc region of an Ig. 73. The method of paragraph 72, wherein the soluble LTPR comprises the sequence set 10 forth in SEQ ID NO:1. 74. The method of paragraph 59, wherein remyelination is monitored by Magnetic Resonance Imaging, Positron-Emission Tomography, Diffusion-Weighted Imaging, Diffusion Tensor Imaging, Myelography, Evoked Potential Testing, or Magnetization Transfer. 75. The method of paragraph 59, wherein remyelination is monitored by an improvement of 15 a symptom of a demyelinating disorder. 76. The method of paragraph 75, wherein the symptom is impaired vision, numbness, weakness in extremities, tremors, heat intolerance, speech impairment, incontinence, or impaired proprioception. 77. A delivery device designed for subcutaneous or intramuscular administration of a 20 soluble LTPR to a human having a demyelinating disorder, wherein said administration is sufficient such that remyelination occurs in the human. 78. The delivery device of paragraph 77, wherein the delivery device comprises lyophilized soluble LTBR. 79. The delivery device of paragraph 77, wherein the soluble LTPR is human LTPR or an 25 LT-binding fragment thereof. 20g 80. The delivery device of paragraph 79, wherein the soluble LTPR comprises a substantial portion of the extracellular region of human LTPR (SEQ ID NO: 2) linked to an Fc region of an Ig. 81. The delivery device of paragraph 80, wherein the soluble LTPR comprises the sequence 5 set forth in SEQ ID NO:1. 82. The delivery device of paragraph 77, wherein the delivery device is a syringe. 83. The delivery device of paragraph 77, wherein the demyelinating disorder is Multiple Sclerosis. 84. A kit comprising (i) one or more unit doses of a soluble LTPR and (ii) reagents and 10 instructions for how to assay for remyelination. 85. The kit of paragraph 84, wherein the kit is for the treatment of Multiple Sclerosis. 86. The kit of paragraph 84, wherein the soluble LTPR is human LTPR or an LT-binding fragment thereof. 87. The kit of paragraph 86, wherein the soluble LTPR comprises a substantial portion of 15 the extracellular region of human LTPR (SEQ ID NO: 2) linked to an Fc region of an Ig. 88. The kit of paragraph 87, wherein the soluble LTPR comprises the sequence set forth in SEQ ID NO:1. 89. A delivery device comprising two compartments, wherein the first compartment comprises a unit dose of a lyophilized soluble LTPR, wherein the unit dose is sufficient such 20 that remyelination occurs in a human; and the second compartment comprises a liquid for reconstituting the soluble LTPR prior to administration to a human. 90. The delivery device of paragraph 88, wherein the soluble LTPR is human LTPR or an LT-binding fragment thereof. 91. The delivery device of paragraph 90, wherein the soluble LTPR comprises a substantial 25 portion of the extracellular region of human LTPR (SEQ ID NO: 2) linked to an Fc region of an Ig. 20h 92. The delivery device of paragraph 91, wherein the soluble LTPR comprises the sequence set forth in SEQ ID NO:1. 93. A method of instructing a patient having a demyelinating disorder to treat the patient's demyelinating disorder, the method comprising (i) providing the patient with at least two unit 5 doses of a soluble LTjR; and (ii) instructing the patient to self-administer the unit doses subcutaneously, one dose at a time, wherein the unit dose of a soluble LTPR is sufficient to induce remyelination in a patient. 94. The method of paragraph 93, further comprising instructing the patient to self-monitor for remyelination. lo 95. The method of paragraph 93, wherein the patient is instructed to self-administer the unit doses biweekly, over the course of at least 4 weeks. 96. The method of paragraph 93, wherein the patient is instructed to self-administer the unit doses monthly, over the course of at least 2 months. 97. The method of paragraph 93, wherein the demyelinating disorder is a form of Multiple 15 Sclerosis. 98. The method of paragraph 93, wherein the soluble LTPR is human LTPR or an LT binding fragment thereof. 99. The method of paragraph 98, wherein the soluble LTPR comprises a substantial portion of the extracellular region of human LTPR (SEQ ID NO: 2) linked to an Fc region of an Ig. 20 100. The method of paragraph 99, wherein the soluble LTPR comprises the sequence set forth in SEQ ID NO:1. The term 'comprise' and variants of the term such as 'comprises' or 'comprising' are used herein to denote the inclusion of a stated integer or stated integers but not to exclude any other integer or any other integers, unless in the context or usage an exclusive interpretation of 25 the term is required. Any reference to publications cited in this specification is not an admission that the disclosures constitute common general knowledge in Australia. 20i Other features and advantages of the invention will be apparent from the following description, from the drawings, and from the claims. DESCRIPTION OF DRAWINGS FIG. 1 is a graph depicting LtR mRNA expression levels in wild-type mice during 5 cuprizone treatment. FIG. 2 is a graph depicting the severity of demyelination in Lt3R/ and wildtype mice. On a scale depicting severity of demyelination, as assayed by LFB-PAS stained paraffin sections, 0 indicates normal myelination, and 3 indicates complete demyelination. Each circle represents an individual mouse: open circles, C57BL6 wild-type (wt); filled circles, LtpR' 10 mice. Horizontal lines indicate the median score of each group. FIG. 3 is a graph depicting numbers of mature oligodendrocytes detected at the midline corpus callosum following treatment with cuprizone. Wild-type mice are indicated by gray bars; LtBR"7" mice are indicated by black bars. FIG. 4 is a graph depicting numbers of microglial/macrophage cells detected at the 15 midline corpus callosum following treatment with cuprizone. Wild-type mice are indicated by gray bars; Lt3R# mice are indicated by black bars. FIG. 5 is a graph depicting the severity of demyelination in wild-type C57BL6 mice following administration of hLtjR-Ig or human Ig control. On a scale depicting severity of demyelination, as assayed by LFB-PAS stained paraffin sections, 0 indicates normal Zo myelination, and 3 indicates complete demyelination. Each circle represents an individual mouse: open circles, human-Ig treated mice; filled circles hLtR-Ig treated mice. Horizontal lines indicate the median score of each group. FIG. 6 is a graph depicting the severity of demyelination in wild-type C57BL6 mice following administration of mLtR-Ig or mouse Ig control. On a scale depicting severity of 25 demyelination, as assayed by LFB-PAS stained paraffin sections, 0 indicates normal myelination, and 3 indicates complete demyelination. Each circle represents an [Text continues on page 21] 20j individual mouse: open circles, human-Ig treated mice; filled circles hLtBR-Ig treated mice. Horizontal lines indicate the median score of each group. DETAILED DESCRIPTION 5 The soluble LtBRs described herein are lymphotoxin (LT) pathway inhibitors and are shown to promote remyelination. Thus, the soluble LtBRs can be useful for the treatment of demyelinating disorders. Demyelinating disorders can include, for example, Multiple Sclerosis (e.g., Relapsing/Remitting Multiple Sclerosis, Secondary Progressive Multiple Sclerosis, Progressive Relapsing Multiple Sclerosis, Primary 10 Progressive Multiple Sclerosis, or Acute Fulminant Multiple Sclerosis), Central Pontine Myelinolysis, Acute Disseminated Encephalomyelitis, Progressive Multifocal Leukoencephalopathy; Subacute Sclerosing Panencephalitis, Post-infectious Encephalomyelitis, Chronic Inflammatory Demyelinating Polyneuropathy, Guillain Barre Syndrome, Progressive Multifocal Leucoencephalopathy, Devic's Disease, 15 Balo's Concentric Sclerosis, and a leukodystrophy (e.g., Metachromatic Leukodystrophy, Krabb6 disease, Adrenoleukodystrophy, Pelizaeus-Merzbacher disease, Canavan disease, Childhood Ataxia with Central Hypomyelination, Alexander disease, or Refsum disease). The agents and methods described herein are particularly suitable for treatment of Multiple Sclerosis. 20 Multiple Sclerosis is an idiopathic disorder of the central nervous system in which the body's immune system attacks myelin in the brain and spinal cord. Whether the disease manifests in repeated episodes of inflammation or as a chronic condition, it often results in multiple scars (scleroses) on the myelin sheath, leading to impairment or loss of nerve function. Multiple Sclerosis, while primarily affecting young adults, 25 can manifest in patients of any age. Symptoms of Multiple Sclerosis include, for example, impaired vision or cognitive function, numbness, weakness in extremities, tremors or spasticity, heat intolerance, speech impairment, incontinence, or impaired proprioception. Patients with Multiple Sclerosis often also present with depression. Following administration of a soluble LTpR (e.g., LTpR-Fc) -containing 30 composition to a subject (e.g., a human patient), the efficacy of the treatment (i.e., the remyelination resulting from the treatment) of a demyelinating disorder (e.g., Multiple Sclerosis) can be assessed, e.g., by comparing the extent of the patient's demyelinating disorder before and after treatment. Post-treatment assessment can occur immediately 21 or shortly after treatment (e.g., one hour after treatment, two hours after treatment, three hours after treatment, six hours after treatment, 12 hours after treatment, or 18 hours after treatment) or can occur at least one day (e.g., at least one day, at least two days, at least three days, at least five days, at least a week, at least two weeks, at least three 5 weeks, at least five weeks, at least two months, at least six months, or at least a year) following treatment. Where progression of the improvement of Multiple Sclerosis following one or more LTpR-Fc treatments (e.g., one or more treatments to induce remyelination) is to be assessed, a patient's symptoms or cognitive abilities can be evaluated or measured at multiple time points following LT$R-Fc treatment (e.g., a one 10 day, two day, and one week evaluation; a one week, one month, and six month evaluation; a one month, six month, and one year evaluation). Progression of the improvement of a demyelinating disorder (e.g., Multiple Sclerosis) can also include measuring or assessing, for example, a change in the size or number of demyelinating lesions in a patient or a change (i.e., an improvement) in nerve function. 15 Suitable methods for evaluating the extent or severity of a demyelinating disorder (e.g., Multiple Sclerosis or any other demyelinating disorder described herein) are well known in the art. For example, the presence, extent, or severity of Multiple Sclerosis can be assessed in a patient through the use of a number of quantitative tests and evaluations. For example, a lumbar puncture (i.e., a spinal tap) can be performed 20 on a patient to obtain a sample of cerebrospinal fluid. The cerebrospinal fluid is then tested for the presence of, e.g., (i) abnormal proteins such as tiny fragments of myelin, (ii) elevated levels of or specific types of lymphocytes, and/or (iii) abnormal levels of immunoglobulin (IgG) molecules. Another example of a quantitative test for a demyelinating disorder is an evoked potential test, which measures nerve activity as a 25 function of how long it takes nerve impulses from the eye, ear, or skin to reach the brain. A demyelinating disorder can also be assessed by evaluating the size and/or number of inflammatory lesions (i.e., scleroses) present at the central nervous system using any of several methods of imaging including, but not limited to, Magnetic Resonance Imaging (MRI) scans, Positron-Emission Tomography (PET) scans, 30 Diffusion-Weighted Imaging (DW-I, or DW-MRI), Diffusion Tensor Imaging, Myelography, Magnetization Transfer. Patients can also be diagnosed using a variety of semi-quantitative or qualitative assessments of their neuropsychology (e.g., the status of various abilities such as memory, arithmetic, attention, judgment and 22 reasoning) or symptoms (clinical parameters) presented by the patient including, e.g., any of the symptoms of Multiple Sclerosis described above. Additionally, the extent or progression of a demyelinating disorder can be detected by testing a patient's urine for elevated levels of myelin basic protein-like material (MBPLM), which substance 5 becomes elevated as axonal damage occurs during disease progression (see, for example, Whitaker et al. (1995) Ann. Neurol. 38(4):635-632). Certain tests for color blindness can also be helpful in tracking the effect of demyelinating disorders on the eyes. Any of the diagnostic methods described above can also be used to evaluate 10 increased remyelination in a subject (e.g., a patient) following treatment with a soluble LT3R (e.g., LTpR-Fc). For example, remyelination can coincide with a reduction in the size or number of scleroses present in a patient as determined through any of the imaging methods described herein. Also, remyelination in a subject could be measured as an increase in the speed of transmission of a signal from the ears, eyes, or skin to the 15 brain, as determined through evoked potential testing. In some cases, remyelination can be evaluated as an increase in white matter volume (e.g., nerve mass of the spine or brain), particularly where the demyelinating disorder has resulted in nerve atrophy. In some instances, the extent or occurrence of remyelination in a subject can be assessed by directly measuring the thickness of myelin in a subject using, e.g., magnetic 20 resonance spectroscopy scans. The efficacy of a given treatment (i.e., the extent of remyelination) in treating a demyelinating disorder (e.g., Multiple Sclerosis) can be defined as an improvement of one or more symptoms of demyelinating disorder (e.g., any of the symptoms described above) by at least 5% (e.g., at least 10%, at least 15%, at least 20%, at least 25%, at 25 least 30%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65% or more). In some cases, efficacy of a soluble LTpR (e.g., LTpR-Fc) treatment can be determined from the stabilization of one or more worsening symptoms associated with Multiple Sclerosis (i.e., the treatments curtail the worsening of one or more symptoms of Multiple Sclerosis). Treatment efficacy or extent of remyelination can also be 30 evaluated in a patient using any of the diagnostic methods described herein, e.g., MRI or PET. For example, the amelioration of the size or number of demyelinating lesions (scleroses) following treatment with an LTpR-Fc can be monitored using MRI. 23 Combination Therapies The methods and compositions described herein can be used in combination with other therapies used for the treatment of demyelinating disorders. For example, a soluble LTpR (e.g., LTpR-Fc) composition can be used in combination with direct 5 therapies for Multiple Sclerosis such as, but not limited to, Interferon Beta la (Avonex), Interferon Beta lb (Rebif), glatiramer acetate (Copaxone), mitoxantrone (Novantrone), azathiprine (Imuran), cyclophosphamide (Cytoxan or Neosar), cyclosporine (Sandimmune), methotrexate, Cladribine (Leustatin), methylprednisone (Depo-Medrol or Solu-Medrol), prednisone (Deltasone), prednisolone (Delta-Cortef), dexamethasone 10 (Medrol or Decadron), adreno-corticotrophic hormone (ACTH), or Corticotropin (Acthar). The methods and compositions (e.g., a soluble LTpR such as LTpR-Fc) provided herein can also be used in combination with therapies designed to treat the symptoms associated with a demyelinating disorder. Where the demyelinating disorder 15 is Multiple Sclerosis, for example, a soluble LT3R (e.g., LT$R-Fc) can be administered in combination with one or more treatments for pain associated with Multiple Sclerosis including, e.g., carbamazepine, gabapentin, topiramate, zonisimide, phenytoin, pentoxifylline, ibuprofen, aspirin, or acetaminophen. A soluble LTpR (e.g., LTPR-Fc) can also be administered in combination with one or more treatments for anxiety or 20 depression associated with Multiple Sclerosis including, e.g., fluoxetine, sertraline, vanlafaxine, citalopram, parocetine, trazodone, buproprion, diazepam, or amitriptyline. Furthermore, a soluble LTpR (e.g., LTpR-Fc) can be administered in combination with one or more treatments for other symptoms of Multiple Sclerosis including, incontinence (e.g., oxybutynin, bethane, or imipramine), tremors or 25 spasticity (e.g, baclofen, dantrolene sodium, or tizanidine), or vertigo (e.g., mecizine, dimenhydrinate, prochlorperazine, or scopolamine). The present invention also includes the use of the methods and compositions described herein in combination with therapies or medicaments that can cause demyelinating conditions. For example, anti-TNF therapy for treatment of rheumatoid 30 arthritis, as a side-effect, can result in a type of demyelinating condition. Thus, a soluble LTPR (e.g., LTpR -Fc) can be administered (e.g, co-administered) in combination with an anti-TNF therapy to prevent, ameliorate, or reverse the 24 demyelination side-effects and to promote remyelination. Anti-TNF therapies include, but are not limited to, adalimumab (Humira), etanercept (Enbrel), or infliximab (Remicade). Any of the methods or compositions described herein generally can be used in 5 any circumstance where increasing remyelination would be advantageous. In some instances, a soluble LTpR (e.g., LT3R-Fc) is used as a second line therapy. For example, a patient who is determined to be unresponsive to one or more therapies for a demyelinating disorder (e.g., Multiple Sclerosis) will stop receiving the one or more treatments and will begin treatment with a soluble LTPR, e.g., LT pR-Fc. 10 Alternatively, the patient will continue to receive the one or more therapies for a demyelinating disorder while receiving treatment with the soluble LT3R. Pharmaceutical Compositions A soluble LT3R, e.g., LTpR-Fc, can be formulated as a pharmaceutical 15 composition, e.g., for administration to a subject to treat a demyelinating disorder, such as Multiple Sclerosis. Typically, a pharmaceutical composition includes a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are 20 physiologically compatible. The composition can include a pharmaceutically acceptable salt, e.g., an acid addition salt or a base addition salt (see e.g., Berge et al., J. Pharm. Sci. 66:1-19, 1977). The soluble LTPR can be formulated according to standard methods. Pharmaceutical formulation is a well-established art, and is further described, e.g., in 25 Gennaro (ed.), Remington: The Science and Practice of Pharmacy, 20th ed., Lippincott, Williams & Wilkins (2000) (ISBN: 0683306472); Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Ed., Lippincott Williams & Wilkins Publishers (1999) (ISBN: 0683305727); and Kibbe (ed.), Handbook of Pharmaceutical Excipients American Pharmaceutical Association, 3rd ed. (2000) (ISBN: 091733096X). 30 In one embodiment, a soluble LTpR (e.g., LTpR-Fc) can be formulated with excipient materials, such as sodium chloride, sodium dibasic phosphate heptahydrate, 25 sodium monobasic phosphate, and a stabilizer. It can be provided, for example, in a buffered solution at a suitable concentration and can be stored at 2-8'C. The pharmaceutical compositions may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., 5 injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The preferred form can depend on the intended mode of administration and therapeutic application. Typically compositions for the agents described herein are in the form of injectable or infusible solutions. Such compositions can be administered by a parenteral mode (e.g., intravenous, 10 subcutaneous, intraperitoneal, or intramuscular injection). The phrases "parenteral administration" and "administered parenterally" as used herein mean modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, 15 subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, intracarotid and intrasternal injection and infusion. The composition can be formulated as a solution, microemulsion, dispersion, liposome, or other ordered structure suitable for stable storage at high concentration. Sterile injectable solutions can be prepared by incorporating an agent described herein 20 in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating an agent described herein into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile 25 injectable solutions, the preferred methods of preparation arevactum drying and freeze-drying that yields a powder of an agent described herein plus any additional desired ingredient from a previously sterile-filtered solution thereof. The proper fluidity of a solution can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and 30 by the use of surfactants. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin. 26 In certain embodiments, the soluble LT3R can be prepared with a carrier that will protect the compound against rapid release, such as a controlled release formulation, including implants, and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, 5 polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known. See, e.g., Sustained and Controlled Release Drug Delivery Systems, J.R. Robinson, ed., Marcel Dekker, Inc., New York, 1978. A soluble LT3R (e.g., LTPR-Fc) can be modified, e.g., with a moiety that 10 improves its stabilization and/or retention in circulation, e.g., in blood, serum, or other tissues, e.g., by at least 1.5, 2, 5, 10, or 50 fold. The modified agent can be evaluated to assess whether it can reach sites of inflammation (e.g., lesions or scleroses) such as can occur in a demyelinating disorder, such as Multiple Sclerosis (e.g., by using a labeled form of the agent). 15 For example, the soluble LTpR can be associated with a polymer, e.g., a substantially non-antigenic polymer, such as a polyalkylene oxide or a polyethylene oxide. Suitable polymers will vary substantially by weight. Polymers having molecular number average weights ranging from about 200 to about 35,000 Daltons (or about 1,000 to about 15,000, and 2,000 to about 12,500) can be used. 20 For example, a soluble LTPR can be conjugated to a water soluble polymer, e.g., a hydrophilic polyvinyl polymer, e.g., polyvinylalcohol or polyvinylpyrrolidone. A non-limiting list of such polymers include polyalkylene oxide homopolymers such as polyethylene glycol (PEG) or polypropylene glycols, polyoxyethylenated polyols, copolymers thereof and block copolymers thereof, provided that the water solubility of 25 the block copolymers is maintained. Additional useful polymers include polyoxyalkylenes such as polyoxyethylene, polyoxypropylene, and block copolymers of polyoxyethylene and polyoxypropylene (Pluronics); polymethacrylates; carbomers; and branched or unbranched polysaccharides. When the soluble LTQR (e.g., LTpR-Fc) is used in combination with a second 30 agent (e.g., any of the therapies for Multiple Sclerosis and other demyelinating disorders described herein), the two agents can be formulated separately or together. For example, the respective pharmaceutical compositions can be mixed, e.g., just prior 27 to administration, and administered together or can be administered separately, e.g., at the same or different times. Administration 5 A soluble LTpR (e.g., LTpR-Fc) can be administered to a subject, e.g., a human subject, by a variety of methods. For many applications, the route of administration is one of: intravenous injection or infusion (IV), subcutaneous injection (SC), intraperitoneally (IP), or intramuscular injection. In some cases, administration may be directly into the CNS, e.g., intrathecal, intracerebroventricular (ICV), intracerebral or 10 intracranial. The agent can be administered as a fixed dose, or in a mg/kg dose. The dose can also be chosen to reduce or avoid production of antibodies against the agent. The route and/or mode of administration of the soluble LTpR can also be tailored for the individual case, e.g., by determining the location, number or size of 15 scleroses in a subject, e.g., using Magnetic Resonance Imaging (MRI) scans, Positron Emission Tomography (PET) scans, Diffusion-Weighted Imaging (DW-I, or DW MRI), Diffusion Tensor Imaging, Myelography, Magnetization Transfer. The severity or extent of a demyelinating disorder can also be determined from lumbar puncture (e.g., to check for elevated white cells in the cerebral-spinal fluid, evoked potential 20 testing as a measure of nerve function, and/or any other standard parameters associated with a demyelinating disorder (e.g., Multiple Sclerosis), e.g., any of the assessment criteria described herein. Dosage regimens are adjusted to provide the desired response, e.g., a therapeutic response or a combinatorial therapeutic effect. The dosage regimen will, 25 for example, cause an increase in remyelination. Generally, a dose of a soluble LTPR (e.g., LT3R-Fc) optionally formulated separately or together with an appropriate dose of a second therapeutic agent can be used to provide a subject with the soluble LTpR. Suitable dosages and/or dose ranges for the soluble LTpR include an amount sufficient to cause increased remyelination in a subject. Suitable dosages can be any of those 30 described herein and include, for example, a dose of at least about 0.001 mg of a soluble LTpR per kg body weight of a subject (e.g., a human patient). 28 A dose of a soluble LTpR (e.g., an LT3R fusion polypeptide such as LTpR-Fc) required to increase remyelination can depend on a variety of factors including, for example, the age, sex, and weight of a subject to be treated. Other factors affecting the dose administered to the subject include, e.g., the type or severity of the demyelinating 5 disorder. For example, a patient with Acute Fulminant Multiple Sclerosis may require a administration of a different dosage of a soluble LTpR than a patient with a milder form of Multiple Sclerosis. Other factors can include, e.g., other disorders concurrently or previously affecting the patient, the general health of the patient, the genetic disposition of the patient, diet, time of administration, rate of excretion, drug combination, and any 10 other additional therapeutics that are administered to the patient. It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon the judgment of the treating physician. The amount of active ingredients will also depend upon the particular described compound and the presence or absence and the nature of the additional anti-viral agent in the composition. 15 Dosage unit form or "fixed dose" as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect (e.g., an crease in remyelination in a subject) in association with the required pharmaceutical carrier and optionally in association with the other agent. 20 Suitable administration frequencies are described elsewhere herein. A pharmaceutical composition may include a therapeutically effective amount of a soluble LTpR described herein. Such effective amounts can be determined based on the effect of the administered agent, or the combinatorial effect of an agent and secondary agent if more than one agent is used. A therapeutically effective amount of 25 an agent can also vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual, e.g., amelioration of at least one disorder parameter, e.g., amelioration of at least one symptom of a demyelinating disorder, e.g., Multiple Sclerosis. For example, a therapeutically effective amount of soluble LTpR will increase 30 remyelination and can also slow and/or ameliorate demyelination. A therapeutically effective amount is also one in which any toxic or detrimental effects of the composition is outweighed by the therapeutically beneficial effects. 29 Devices and Kits Pharmaceutical compositions that include a soluble LTpR (e.g., an LTPR-Fc) can be administered with a medical device. The device can be designed with features such as portability, room temperature storage, and ease of use so that it can be used in 5 emergency situations, e.g., by an untrained subject or by emergency personnel in the field, removed to medical facilities and other medical equipment. The device can include, e.g., one or more housings for storing pharmaceutical preparations that include a soluble LTpR, and can be configured to deliver one or more unit doses of the agent. For example, the pharmaceutical composition can be administered with a 10 transcutaneous delivery device, such as a syringe, including a hypodermic or multichamber syringe. Other suitable delivery devices include stents, catheters, transcutaneous patches, microneedles, and implantable controlled release devices. The device (e.g., a syringe) can include a soluble LTpR in a dry or liquid form at a dose sufficient to cause remyelination. The device can also be a dual-chambered 15 device, wherein one chamber contains a unit dose of lyophilized soluble LT$R (e.g., LT3R-Fc) sufficient to cause increased remyelination in a subject, and a second chamber containing a liquid (e.g., a buffer) for reconstituting the lyophilized unit dos'e of a soluble LTpR. In other examples, the pharmaceutical composition can be administered with a 20 needleless hypodermic injection device, such as the devices described in US 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824; or 4,596,556. Examples of well-known implants and modules are described in, e.g., US 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; US 4,486,194, which discloses a therapeutic device for administering medications through 25 the skin; US 4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; US 4,447,224, which discloses a variable flow implantable infusion apparatus for continuous drug delivery; US 4,439,196, which discloses an osmotic drug delivery system having multi-chamber compartments; and US 4,475,196, which discloses an osmotic drug delivery system. Many other devices, 30 implants, delivery systems, and modules are also known. A soluble LT3R (e.g., an LT3R-Fc) can be provided in a kit. In one embodiment, the kit includes (a) a container that contains a composition that includes 30 one or more unit doses of a soluble LTPR, and optionally (b) informational material. The unit doses of soluble LTpR are sufficient to cause increased remyelination in a subject. The informational material can be descriptive, instructional, marketing or other material that relates to the methods described herein and/or the use of the agents 5 for therapeutic benefit. The kit can also include reagents and instructions useful in the testing (assaying) for remyelination. Such methods of assaying for remyelination include, but are not limited to, any of the testing methods described herein. In one embodiment, the kit includes one or more additional agents for treating a demyelinating disorder, such as one or more agents to treat Multiple Sclerosis. For example, the kit 10 includes a first container that contains a composition that includes the soluble LTPR, and a second container that includes the one or more additional agents. The informational material of the kits is not limited in its form. In one embodiment, the informational material can include information about production of the compound, molecular weight of the compound, concentration, date of expiration, 15 batch or production site information, and so forth. In one embodiment, the informational material relates to methods of administering the soluble LTpR (e.g., LTPR-Fc), e.g., in a suitable dose, dosage form, or mode of administration (e.g., a dose, dosage form, or mode of administration described herein), to treat a subject who has a demyelinating disorder, or who is at risk of developing, or for experiencing an episode 20 associated with a demyelinating disorder. The information can be provided in a variety of formats, including printed text, computer readable material, video recording, or audio recording, or a information that provides a link or address to substantive material. In addition to the agent, the composition in the kit can include other ingredients, such as a solvent or buffer, a stabilizer, or a preservative. The agent can be provided in 25 any form, e.g., liquid, dried or lyophilized fonm, preferably substantially pure and/or sterile. When the agents are provided in a liquid solution, the liquid solution preferably is an aqueous solution. When the agents are provided as a dried form, reconstitution generally is by the addition of a suitable solvent. The solvent, e.g., sterile water or buffer, can optionally be provided in the kit. 30 The kit can include one or more containers for the composition or compositions containing the agents. In some embodiments, the kit contains separate containers, dividers or compartments for the composition and informational material. For example, the composition can be contained in a bottle, vial, or syringe, and the 31 informational material can be contained in a plastic sleeve or packet. In other embodiments, the separate elements of the kit are contained within a single, undivided container. For example, the composition is contained in a bottle, vial or syringe that has attached thereto the informational material in the form of a label. In some 5 embodiments, the kit includes a plurality (e.g., a pack) of individual containers, each containing one or more unit dosage forms (e.g., a dosage form described herein) of the agents. The containers can include a combination unit dosage, e.g., a unit that includes both the soluble LTPR and the second agent, e.g., in a desired ratio. For example, the kit includes a plurality of syringes, ampules, foil packets, blister packs, or medical 10 devices, e.g., each containing a single combination unit dose. The containers of the kits can be air tight, waterproof (e.g., impermeable to changes in moisture or evaporation), and/or light-tight. The kit optionally includes a device suitable for administration of the composition, e.g., a syringe or other suitable delivery device. The device can be 15 provided pre-loaded with one or both of the agents or can be empty, but suitable for loading. Methods of making soluble LTBRs Suitable methods of making soluble LT3Rs are known in the art and are 20 described, for example, in WO 97/03687, WO 98/17313, WO 00/21558, WO 99/38525, WO 00/36092. For example, an LTpR immunoglobulin fusion protein can be expressed in cell culture (e.g., mammalian cell culture (such as monkey COS cells or Chinese hamster ovary cells) or yeast cell culture) at a reduced temperature to produce an increased amount of properly folded fusion protein. The expressed fusion protein 25 can be purified, e.g., by affinity or conventional chromatography techniques ( see, e.g., WO 00/36092). All the above-mentioned PCT applications are incorporated herein by reference in their entirety. The following examples are meant to illustrate, not limit, the invention. 30 32 EXAMPLES Example 1. Materials and Methods Animals. C57BL6 mice were purchased from Jackson Laboratories (Bar Harbor, Maine) and bred in house at the University of North Carolina (UNC) animal 5 facility. LtpR- mice were bred in house at the UNC animal facility. All procedures were conducted in accordance with the National Institutes of Health (NIH) and were approved by the Institutional Guidefor the Care and Use of Laboratory Animals Animal Care and Use Committee of UNC at Chapel Hill. All mice were at 8-10 weeks of age prior to the start of cuprizone treatment. 10 Treatment of mice. Male LtfR' and C57BL6 wild-type mice were fed ad libitum 0.2% cuprizone [oxalic bis(cyclohexylidenehydrazide)] (Aldrich, St. Louis, MO) mixed into milled chow. Mice were treated for 3, 3.5, 4, or 5 weeks to study the demyelination process. For remyelination, mice were returned to a diet of normal 15 pellet chow for 1, 2 or 4 weeks following 6 full weeks of cuprizone treatment. Untreated mice were maintained on a diet of normal pellet chow. Both human and mouse LtpR-Ig and their controls were kindly provided by Dr. J. Browning (Biogen Idec, Cambridge, MA) and are described in Gommerman et al. (2003) J. Clin. Invest. 112:755-767. To study demyelination, mice were pretreated on 20 day -1 and weekly thereafter with intraperitoneal injections of 5mg/kg of either human LtpR-human Ig (hLtpR-IgG- 1 Fc) or human-Ig control. The post-treatment paradigm consisted of cuprizone treatment for 6 full weeks. After 5 weeks plus 2 days (approximate height of demyelination) of cuprizone treatment, mice were given intraperitoneal injections of either mouse LtpR-mouseIgG-1 or matched control 25 MOPC-21 followed by weekly injections out to 10 weeks. This murine version of Lt3R-Ig has been shown to be less antigenic in the mouse. Tissue preparation and histopathological analysis. Paraffin-embedded coronal brain sections were prepared from the fomix region of the corpus callosum. Luxol fast 30 blue-periodic acid Schiff (LFB-PAS) stained sections were read by three double blinded readers and graded on a scale from 0 (complete myelination) to 3 (complete 33 demyelination), as described in Arnett et al. (2001) Nat. Neurosci. 4:1116-1122 and Plant et al. (2005) Glia 49:1-14. Immunohistochemistry. Detection of mature oligodendrocytes, 5 microglia/macrophages and astrocytes was performed by immunohistochemistry (Plant et al. (2005) Glia 49:1-14). Quantitative analyses of GSTn and RCA-I positive cells were restricted to a 0.033mm 2 area at midline corpus callosum. Only immunopositive cells with an observable DAPI-stained nucleus were included in the quantification. Cell counts are averages of at least 9 and up to 14 mice per time point. Myelinated 10 fibers were detected by immunohistochemistry with a primary antibody to myelin basic protein (Sternberger Monoclonals Inc. Lutherville, MD) followed by flourescein conjugated anti-mouse IgG (Invitrogen, Carlsbad, CA) diluted 1:1000. In situ hybridization. Following cuprizone treatment, mice were perfused with 15 RNase-free PBS and then 4% paraformaldehyde. Brains were removed and incubated in fixative until mounted for cryosectioning. Detection of mRNA for LtPR was performed by in situ hybridization as described in Schmid et al. (2002) J. Neurochem. 83:1309-1320. 20 RT-PCR and Quantitative Realtime RT-PCR. Total RNA was isolated from a dissected region of the brain containing the corpus callosum of wild-type and LtpR mice at several points during and after cuprizone treatment. RNA isolation was performed using the Qiagen RNeasy kit under RNase-free conditions (Qiagen, Valencia, CA). RT-PCR for LIGHT was performed in 20 pl reactions using the 25 following primers: 5' primer: CTGGCATGGAGAGTGTGGTA (SEQ ID NO:3); 3' primer: GATACGTCAAGCCCCTCAAG (SEQ ID NO:4). TaqMan 5' nuclease quantitative real-time PCR assays were performed using an ABI Prism 7900 sequence-detection system (PE Applied Biosystems, Foster City, CA) in a 15il reaction with universal master mix (Invitrogen), 200 nM LtpR target primers, 30 and 100 nM probe. LtpR specific primers were designed to span intron-exon junctions to differentiate between cDNA and genomic DNA. The primers and probe used to detect mouse LtfR were as follows: 5' primer, 34 GTACTCTGCCAGCCTGGCACAGAAGCCGAGGTCACAGATG (SEQ ID NO:5); 3' primer, GGTATGGGGTTGACAGCGGGCTCGAGGGGAGG (SEQ ID NO:6); probe, Fam-ACGTCAACTGTGTCCC-Tamra (SEQ ID NO:7). The primers and probe for mouse 18 S ribosomal RNA were 5' primer, GCTGCTGGCACCAGACTT (SEQ ID 5 NO:8); 3' primer, CGGCTACCACATCCAAGG (SEQ ID NO:9); probe, Fam CAAATTACCCACTCCCGACCCG-Tamra (SEQ ID NO:10). Thermal cycle parameters were optimized to 2 min at 50 C, 2 min at 95*C, and 40 cycles comprising denaturation at 95'C for 15 sec and annealing-extension at 56'C for 1.5 min. Reactions for 18 S were performed alongside LtpR during each experiment and used to normalize 10 for amounts of cDNA. Statistical analysis. Unpaired Student's t tests were used to statistically evaluate significant differences. Data are expressed as mean ± s.e.m. 15 Example 2: LtpR localization and LIGHT expression in the brain Ltax and LtP are found on a wide variety of haematopoietic cells while LtpR is expressed on dendritic cells and monocytes as well as most lineages of non haematopoietic cells. follicular dendritic cells and high endothelial venules (Gommerman et al. (2003) Nat. Rev. Immunol. 3:642-655). Lta and Lt have also 20 been detected on astrocytes while LtPR has been detected on astrocytes and cells of monocytic origin (Cannella et al. (1997) J. Neuroimmunol. 78:172-179 and Plant et al. Glia 49:1-14). To assess LtpR expression in the cuprizone model, we performed quantitative real-time RT-PCR to examine the level of LtpR in the brains of untreated and cuprizone treated mice. Demyelination time points were obtained from mice 25 treated for 3, 3.5, 4 or 5 weeks with cuprizone while remyelination time points were obtained from mice treated for 6 weeks and then released from cuprizone for 1, 2 or 4 weeks, corresponding to weeks 7, 8 and 10. Taqman probes specific for the LtpR gene and ribosomal 18S were used to detect transcripts in cDNA generated from brain RNA samples. As shown in FIG. 1, LtBR mRNA expression rose moderately in wild-type 30 mice during cuprizone treatment (through week 6) (throughout the demyelination phase). LtBR mRNA expression levels declined to normal levels during the 35 remyelination phase (weeks 7-10). Low levels of LtR were detected in control untreated mice. To define the cell type that expresses LtpR, in situ hybridization was used to localize LtpR in brains of untreated and cuprizone treated mice. Lt3R was not 5 expressed in brain prior to treatment. By 3 weeks of cuprizone treatment, a small amount of LtpR was detected in the corpus callosum region, however, by 5 weeks of treatment, a dramatic upregulation of LtPR was detected in this inflamed region. To determine which cell type expressed LtpR, in situ hybridization was coupled with immunohistochemical analysis. Microglia and macrophages were visualized in brain 10 cyrosections using biotinylated tomato lectin, astrocytes were visualized using GFAP specific antibodies, oligodendrocytes using CNP-specific antibodies and neurons using NeuN-specific antibodies. LtpR expression could only be detected in lectin-positive cells. These results indicated that activated microglia and/or macrophages rather than astrocytes, oligodendrocytes or neurons express LtpR during cuprizone-induced 15 inflammation and demyelination. While not limited by any particular theory or mechanism, in view of previous findings that astrocytes are the source of Ltu (Plant et al. (2005) Glia 49:1-14), these data suggested that Ltcap-LtPR signaling between astrocytes and microglia is primarily involved in the inflammatory demyelinating process that occurs during cuprizone 20 treatment. In addition to Ltc4p, LtpR interacts with the membrane-bound ligand, LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for the herpes-virus entry mediator (HVEM), a receptor expressed by T lymphocytes) (Granger et al. (2001) J. Clin. Invest. 108:1741-1742). LIGHT appears to be localized primarily to T cells, immature 25 dendritic cells, granulocytes and monocytes (Gommerman et al. Nat. Rev. Immunol. 3:642-655), but has not been well-characterized in the brain. To determine if LIGHT expression was altered during cuprizone treatment, brain tissues were analyzed for LIGHT expression by RT-PCR. While LIGHT is found at high levels in the control spleen and thymus, extremely low to negligible levels were found in the brains of 30 untreated or cuprizone treated mice. In addition, LIGHT was not regulated by the presence of Lt3R as mice lacking LtpR express similar levels of LIGHT in the brain. 36 While not limited by any particular theory or mechanism, these data suggested that LIGHT does not play a significant role during cuprizone-induced inflammation. Example 3. Delayed demvelination in LtpR-/- mice 5 The presence of Ltct exacerbated demyelination induced by cuprizone treatment (Plant et al. (2005) Glia 49:1-14). Furthermore, the lack of Lta did not alter the course of remyelination nor the proliferation of oligodendrocyte progenitors following removal of cuprizone from the diet. Ltax can function as a homotrimeric molecule signaling through the TNF receptors, as well as a heterotrimeric molecule with LtP to 10 signal through the LtpR. While the role of TNF receptors in the cuprizone model has been previously analyzed (Arnett et al. (2001) Nat. Neurosci. 4:1116-1122), the role of LtpR in this model was unknown. To analyze the role of LtpR, mice lacking this gene and wild-type controls were treated with 0.2% cuprizone in their diet for 3, 3.5, 4 or 5 weeks. Compared to wild-type mice, a significant delay in demyelination was 15 exhibited by the Lt3R~ mice as assessed by LFB-PAS staining (FIG. 2). The LFB PAS stained paraffin sections were assessed by three double-blind investigators. Significant differences in demyelination were seen between wt and LtBR~'- mice at 3 weeks (p<O.0 2 ), 3.5 weeks (p<0.01) and 4 weeks (p<.00 1). While not limited by any particular theory or mechanism, these data indicated that signaling through LtPR 20 exacerbates the inflammatory demyelinating process. This delay could be seen as early as 3 weeks (p < .02) of cuprizone treatment but was most pronounced at 3.5 weeks (p < .01) and 4 weeks (p <.001) of treatment and is clearly revealed by representative LFB-PAS images of wild-type and LtpR~'~ mice at 4 weeks of treatment. The delay in 25 demyelination in LtpR-' mice was similar to the delay in demyelination seen in Lt-' mice (Plant et al. (2005) Glia 49:1-14), therefore, while not limited by any particular theory or mechanism, these data suggested that membrane bound Lta signaling through the LtR is involved in the demyelination process. 37 Example 4. Delayed remyelination in LUpR: mice The ability of mature oligodendrocytes to remyelinate the corpus callosum was studied in LFB-PAS stained paraffin sections from wild-type and Lt3R' mice. Modest, but significant, differences in remyelination were observed between wild-type 5 and LtpR'- mice at 7 (p <.001) and 10 weeks (p < .02) (FIG. 2). By 12 weeks, LtpR mice remyelinated to the same extent as wild-type controls (p = .11). These differences during remyelination were less than 0.5 on our scale of severity of demyelination whereas differences seen in studies of TNF(' vs wild-type mice were greater than 1.5 on the scale (Arnett et al. (2001) Nat. Neurosci. 4:1116-1122), and persisted up to 14 10 weeks. While not limited by any particular theory or mechanism, while remyelination appeared to be delayed in LtpR' mice, it eventually resolved. Example 5. Delayed oligodendrocyte loss in LtpRfi mice during demyelination To verify that the delay in demyelination observed by LFB-PAS was 15 accompanied by changes in oligodendrocytes, immunohistochemistry was performed to detect mature oligodendrocytes in paraffin sections adjacent to those used for LFB staining. GST-g+ was used as a marker for oligodendrocytes, and the cells at the midline corpus callosum were quantitated. In both wild-type and LipR-/- mice, abundant oligodendrocytes were detected in untreated mice. However, after 3 and 3.5 20 weeks of treatment, more oligodendrocytes were detected in LtpR' mice compared to wild-type mice (3.5 weeks; p < .0 1). No difference in oligodendrocyte numbers was found between wild-type and LtpR'- mice at 4 weeks. These data were similar to the LFB staining results, except for the 4 week time point, where LFB staining showed reduced demyelination in the LtpR* mice. In contrast, GSTh+ staining was not 25 different between Lt3R' and wildtype mice. While not limited by any particular theory or mechanism, the difference between GSTit+ and LFB staining likely resulted from a delay between the disappearance of GSTn+ cells and the actual loss of myelin. By 5 weeks of cuprizone treatment, few GST7c+ oligodendrocytes were detected in the corpus callosum of wild-type and LtpR' mice. While not limited by any particular 30 theory or mechanism, again, these data are consistent with the severe demyelination for both mouse strains. 38 Example 6. Unchanged oligodendrocyte repopulation of corpus callosum in LtpRV mice during the remvelination phase The involvement of Lt3R in the reparative remyelination process was explored 5 by examining paraffin sections at 7, 8, 10, and 12 weeks (1, 2, 4, and 6 weeks after the removal of cuprizone from the diet). To detect the presence of mature oligodendrocytes in the corpus callosum during the remyelination phase, immunohistochemistry using the GSTnr antibody was performed on paraffin sections from wild-type and LtpR'- mice, followed by the quantitation of GSTit positive cells. 10 As shown in FIG. 3, more GSTh+ cells were found in LtBR'- mice compared to wild type mice at 3 weeks (p = .09), significantly more GST7t+ cells were found in LtBR mice at 3.5 weeks (p < .03), and no differences in oligodendrocytes were found at 4 and 5 weeks of cuprizone treatment. After the removal of cuprizone, no differences in oligodendrocyte repopulation of the corpus callosum were observed between wild-type 15 and LtBR -mice. Thus, even though rare oligodendrocytes were detected in these brains at the height of demyelination (5 weeks), just one week after the removal of cuprizone (7 weeks), the corpus callosum was repopulated to approximately 75% of its original numbers of mature oligodendrocytes. By week 10, the number of mature oligodendrocytes residing in the corpus callosum recovered to pretreatment levels in 20 both wild-type and LtpR-' mice. While not limited by any particular theory or mechanism, these data indicated that LtpR was not required for oligodendrocyte progenitor proliferation and maturation during the remyelination phase. Example 7. Unaltered Microglia/Macrophage recruitment in LtpR+ mice 25 Cuprizone induces a chronic inflammatory state in the brain including the recruitment of activated microglia and macrophages to the sites of insult (Matsushima et al. (2001) Brain Pathol. 11:107-116). Paraffin sections from LtpR'- and wild-type mice were stained with the lectin RCA-1, and microglia/macrophages at midline corpus callosum were quantitated. As shown in FIG. 4, accumulation of 30 microglia/macrophages at the midline corpus callosum was unaffected by the presence of LtBR. No significant differences in numbers of RCA-1+ cells were observed at any time point during the demyelination or remyelination phases of this model. 39 Example 8. Inhibition of functional LtR reduces demyelination While not limited by any particular theory or mechanism, these studies suggested that LtpR had a dramatic exacerbating effect on demyelination, but a 5 potentially modest beneficial effect during remyelination. However, mice lacking LtPR from birth have significant developmental problems. For example, LtpR'- mice do not have mesenteric lymph nodes, Peyer's patches, and colon-associated lymphoid tissues and thus do not have a fully functioning immune system (Futterer et al. (1998) Immunity 9:59-70). In addition, it was known in the art that levels of chemokine and 10 cytokine synthesis are controlled by LtPR (Chin et al. (2003) Immuno. Rev. 195:190 201), but the full impact of LtpR control of chemokines and cytokines on the CNS is not known. Furthermore, natural killer cells in LtIR' mice do not have surface expression of the NKL.1 receptor due to the proximity of the encoding gene and the Ltbr gene (Wu et al. (2001) J. Immunol. 166:1684-1689). 15 Functional inhibition of Lt3R in wild-type mice was possible using a fusion decoy protein. To assess the validity of the aforementioned data in LtpR- mice, which demonstrated a detrimental role for LtpR during cuprizone-induced demyelination, C57BL6 mice were treated with either LtpR-Ig (human IgGi Fc, mouse LtPR) fusion decoy protein or polyclonal human IgG control during cuprizone treatment. Mice were 20 pretreated on day -1 and weekly thereafter with intraperitoneal injections (5mg/kg) and were maintained on an ad libitum diet of 0.2% cuprizone for 3.5 weeks. After 3.5 weeks, mice were perfused and paraffin brain sections were stained by the LFB-PAS method to assess the extent of demyelination at midline corpus callosum. Mice treated with human-Ig control were significantly more demyelinated than mice that received 25 the LtpR-Ig inhibitor decoy protein (p <.02) (FIG. 5). After 3.5 weeks, the average demyelination score of mice receiving control-Ig injections was very similar to wild type mice treated for 4 weeks with cuprizone, while the average demyelination score of mice receiving injections of LtpR-Ig were very similar to Lt R-- mice treated for 4 weeks with cuprizone. Immunohistochemistry for myelin basic protein (MBP) 30 confirmed the lack of myelinated fibers in mice treated with human-Ig control compared to LtPR-Ig treated mice. In conclusion, these results suggested that 40 demyelination in cuprizone-treated mice was significantly delayed by inhibition of the LtpR. Example 9. Inhibition of LtpR enhances remyelination 5 Next, the ability of the LtpR-IgG1 treatment to alter the extent of remyetination after significant demyelination had already occurred was examined. An advantage of the cuprizone model was the capacity to examine events that influence remyelination. To investigate the role of LtpR in the process of remyelination, C57BL6 mice were treated with 0.2% cuprizone for 6 weeks. This period of cuprizone treatment 10 reproducibly resulted in complete demyelination in all mice studied to date, including the wildtype C57BL6 mice (Arnett et al. (2001) Nat. Neurosci. 4:1116-1122 and Plant et al. (2005) Glia 49:1-14). After 5 weeks plus 2 days of cuprizone treatment, mice were injected with either mouse LtpR-IgG-1 or control mouseIgG-1. This was followed by the weekly injection of either mouse LtpR-IgGI or control mouse-IgG1 15 until week 10, when remyelination was clear. Due to the concern that human Fe might elicit an immune response in this prolonged experiment, a fusion protein consisting of m se LpR and mouse IgG1 Fc were used in this experiment. LFB stained sections were analyzed as above. Remarkably and surprisingly, mice treated with mLtpR mIgG1 showed significantly more remyelination (p < .007) than mice treated with the 20 control-mIgGI (FIG. 6). Additionally, immunohistochemistry for MBP confirmed a reduced remyelination in mice treated with human-Ig control compared to LtpR-Ig treated mice. To verify these data, the number of mature oligodendrocytes within the corpus callosum at 10 weeks was quantitated. GSTxt positive oligodendrocytes were more abundant in the corpus callosum of mLtpR-IgG 1 treated mice compared to 25 control mouse-Ig treated controls (p <.04). In conclusion, remyelination in cuprizone treated mice was significantly enhanced by post-treatment with an inhibitor of LtpR signaling. A number of embodiments of the invention have been described. Nevertheless, 30 it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims. 41

Claims (12)

1. A composition comprising a lymphotoxin-p receptor (LTjR)-Ig fusion protein comprising a portion of an LTPR extracellular domain and a portion of an immunoglobulin constant region, wherein the portion of the LTPR extracellular domain consists of amino acids 5 32 to 225 of SEQ ID NO: 2.

2. The composition of claim 1, wherein the portion of the immunoglobulin constant region consists of the amino acid sequence set forth in bold in SEQ ID NO: 1.

3. The composition of claim 1, wherein the portion of the LTPR extracellular domain and the portion of the immunoglobulin constant region are linked by an amino acid linker. lo

4. The composition of claim 3, wherein the linker consists of a valine residue.

5. The composition of claim 2, wherein the portion of the LTPR extracellular domain and the portion of the immunoglobulin constant region are linked by amino acid linker.

6. The composition of claim 5, wherein the linker consists of a valine residue.

7. The composition of claim 6, further comprising a pharmaceutically acceptable carrier. 15

8. The composition of claim 7, formulated for subcutaneous administration.

9. The composition of claim 7 or claim 8, for use in the treatment of multiple sclerosis.

10. Use of the composition of claim 7 or claim 8 in the manufacture of a medicament for the treatment of multiple sclerosis.

11. A method of treating multiple sclerosis comprising the administration of an effective 20 amount of the composition of claim 7 or claim 8. Date:

12 April 2013 42