Ingested (oral) rituximab inhibits EAE.

BACKGROUND: Blocking CD20 can inhibit autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA). OBJECTIVE: We examined whether an antibody against CD20, rituximab (RTX) (Rituxan®), used clinically in oncology, MS and RA would have similar anti-inflammatory effects in EAE after oral administration. DESIGN/METHODS: B6 mice were immunized with MOG peptide 35-55 and gavaged with control saline or RTX during ongoing disease. Splenocytes or CD4(+) T cells from control fed or RTX fed mice were adoptively transferred into active MOG peptide 35-55 immunized recipient mice during ongoing disease. Actively fed and recipient mice were examined for disease inhibition, inflammation, and cytokine responses. RESULTS: Ingested (oral) RTX inhibited ongoing disease and decreased inflammation. Adoptively transferred cells from RTX fed donors protected against actively induced disease and decreased inflammation. There was a decrease in Th1-like cytokines IFN-γ and IL-12, IL-17 and TNF-α in active fed and adoptively treated recipients without upregulation of counter-regulatory cytokines. CONCLUSIONS: Ingested (orally administered) RTX can inhibit disease, CNS inflammation, decrease pro-inflammatory IL-17 and Th1-like cytokines without increases in Th2-like anti-inflammatory cytokines.

Chronic cerebrospinal venous insufficiency: case-control neurosonography results.

OBJECTIVE: Chronic cerebrospinal venous insufficiency (CCSVI) has been implicated in the pathophysiology of multiple sclerosis (MS). We sought to determine whether neurosonography (NS) provides reliable information on cerebral venous outflow patterns specific to MS. METHODS: This was a single-center, prospective case-control study of volunteer MS and non-MS participants. A neurosonologist, blind to the subjects' diagnosis, used high-resolution B-mode imaging with color and spectral Doppler to systematically investigate, capture, and record extracranial and intracranial venous drainage. These neuroimaging results were evaluated and scored by an expert blinded to subjects' information and with no interactions with the participants. RESULTS: Altogether, 276 subjects were studied: 206 with MS and 70 non-MS. MS patients were older than non-MS subjects (48.3±9.9 vs 44.3±11.8 years, p<0.007), with durations from first symptoms and diagnosis of 13.7±10 and 9.9±7.8 years, and Expanded Disability Status Scale of 2.6±2.0. Overall, 82 subjects (29.7%) fulfilled 1 of 5 NS criteria proposed for CCSVI; 13 (4.7%) fulfilled 2 criteria required for diagnosis, and none fulfilled >2 criteria. The distribution of subjects with 0, 1, or 2 criteria did not differ significantly across all diagnostic groupings, between MS and non-MS subjects, or within MS subgroups. CCSVI was present in 7.14% of non-MS and 3.88% of MS patients (p=0.266). No significant differences emerged between MS and non-MS subjects for extracranial or intracranial venous flow rates. INTERPRETATION: NS findings described as CCSVI are much less prevalent than initially reported, and do not distinguish MS from other subjects. Our findings do not support the hypothesis that CCSVI is causally associated with MS.

Ingested (oral) tocilizumab inhibits EAE.

BACKGROUND: Blocking the activity of IL-6 can inhibit autoimmune diseases such as rheumatoid arthritis and Crohn's disease. OBJECTIVE: We examined whether an antibody against IL-6, tocilizumab (TCZ) (Actemra®), used clinically in rheumatoid arthritis (RA) would have similar anti-inflammatory effects in EAE after oral administration. DESIGN/METHOD: B6 mice were immunized with MOG peptide 35-55 and gavaged with control saline or TCZ during ongoing disease. Splenocytes, CD4(+) T cells or macrophages/monocyte lineage cells (CD11b(+)) from control fed or TCZ fed mice were adoptively transferred into active MOG peptide 35-55 immunized recipient mice during ongoing disease. Actively fed and recipient mice were examined for disease inhibition, inflammation, and cytokine responses. RESULTS: Ingested (oral) TCZ inhibited ongoing disease and decreased inflammation. Adoptively transferred cells from TCZ fed donors protected against actively induced disease and decreased inflammation. There was a decrease in IL-6 in actively treated spleen, decrease in TNF-α, Th1-like cytokine IL-12 and increase in Th2-like cytokine IL-10 in active fed and adoptively treated recipients. CONCLUSIONS: Ingested (orally administered) TCZ can inhibit disease, CNS inflammation, decrease pro-inflammatory Th1-like cytokines and increase Th2-like anti-inflammatory cytokines.

Contrast enhanced MR venography with gadofosveset trisodium: evaluation of the intracranial and extracranial venous system.

PURPOSE: To demonstrate the efficacy of contrast enhanced magnetic resonance venography (CEMRV) using gadofosveset trisodium in the comprehensive evaluation of the intracranial and extracranial venous system. MATERIALS AND METHODS: Temporal signal decay, in-plane saturation and flow artifacts were assessed in an institutional review board approved, HIPAA compliant CEMRV study of 99 subjects. In a 39 subject subset, percent diameter narrowing of the internal jugular (IJ), brachiocephalic and azygous veins were coded according to the following ordinal grades for both catheter venography (CV) and CEMRV: grade 0 ≤ 50%, grade 1 >50% and ≤ 75%, grade 2 >75% and <100% and grade 3 = 100% and compared with pressure gradient measurements obtained during CV. RESULTS: There was no significant signal decay, in-plane saturation or flow artifacts identified on CEMRV or hemodynamically significant pressure gradients identified on CV. All brachiocephalic and azygous veins had matched grade 0 narrowing on both modalities. Discrepancy between modalities occurred in the IJ veins at the level of thyroid gland where 15% of IJ veins had CEMRV grade ≥ 1 narrowing compared with 4% for CV or below the thyroid gland where 5% of IJ veins had CEMRV grade ≥ 1 narrowing compared with 20% for CV. There was fair agreement (κ = 0.24) between modalities for grade of narrowing in the combined data set of all coded veins. CONCLUSION: CEMRV using gadofosveset trisodium is accurate in the evaluation of the venous system.

Ingested (oral) adrenocorticotropic hormone (ACTH) inhibits interleukin-17 in the central nervous system after adoptive transfer of T helper (Th)1/Th17 T cells in the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis.

BACKGROUND: Experimental autoimmune encephalomyelitis (EAE) is an inflammatory autoimmune disease of the central nervous system (CNS) that resembles multiple sclerosis (MS) and provides a useful animal model for the evaluation of mechanisms of action for potential immunomodulatory therapies. We have previously shown that oral adrenocorticotropic hormone (ACTH) decreased either interleukin (IL)-17 and/or interferon (IFN)γ in the CNS during EAE. OBJECTIVE: We wanted to examine whether oral ACTH showed a preferential effect on Th17 as opposed to Th1 phenotypes. DESIGN/METHODS: We therefore examined whether oral ACTH could inhibit EAE in the C57BL/6 (B6) mouse strain after adoptive transfer of equal quantities of Th17 (CD4+IL-17+) and Th1 (CD4+IFN-γ+) T cells generated after in vitro skewing. B6 mice were injected with a 1:1 ratio of Th1:Th17 T cells and were gavaged daily with control scrambled peptide (s-MSH) or 10 µg ACTH. RESULTS: Ingested (oral) ACTH attenuated ongoing clinical EAE disease and decreased the frequencies of Th17 cells in the spleen and in the CNS, but not Th1. CONCLUSIONS: These findings suggest that there was preferential regulation of Th17 cells by oral ACTH compared to Th1 T cells in the CNS.

Ingested (oral) thyrotropin releasing factor (TRH) inhibits EAE.

BACKGROUND: Ingested immunoactive proteins type I IFN, SIRS peptide 1-21, α-MSH, ACTH, SST inhibit clinical attacks and inflammation in acute EAE by decreasing Th1-like cytokines, increasing Th2-like cytokines or increasing T(reg) cell frequencies. OBJECTIVE: We examined whether another protein, thyrotropin releasing factor (TRH), would have similar anti-inflammatory effects in EAE after oral administration. DESIGN/METHODS: B6 mice were immunized with MOG peptide 35-55 and gavaged with control saline or TRH during ongoing disease. Splenocytes from mock fed or TRH fed mice were adoptively transferred into active MOG peptide 35-55 immunized recipient mice during ongoing disease. RESULTS: Ingested (oral) TRH inhibited ongoing disease and decreased inflammation. Adoptively transferred cells from TRH fed donors protected against actively induced disease and decreased inflammation. In actively fed mice, oral TRH decreased IL-17 and TNF-α cytokines in both the spleen and the CNS. In recipients of donor cells from TRH fed mice there was a reduction of Th1 and Th17 and induction of Th2-like IL-13 cytokines in both the spleen and CNS. Oral TRH decreased clinical score and decreased inflammatory foci in both actively fed and recipients of actively fed mice. There was no significant increase in T(reg) cell frequencies in actively fed or recipients of TRH fed donor cells. CONCLUSIONS: Ingested (orally administered) TRH can inhibit clinical disease, inhibit CNS inflammation by decreasing Th1-like, Th17 and TNF-α cytokines and increasing Th2-like cytokines (IL-13) in the CNS.

Chronic cerebrospinal venous insufficiency: masked multimodal imaging assessment.

BACKGROUND: Chronic cerebrospinal venous insufficiency (CCSVI) was implicated in the pathophysiology of multiple sclerosis (MS). OBJECTIVE: We evaluated neurosonography (NS), magnetic resonance venography (MRV), and transluminal venography (TLV) in subsets of MS patients drawn from a single-center, prospective, case-control study of 206 MS and 70 non-MS volunteers. METHODS: As previously reported, findings on high-resolution B-mode NS imaging with color and spectral Doppler of the extracranial and intracranial venous drainage consistent with CCSVI were similar among MS and non-MS volunteers (3.88% vs 7.14%; p = 0.266). Ninety-nine MS participants consented to intravascular contrast-enhanced 3D MRV to assess their major systemic and intracranial venous circulation, and 40 advanced to TLV that included pressure measurements of the superior vena cava, internal jugular, brachiocephalic, and azygous veins. RESULTS: NS findings and MRV patterns were discrepant for 26/98 evaluable subjects, including four with abnormal findings on NS that had normal venous anatomy by MRV. In no instance were TLV pressure gradients indicative of clinically significant functional stenosis encountered. The three imaging approaches provided generally consistent data with discrepancies referable to inherent technique properties. CONCLUSIONS: Our findings lend no support for altered venous outflow dynamics as common among MS patients, nor do they likely contribute to the disease process.

A proposal: How to study pro-myelinating proteins in MS.

Multiple sclerosis (MS) is an inflammatory and degenerative disease of the CNS. An unmet need in MS is repair i.e.,promoting endogenous regeneration and remyelination after demyelinating inflammatory injury. Remyelination is critical in neuronal preservation and the prevention of clinical progression. There is a good deal of evidence for histological repair and remyelination in MS patients. Repair is driven by several prominent endogenous pro-myelinating proteinsincluding neural cellular adhesion molecule (N-CAM) and brain derived neurotrophic factor (BDNF) among others. To follow changes during acute re-myelination in vivo in MS subjects, non conventional MRI techniques are necessary such as quantitative susceptibility mapping (QSM) that detects the release of Fe from dying oligodendroglial cells and myelin water imaging (MWI) that detects water captured within newly formed myelin. The best time to monitor changes in pro-myelinating proteins and link those changes to imaging evolution is immediately after the acute inflammatory response in MS lesions (gadolinium enhancement [Gd+]) during an intense period of remyelination. We can monitor MS subjects with new Gd + lesions with periodic imaging along with sampling of blood and CSF and determine if myelin formation is linked with increases in pro-myelinating proteins. This would lead to potential therapeutic manipulation with directly administered proteins to promote CNS re-myelination in animal models and in early clinical trials.

Anti-Inflammatory Agents: An Approach to Prevent Cognitive Decline in Alzheimer's Disease.

Systemic inflammation is an organism's response to an assault by the non-self. However, that inflammation may predispose humans to illnesses targeted to organs, including Alzheimer's disease (AD). Lesions in AD have pro-inflammatory cytokines and activated microglial/monocyte/macrophage cells. Up to this point, clinical trials using anti-amyloid monoclonal antibodies have not shown success. Maybe it is time to look elsewhere by combating inflammation. Neuroinflammation with CNS cellular activation and excessive expression of immune cytokines is suspected as the "principal culprit" in the higher risk for sporadic AD. Microglia, the resident immune cell of the CNS, perivascular myeloid cells, and activated macrophages produce IL-1, IL-6 at higher levels in patients with AD. Anti-inflammatory measures that target cellular/cytokine-mediated damage provide a rational therapeutic strategy. We propose a clinical trial using oral type 1 IFNs to act as such an agent; one that decreases IL-1 and IL-6 secretion by activating lamina propria lymphocytes in the gut associated lymphoid tissue with subsequent migration to the brain undergoing inflammatory responses. A clinical trial would be double-blind, parallel 1-year clinical trial randomized 1 : 1 oral active type 1 IFN versus best medical therapy to determine whether ingested type I IFN would decrease the rate of cognitive decline in mild cognitive impairment or mild AD. Using cognitive psychometrics, imaging, and fluid biomarkers (MxA for effective type I IFN activity beyond the gut), we can determine if oral type I IFN can prevent cognitive decline in AD.

The genealogy, methodology, similarities and differences of immune reconstitution therapies for multiple sclerosis and neuromyelitis optica.

Immune reconstitution therapies (IRTs) are a type of short course procedure or pharmaceutical agent within the MS pharmacopeia. They emanate from oncology and induce transient incomplete lympho-ablation with or without myelo-ablation, resulting in potential prolonged immunomodulation. Thus, they provide significant prophylaxis from disease activity without retreatment. Modern IRT for autoimmunity encompasses a heterogeneous group of pulsed lympho- and non-myelo-ablative treatments designed to re-boot the adaptive immune system in a quasi-permanent manner - a re-induction of ontogeny. IRT is the extensive debulking of an auto-aggressive immune system to attempt to reach the Holy Grail of immune tolerance. This incomplete yet significant lympho-ablation induces lymphoproliferation, reduces pathogenic clonal cells, causes thymopoiesis and results in the induction of immune tolerance. Lympho-ablation with immune reconstitution can result in minimal residual autoimmunity. There is a resetting of the immune thermostat - i.e., the immunostat. IRTs have the potential to provide prolonged periods of disease inactivity without retreatment in part through the immunological results of their pulsatile lymphocyte depletion. It is vital to increase our understanding of how IRTs alter a patient's immune response to the antigenic target of the disease so that we can devise newer, more durable and safer forms of such agents. What common features do extant IRTs (i.e., stem cell transplant, alemtuzumab and oral cladribine) have to produce the durable therapeutic response without long term treatment in neuroimmunological diseases such as MS (multiple sclerosis) and NMOSD (neuromyelitis optica spectrum disorders)? Can we learn from these critical features to predict what other maneuvers or agents might effect similar clinical results with equal or greater efficacy and safety?

Ingested (Oral) Adrenocorticotropic Hormone Inhibits IL-17 in the Central Nervous System in the Mouse Model of Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory autoimmune disease of the CNS that resembles multiple sclerosis and provides a useful animal model for the evaluation of mechanisms of action for potential immunomodulatory therapies. We have previously shown that oral adrenocorticotropic hormone (ACTH) decreased IL-17 in the gut lamina propria and the spleen and increased CD4+ Foxp3+ T regulatory cells and IL-10 in the spleen during EAE in the C57BL/6 mouse. However, we did not investigate the specific cellular alterations of proinflammatory and anti-inflammatory factors in the CNS. The aim was to determine if oral ACTH would have a similar clinical effect on inflammatory cytokines in the gut and define specific cellular effects in the CNS in an alternative strain of mice. SJL/J mice were immunized with proteolipid protein peptide 138-151 and gavaged with scrambled ACTH (scrambled α-melanocyte-stimulating hormone) or ACTH 1-39 during ongoing disease. Ingested (oral) ACTH attenuated ongoing clinical EAE disease, decreased IL-6 production, and increased T regulatory cells in the lamina propria and decreased CD4+ and γδ IL-17 production in the CNS. Ingested ACTH attenuated EAE clinical disease by decreasing IL-6 in the gut-associated lymphoid tissue and decreasing IL-17 in the CNS.

Immune reconstitution therapy in NMOSD.

IMPORTANCE: NMO spectrum disorders [NMOSD] is a relapsing autoimmune disorder with attacks of optic neuritis (ON) and transverse myelitis (TM). A large proportion of NMOSD patients have no or a partial recovery after relapse. OBSERVATIONS: The neuro-immunological community now has a number of indicated agents for NMOSD therapy including eculizumab [Soliris®], inebilizumab (Uplizna®) and satralizumab (Enspryng®) with different mechanisms of action (MOA), rapidity of the onset of action (OOA) and issues of long-term safety. Autologous hematopoietic stem cell transplantation (AHSCT) may be another therapeutic option. CONCLUSIONS AND RELEVANCE: The advantages of eculizumab are preservation of immunosurveillance, immediate onset of action and persistent efficacy but frequent IV administration and cost are important drawbacks. Inebilizumab allows a slight decrease in relapse free subjects over time but decreases B and plasmablast cell disease-inducing pathogenic antibody production. However, inebilizumab may cause immunosuppression. Satralizumab is immunomodulatory and self-administration but has delayed onset of action. AHSCT may be the best therapeutic option for the prevention and therefore the progression of NMO. In NMO, control the complement (eculizumab), reconstitute the immune system (AHSCT), transition to immunomodulation (satralizumab) and reserve immunosuppression (inebilizumab) as 4th line. AHSCT might also be used as rescue therapy for severe breakthrough disease after NMO-DMTs.

Review of approved NMO therapies based on mechanism of action, efficacy and long-term effects.

IMPORTANCE: Neuromyelitis optica (NMO - including NMO spectrum disorders [NMOSD]) is a devastating disease. Eighty-three percent of patients with transverse myelitic (TM) attacks and 67% of patients with optic neuritis (ON) attacks have no or a partial recovery. OBSERVATIONS: Up until recently, there was no proven agent to treat to prevent relapses. The neuro-immunological community had a dearth of indicated agents for NMOSD. We now have three agents indicated for the treatment of NMO including (eculizumab [Soliris®]), an anti-C5 complement inhibitor, satralizumab (ENSRYNG®), a monoclonal antibody against the IL-6 receptor (IL-6R) that blocks B cell antibody production and inebilizumab (Uplinza®), a monoclonal antibody that binds to the B-cell surface antigen CD19 with subsequent B and plasmablast cell lymphocytolysis with decreasing antibody production. Autologous hematopoietic stem cell bone marrow transplantation (AHSCBMT) has also been used. How do we sequence NMO therapies with the understanding of the acuteness and severity of the disease, the individual mechanism of action (MOA) and rapidity of onset of action, onset of efficacy and long-term safety of each agent? CONCLUSIONS AND RELEVANCE: We might suggest the following sequence - 1st line using eculizumab for rapid efficacy and stabilization without effect on the acquired immune system followed by satrilizumab (long term immunomodulation). Reserve inebilizumab (immunosuppressant) for breakthrough disease and salvage the severe with AHSCBMT. In NMO, control the complement, transition to modulation, and reserve suppression - and salvage the severe with AHSCBMT.

In MS: Immunosuppression is passé.

IMPORTANCE: Prolonged and significant alterations of the immune system by immunosuppression makes multiple sclerosis (MS) patients susceptible to opportunistic infections and malignancies over long periods of treatment. OBSERVATIONS: A reasonable clinical and practical definition of immunosuppression is a temporary or permanent alteration of the body's immune system and subsequent lack of ability to fight infections and malignancies. Immunosurveillance is the sine qua non of the immune system. Immunosurveillance is the constant process by which the immune system looks for and recognizes foreign pathogens such as bacteria and viruses or pre-cancerous or cancerous cells in the body. Immunomodulation (a decrease or increase in pitch or tone - in this case a decrease) maintains immunosurveillance. Immunosuppression (quashing, stamping out) impedes immunosurveillance by one mechanism or another. Immunosuppressive agents need to be administered continually in order to maintain effectiveness. In contrast, immune reconstitution therapies (IRTs) are short course agents that are initially immunosuppressive but ultimately immunomodulatory and can provide significant decreased disease activity over time without retreatment. CONCLUSIONS AND RELEVANCE: The goal of disease modifying therapies in MS is effectiveness over long periods of time with minimal risk. The preservation, reduction or elimination of immunosurveillance should be an important consideration in deciding on the optimal disease modifying treatments (DMT) for an individual MS patient. IRTs have the advantage of providing long term control of disease activity with short term immunosuppression followed by long term immunomodulation without retreatment. For most MS patients with mild or modest disease activity, initial immunomodulation followed by IRT for breakthrough disease may be the best option. In MS, immunosuppression may be passé.

Ingested ACTH blocks Th17 production by inhibiting GALT IL-6.

BACKGROUND: EAE is an inflammatory autoimmune process of the CNS that resembles multiple sclerosis (MS) and provides a useful animal model for the evaluation of mechanisms of action for potential immunomodulatory therapies. Oral ACTH (adrenocorticotropic hormone) can decrease clinical disease, IL-17 and Th1-like encephalitogenic IFN-γ secretion and increase Treg frequency. The mechanism by which oral ACTH decreases inflammatory proteins and increases Treg cell frequencies is unknown. OBJECTIVE: IL-6 is a pivotal cytokine in the gut that determines the relative frequencies of Th17 vs Treg cells. We examined whether oral ACTH inhibited IL-6 in the gut associated lymphoid tissue (GALT) in EAE. DESIGN/METHODS: B6 mice were immunized with MOG peptide 35-55 and gavaged with scrambled ACTH (scrambled melanocyte stimulating hormone [scrambled α-MSH]) or ACTH 1-39 during ongoing disease. RESULTS: Ingested (oral) ACTH inhibited ongoing clinical disease. In the lamina propria (LP) immune compartment, there were significantly less CD11b + IL-6 and IL-17 producing lymphocytes from ACTH fed mice compared to s-MSH fed mice. There was also a decrease in the frequency of IL-17 and IFN-γ producing spleen cells and an increase in CD4 + FoxP3+ Treg cell frequency in ACTH fed mice compared to s-MSH fed control spleens. There were less IFN-γ producing CNS lymphocytes in ACTH fed mice compared to s-MSH fed control CNS. CONCLUSIONS: Ingested ACTH inhibits EAE clinical disease by inhibiting IL-6 in the GALT.

Myelinating Proteins in MS Are Linked to Volumetric Brain MRI Changes.

BACKGROUND AND PURPOSE: There is evidence of a relationship between promyelinating proteins and clinical multiple sclerosis (MS) activity during clinical relapse or recovery from clinical relapses. We examined the linkage between promyelinating biomarkers and volumetric changes in MS subjects during serial magnetic resonance imaging (MRI). METHODS: We enrolled 13 MS subjects with active brain MRI scans not on disease modifying therapies. Subjects underwent baseline MRI, serum, and cerebrospinal fluid (CSF) sampling. Qualitative changes, new/resolving gadolinium, new/enlarging/diminishing T2 and T1 hypointense lesions, were compared to baseline in subsequent MRI scans, and volumetric analysis was calculated. Analysis of biomarkers on serial CSF samples was performed only in subjects with qualitative (and quantitative) changes on MRI. The study was performed at a MS Center of Excellence academic medical center. RESULTS: There was increased CSF neural cell adhesion molecule (N-CAM) during increased qualitative T1 activity. A positive correlation between CSF and serum N-CAM and T1 lesion volume was observed. A negative correlation between serum brain-derived neurotrophic factor (BDNF) and BPH (T1 vol/T2 vol + T1 vol) was observed. CONCLUSIONS: Increased N-CAM levels may be related to repair or remyelination following injury to the brain as shown by increased T1 volumes. Our data suggest an early kind of blood signaling that induces release of peripheral BDNF levels.

Tumefactive demyelination: Clinical outcomes, lesion evolution and treatments.

OBJECTIVE: Large demyelinating lesions with possible mass effect (tumefactive multiple sclerosis or tumefactive demyelination) can be mistaken for tumour-like space-occupying lesions suggesting a malignant outcome. METHODS: We reviewed our own experience of multiple sclerosis subjects (n = 28) with tumefactive demyelination to determine the relationship between clinical outcomes and lesion evolution, clinical outcomes and their relationship to different therapies. Patients with central nervous system demyelinating disease were identified from our database over the last 10 years. RESULTS: No patient increased in extended disability status scale (EDSS). Overall, lesion regression was associated with improved EDSS. Lesion regression was also associated with therapy versus no therapy. No specific therapy or corticosteroid infusions improved EDSS over the long term. The absence of enhancement on follow up on magnetic resonance imaging portended lesion regression. CONCLUSION: Tumefactive demyelination may predict a more benign overall course and is susceptible to traditional immunomodulatory treatments.

Ingested (oral) SIRS peptide 1-21 suppresses type 1 diabetes in NOD mice.

Type 1 diabetes (T1D) is a chronic disorder that results from autoimmune destruction of the insulin-producing pancreatic beta cell. The nonobese diabetic (NOD) mouse is a model of the human autoimmune disease T1D. Soluble immune response suppressor (SIRS) is a nonspecific protein suppressor of immune response produced by immunomodulatory T cells stimulated by type I interferon (IFN). SIRS inhibits antibody responses in vivo, lipopolysaccharide (LPS)-induced fever, and delayed-type hypersensitivity (DTH) responses. Previous investigators have isolated the N-terminal sequence of SIRS protein consisting of 21 amino acids. Mice ingesting 1 microg SIRS peptide 1-21 showed significant delayed onset of T1D and a decreased frequency of T1D compared with mock-fed and 10-microg-fed mice and a significant decrease in islet inflammation. There were significant decreases in islet lymphocyte chemokine production of granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage inflammatory protein-1 gamma (MIP-1 gamma), regulated upon activation, normal T cell-expressed, and presumably secreted (RANTES), and stromal cell-derived factor-1 (SDF-1) in the SIRS-fed mice, factors important in migration of inflammatory cell into the islets. Ingested (oral) SIRS peptide inhibits clinical T1D by decreasing target organ cellular migration of islet destructive populations by suppression of islet lymphocyte chemokine secretion.

Ingested (oral) alpha-MSH inhibits acute EAE.

Ingested type I IFN and SIRS peptide administered orally inhibit EAE. We examined whether another immunoactive protein, tridecapeptide alpha-MSH, would have similar anti-inflammatory effects in EAE after oral administration. B6 mice were immunized with MOG peptide 35-55 and gavaged with 0.1 ml of control saline or alpha-MSH peptide starting on day -7 preceding active immunization, and continuing through day +14 post-immunization. Alpha-MSH peptide delayed disease onset and decreased inflammatory foci. CNS lymphocytes showed decreases in Th1-like encephalitogenic cytokines IL-2 and IL12p70 in the alpha-MSH fed group compared to the mock fed group. For Th2-like counter-regulatory cytokines, there were increases in peripheral SDF-1 levels comparing alpha-MSH fed vs mock fed groups. There were decreases of chemokines MIP-1-alpha and MIP-1-gamma in the CNS comparing alpha-MSH fed mice vs mock fed mice. Ingested (orally administered) alpha-MSH peptide can reduce clinical disease and inhibit CNS inflammation by decreasing migration of antigen driven CNS Th1 cells into the target organ.

Ingested (oral) SIRS peptide 1-21 inhibits acute EAE by inducing Th2-like cytokines.

OBJECTIVE: Ingested type I IFN inhibits clinical attacks, relapses and inflammation in murine chronic relapsing EAE by inhibiting Th1-like cytokines. Type I IFN activates human suppressor T cells that produce SIRS. METHODS: We examined whether oral (ingested) SIRS peptide inhibits EAE by decreasing Th1-like cytokines. RESULTS: Parenteral SIRS peptide 1-21 showed a significant inhibition of disease severity in murine EAE. Ingested SIRS peptide at 10 and 100 microg SIRS peptide showed a significant inhibition of disease severity but also a prolonged delay in the onset of disease compared to placebo. There were significantly less inflammatory foci in the SIRS peptide fed group compared to the control mock fed group. Splenocytes from SIRS peptide 1-21 fed mice showed increased production of Th2-like CD30L, IL-13, TCA-3 cytokines/chemokines and decreased production of Th1-like cytokine lymphotactin. INTERPRETATION: Ingested (oral) SIRS peptide significantly inhibits both clinical EAE and inflammation predominately via counter-regulatory type 2-like cytokines/chemokines IL-13, CD30L and TCA-3.