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.

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.

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.

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.

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.

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.

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.

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.

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 T frequency. The mechanism by which oral ACTH decreases inflammatory proteins and increases T cell frequencies is unknown.

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 ( = 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.

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.

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.

Ingested (oral) anti-IL-12/23 inhibits EAE.

Background: Blocking the activity of IL-12/23 can inhibit autoimmune diseases such as psoriasis.

Objective: We examined whether an antibody against IL-12/23, ustekinumab (UTZ) (Stelera®), used clinically in psoriasis 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 isotype IgG control or UTZ during ongoing disease.

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.

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.

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.

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.

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.

Ingested (oral) neuropeptide Y inhibits EAE.

Background: Ingested immunoactive proteins, type I IFN, SIRS peptide 1-21, α-MSH, ACTH, and 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, neuropeptide Y, 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 NPY during ongoing disease.

Oral ACTH (H.P. Acthar(®)Gel) inhibits IL-1 and IL-17 secretion in humans.

Objective: We have shown that oral corticotropin hormone (ACTH) decreased clinical score, inflammatory foci and T(eff) IL-17 in fed and adoptive transferred recipient mice with experimental autoimmune encephalomyelitis (EAE). Therefore, we determined whether oral administration of ACTH had immunological and endocrinological effects and was safe in humans.

Methods: Three groups of three healthy adult volunteers were assayed for total serum ACTH, cortisol and a set of pro-inflammatory and counter-regulatory cytokines after ingested dose(s) of ACTH 4 IU (n=3), 41 IU (n=3), or 123 IU (n=3) over 5 days.

Ingested (oral) SST inhibits EAE.

Background: Ingested immunoactive proteins type I interferon, soluble immune response suppressor peptide 1-21 and melanocyte-stimulating hormone inhibit clinical attacks and inflammation in acute experimental autoimmune encephalomyelitis (EAE).

Objective: We examined whether another immunoactive protein, somatostatin (SST), would have similar anti-inflammatory effects on EAE after oral administration.

Design/methods: B6 mice were immunized with MOG peptide 35-55 and gavaged with control saline or SST during ongoing disease.

Ingested (oral) ACTH inhibits EAE.

Ingested type I IFN and SIRS peptide inhibit EAE. We examined whether another immunoactive protein, ACTH, would have similar anti-inflammatory effects in EAE after oral administration. B6 mice were immunized and gavaged with control saline or ACTH starting on the onset of disease.

Ingested Type I Interferon-State of the Art as Treatment for Autoimmunity Part 2.

We have proposed a unifying hypothesis of the etiopathogenesis of autoimmunity that defines autoimmunity as a type I interferon (IFN) immunodeficiency syndrome. We have examined toxicity and potential efficacy in two phase I (type 1 diabetes [T1D], multiple sclerosis [MS]) and phase II clinical trials in T1D and MS. In a phase I open label trial in T1D, ingested IFN-alpha preserved residual beta-cell function in recent onset patients.

Effect of ingested interferon-alpha on beta-cell function in children with new-onset type 1 diabetes.

Objective: To evaluate the safety and efficacy of ingested human recombinant interferon-alpha (hrIFN-alpha) for preservation of beta-cell function in young patients with recent-onset type 1 diabetes.

Research Design And Methods: Subjects aged 3-25 years in whom type 1 diabetes was diagnosed within 6 weeks of enrollment were randomly assigned to receive ingested hrIFN-alpha at 5,000 or 30,000 units or placebo once daily for 1 year. The primary outcome was change in C-peptide secretion after a mixed meal.

Bio-equivalence of IM and SQ H.P. Acthar Gel.

Objective: IM Acthar Gel (Acthar) is a natural-source ACTH used for the treatment of MS exacerbations. It is not known if subcutaneous (SQ) administration of Acthar is equivalent to IM administration or if lower doses of Acthar would provide comparable serum cortisol responses.

Methods: We compared IM and SQ administration of Acthar to explore bio-equivalency between the two routes of administration.