Immune Tolerance in Autoimmune Disease

Autoimmune diseases occur when the immune system mistakenly flags certain cells in the body as foreign invaders. The resulting attack can cause irreparable damage to critical organs and tissues. For example, in multiple sclerosis, it’s the myelin coating that insulates nerve cells; in lupus, it can be any number of organs or systems that are damaged. Currently, many of the primary methods to treat patients with autoimmune disease utilize immune suppressors, which help reduce the inflammatory attack on tissues but can put patients at higher risk for developing infections.

Immune tolerance therapies are designed to stop, or even prevent, the autoimmune disease while leaving the body's disease-fighting abilities intact. These tolerance therapies essentially reprogram the immune system, so that a short course of treatment will have long-lasting, perhaps lifelong effects. While immune tolerance therapies are mainly experimental, the Immune Tolerance Network (ITN) believes that targeted reprogramming of the immune system holds a great deal of promise to effectively treat autoimmune diseases with fewer side effects than current drugs.

Research Focus - Autoimmune Disease

The clinical heterogeneity of the more than 80 autoimmune diseases presents a significant challenge with respect to the development of therapies designed to re-establish self-tolerance. The ITN’s approach to tolerance in autoimmune diseases attempts to address these challenges through a coordinated program of clinical studies aimed at establishing proof-of-principle either in diseases where a self-antigen has been identified, the target organ is accessible for further study or the disease pathogenesis has been relatively well established.

Given the complex nature of these diseases, and following the approaches being developed in the transplant and allergy portfolios, the ITN builds on results from ongoing trials by developing combination approaches affecting humoral and cellular, as well as adaptive and innate, immune responses. This includes combinations that ablate or anergize effector responses, deviate induced responses and boost regulatory responses. Because combination therapy trials can be logistically and scientifically challenging, the ITN has adopted the use of smaller, mechanistically-based studies as a first step in evaluating promising combinations and establishing a mechanistic plan that will inform on the pathways of tolerance.

Clinical Trials - Autoimmune Disease

Active

Efficacy of Ustekinumab followed by Abatacept for the Treatment of Psoriasis Vulgaris (PAUSE)

Principal Investigator:
James Krueger, MD, PhD , Rockefeller University , New York, NY

PAUSE is a clinical trial testing the effectiveness of ustekinumab (STELARA ®) followed by an investigational drug, abatacept, for the treatment of psoriasis. The main goal of the study is to determine the efficacy of abatacept to induce prolonged remission.

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A Cooperative Clinical Study of Abatacept in Multiple Sclerosis (ACCLAIM)

Principal Investigator:
Samia Khoury, Harvard Medical School, Boston, MA

ACCLAIM is a Phase II clinical research trial of the safety and efficacy of abatacept in adults with relapsing-remitting multiple sclerosis (RRMS). The study is testing whether abatacept works differently from most other MS treatments, as it is more specific in the immune cells that it targets.

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High Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT-MS)

Principal Investigator:
Richard A. Nash, Fred Hutchinson Cancer Research Center, Seattle, WA

The HALT-MS study is investigating an experimental treatment of intensive immunosuppression followed by a transplant of the participant’s own stem cells, to see whether it can stabilize multiple sclerosis. Bone marrow CD34+ stem cells are collected from the participant, and transplanted back into the body following treatment with high doses of chemotherapy drugs. This study is for individuals with relapsing-remitting or progressive-relapsing MS, who have experienced relapses while on other MS treatments.

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Abatacept and Cyclophosphamide Combination Therapy for Lupus Nephritis (ACCESS)

Principal Investigator:
David Wofsy, University of California, San Francisco, CA

Betty Diamond, Feinstein Institute, Manhasset, NY

This study is for people with systemic lupus who have developed complications in their kidneys, called 'lupus nephritis.' The study will determine whether adding the experimental medication abatacept to standard cyclophosphamide therapy is more effective in improving lupus nephritis than standard cyclophosphamide therapy by itself.

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Completed

A Study to Determine the Immunogenicity and Oral Tolerance to Keyhole Limpet Hemocyanin (KLH) (TAKE)

Principal Investigator:
Lloyd Mayer, MD, Mount Sinai Medical Center, New York, NY

The purpose of this study is to determine whether Immucothel, a Keyhole Lymphocyte Antigen (KLH) product, can trigger an immune response when ingested orally and create "oral tolerance" to KLH. If not, Immucothel will be tested with another agent to enhance the immune response.

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Mechanistic Studies in a Phase II Trial of Multiple Sclerosis with Altered Peptide Ligand (APL)

Principal Investigator:
Jack Antel, Montreal Neurological Institute, Montreal, Quebec, Canada

This study aims to evaluate the safety and tolerability of a 5 mg dose of the study drug, NBI-5788, for treatment of relapsing-remitting multiple sclerosis patients. A prior phase 2 trial conducted with this drug demonstrated suggestive evidence of treatment benefit with a 5 mg dose of NBI-5788.

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Monitoring of CMV-specific T-cells following tolerance induction protocols: A safety approach

Principal Investigator:
Florian Kern, Institut für Medizinische Immunologie, Berlin, Germany

This study seeks to optimize and standardize an existing assay which allows the T-cell response directed against in transplant recipients who undergo immune tolerance induction. This study employs a rapid laboratory test that would enable the transplant physicians to look at the patient's immune response to this model virus.

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Follow-up of individual T cell mobilization through TCR integration

Principal Investigator:
Jean Paul Soullilou, Institute de Transplantation, Nantes, France

This trial investigates the landscape of blood T lymphocytes in patients with active forms of multiple sclerosis. The goal of the study is to demonstrate T cell receptor (TCR) patterns that are specific for disease activity at the patient level and then to use this “TCR signature” to follow regulation of auto reactive T cells, particularly during tolerance induction.

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Treatment of Psoriatic Arthritis with hOKT3γ(Ala-Ala): Psoriatic Arthritis Research Trial (PART)

Principal Investigator:
Marcus Clark, University of Chicago, Chicago, IL

hOKT3gamma1 (Ala-Ala) is a man-made antibody that is commonly used to prevent organ rejection. The purpose of this study is to determine whether hOKT3gamma1 (Ala-Ala) is safe and effective in psoriatic arthritis patients who are unable to control their arthritis with methotrexate or azathioprine.

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Rituximab for the Treatment of Wegener's Granulomatosis and Microscopic Polyangiitis (RAVE)

Principal Investigator:
John H. Stone, Johns Hopkins University

Ulrich Specks, Mayo Clinic

Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis is the most common type of small blood vessel inflammation in adults. ANCA-associated vasculitis includes Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA). Rituximab is a man-made antibody used to treat certain types of cancer. The purpose of this study is to determine the effectiveness of rituximab in treating adults with WG and MPA.

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Atorvastatin (Lipitor) Therapy in Patients With Clinically Isolated Syndrome (CIS) at Risk for Multiple Sclerosis (STAYCIS)

Principal Investigator:
Scott Zamvil, University of California, San Francisco, CA

Patients who have been diagnosed with clinically isolated syndrome (CIS) often develop problems related to the central nervous system, which controls the nerves in the body. Some of these patients may later be diagnosed with multiple sclerosis (MS), a progressive disease of the nervous system. The purpose of this study is to determine if the drug atorvastatin is helpful to CIS patients.

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A Phase I Study: Safety of RG2077 (CTLA4-IgG4m) in Patients With Relapsing-Remitting Multiple Sclerosis

Principal Investigator:
Samia Khoury, Brigham & Women's Hospital, Boston, MA

Multiple sclerosis (MS) is an autoimmune disorder. In this disease, the body's immune system attacks and destroys the cells that cover and protect nerves. This study will test the safety of a new drug called RG2077 that is designed to treat MS. The study will not determine whether RG2077 is effective in treating MS, only whether it is safe to use in patients with MS.

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