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NIAID Plan for Research on Immune Tolerance

Part 3: Detailed Research Plan

B: Autoimmune Diseases

Efforts to induce tolerance in autoimmunity have focused primarily on the oral administration of antigens. Oral administration of both high-and-low dose antigen results in a phenomenon termed "oral tolerance" in which the immune response to subsequent systemic administration of antigen is blocked. Oral tolerance can be induced in animal models and is now being evaluated in human diseases. However, the encouraging responses in animal studies have not been duplicated in recent clinical trials of rheumatoid arthritis and multiple sclerosis. A clinical trial of oral insulin comprises one limb of the NIH-sponsored Type 1 Diabetes Prevention Trial (DPT-1). Results of this large clinical trial, which also includes low-dose parenteral insulin for at-risk nondiabetic relatives of individuals with type 1 diabetes mellitus, will not be available for several years. However, there are a number of promising tolerogenic approaches other than oral tolerance that can now be pursued in immune-mediated diabetes and other autoimmune diseases. These include: co-stimulatory blockade; anti-cytokine monoclonal antibodies; hematopoietic stem cell and bone marrow transplantation; and gene transfer-based therapies for cytokine modulation.

These approaches will require extensive collaborations among basic immunologists and clinical investigators from many specialties. Therefore, a major thrust of the research initiatives in this area focuses on the establishment of cooperative research programs capable of incorporating the basic science and clinical expertise necessary to accelerate progress.

The rationale for initiating pilot clinical trials is based on multiple factors. First, several mouse studies have indicated that co-stimulatory blockade (e.g., anti-CD40 ligand or CTLA4-Ig antibody treatment) can reverse experimental autoimmune disease. Second, very few non-human primate models of human autoimmune disease exist and the models that do exist have not proved useful for pre-clinical evaluation of therapeutic approaches. Finally, studies in humans are already underway under the sponsorship of several pharmaceutical and biotechnology companies.

Autoimmune Diseases: Specific Initiatives

  • Individual pilot clinical trials of the safety and potential efficacy of tolerogenic molecules/reagents.

  • Establishment of a Cooperative Clinical Trial Group for the study of immune tolerance in autoimmunity.

Autoimmune Diseases: Detailed Research Plan

Pilot Clinical Trials

Support for pilot clinical trials to evaluate the safety and potential efficacy of promising tolerogenic approaches will be the initial phase of development. Investigators are currently developing pilot clinical studies to delay disease progression for newly diagnosed type 1 diabetics and in diabetic patients refractory to standard therapy. In addition, industry and some individual investigators are targeting systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. Clinical trials underway include:

Company/Investigator Product Disease
Anergen AnervaX
rheumatoid arthritis
multiple sclerosis
Biogen anti-CD40L lupus nephritis
thrombocytopenic purpura
Bristol-Meyers Squibb CTLA4-Ig psoriasis
Jeffrey Bluestone anti-CD3 type 1 diabetes

Examples of the research being carried out at present include Biogen's ongoing work with anti-CD40 ligand antibody for the treatment of Idiopathic Thrombocytopenia Purpura (ITP) and lupus nephritis. ITP is a T cell-dependent, antibody-mediated autoimmune disease in which platelets are destroyed. Two-thirds of ITP patients are cured by splenectomy, but one-third are refractory to this aggressive treatment and remain chronically at risk for life-threatening hemorrhage, especially in the central nervous system. The rationale underlying this therapeutic approach is the ability of anti-CD40 ligand antibody to regulate T cell-dependent antibody production. In addition, the endpoints for therapeutic response are readily discernable, i.e., a rise in platelet counts and decreases in titers of anti-platelet antibodies and in the number of transfusions required. Research of this type offers the opportunity to: study mechanisms of disease amelioration; determine the effects of anti-CD40 ligand antibody on autoantibody production; and examine the potential application of this therapy for other T cell-dependent, antibody-mediated autoimmune diseases, such as systemic lupus erythematosus.

Biogen has promising preliminary results from studies of anti-CD40 ligand antibody in mice with lupus nephritis, also a T cell-dependent, autoantibody-mediated autoimmune disease. This treatment prevented the onset of disease and, in mice with advanced lupus nephritis, has produced a dramatic increase in survival and a decrease in proteinurea. In addition, the treatment has resulted in a partial reversal of the normally severe glomerular injury characteristic of this disease. Testing safety and potential efficacy in humans will be the next step in the development of this molecule and, if successful, could pave the way for its use to treat and prevent other complications of this disease, e.g., neurologic, rheumatologic and hematologic.

In other autoimmune diseases, interactions between antigen-presenting cells and T cells produce inflammatory molecules responsible for tissue, nerve and organ damage. One promising therapeutic approach involves interrupting or preventing these interactions. Two products, developed by Anergen Inc., are being evaluated in clinical trials of multiple sclerosis and rheumatoid arthiritis. AnergiX uses specific self-peptides, complexed with soluble Major Histocompatibility Complex (MHC) class II molecules, to stimulate disease-specific T cells in the absence of a co-stimulatory signal. As a result, specific T cells are inactivated and no longer produce inflammatory molecules. Pilot clinical trials are underway and preliminary results are promising.

The second product, AnervaX, is based on the same principle, but does not require knowing the identify of the disease-causing autoantigen. AnervaX exploits the strong MHC-linkage of many autoimmune diseases by vaccinating with an immunodominant epitope of the disease-linked MHC molecules to induce a host-immune response which blocks subsequent antigen presentation by those molecules to disease-causing autoreactive T cells. As a result, the T cell is not activated, no inflammatory mediators are produced, and disease is prevented. Phase II trials for rheumatoid arthritis are underway and appear promising.

NIAID Cooperative Clinical Trial of Immune Tolerance for Autoimmune Diseases

The NIAID Cooperative Clinical Tnamerial of Immune Tolerance for Autoimmune Diseases will design and conduct efficacy studies in type 1 diabetes, multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus, with all studies incorporating investigations of underlying mechanisms. A cooperative approach has many important strengths. The multi-site infrastructure will ensure that adequate numbers of patients are available for clinical trials. This is particularly important for the many autoimmune diseases which afflict only a small proportion of the population. In addition, such a network promotes the participation of multiple clinical specialties relevant for autoimmune disease and collaboration among clinical and basic scientists to further understanding of the underlying immune mechanisms. A cooperative research program will also enable the participation of multiple NIH Institutes with responsibility for research on specific autoimmune diseases and aid in bringing together the clinical investigators supported by other NIH components and the basic immunology community within NIAID's portfolio. As noted above, several pharmaceutical and biotechnology companies and individual investigators are already pursuing pre-clinical and clinical research on immune tolerance in autoimmunity and the potential for collaborative efforts is promising.

Current NIAID efforts to develop collaborations with companies for pilot clinical trials will lay the groundwork for cooperative, multi-site Phase II and III clinical trials using this infrastructure. In addition, the participation of other NIH Institutes will be encouraged and pursued.

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NIAID Archive

Important note: Information in this report was accurate at the time of publication. The state of the science may have evolved since the publication date. Formatting and links on this page are no longer being updated.

Last Updated September 29, 2010

Last Reviewed September 16, 2010