There now exist numerous opportunities for replacing global immunosuppression with selective, tolerance therapies for autoimmune diseases such as type 1 diabetes, rheumatoid arthritis, multiple sclerosis, lupus erythematosus, and others. Agents currently in development include monoclonal antibodies or antagonists against the major histocompatibility complex, the T cell receptor and autoantigen. Additional targets include costimulatory signals and various cytokines or chemokines and their receptors.

1) ALTERING TCR SIGNALLING

a) Antigen-non-specific approaches

Initial trials using anti-T cell mAbs will be entertained, to determine 1) if non-depleting dosages of newer antibodies can alter surrogate markers of disease progression, and 2) if anti-T cell antibodies can synergize with therapies that block co-stimulation or that neutralize pro-inflammatory cytokines.

b) Antigen-specific approaches

To date, Glatarimer acetate (Copaxone) remains the only FDA approved "antigen specific" immunotherapy. Its efficacy appears to depend on TCR degeneracy and the high frequency of autoantigen specific T cells observed in patients with MS. The network will entertain clinical evaluation of oral administration of glatarimer acetate in MS, to take advantage of the generation of mucosal tolerance to orally administered antigens.

Additional antigen-specific therapies may be directed towards "disease tissue specific targets" using antigenic peptides with or without associated MHC class II binding structures (i.e. the shared epitope on HLA DR4 molecules, a principal target antigen of T cell reactivity in rheumatoid arthritis). With a variety of target candidates now available, candidate antigen-specific therapeutic approaches are invited for evaluation within Network-sponsored trials. Special consideration will be given to proof-of-concept trials in disease settings where there is some consensus on the identity of an individual autoantigen candidate (e.g. myasthenia gravis). Similarly, special consideration will be given to trials which are made simpler or less expensive by the pre-existence of clear surrogate markers (e.g. anti-DNA Abs in SLE; anti-AchR Abs in myasthenia gravis), simple clinical outcomes (e.g. pemphigus vulgaris, rheumatoid arthritis), and easy access to both pre- and post-treatment organ-specific tissue, for use in mechanistic studies (e.g. inflammatory bowel disease).

2) COSTIMULATORY BLOCKADE

Reagents which block signal 2, required to activate autoreactive T cells, require no knowledge of the target antigen/MHC complex or the TCRs involved in antigen recognition. Thus, they are attractive candidates for study in the autoimmune setting.

a) CTLA4Ig

Early stage clinical studies of blockade of the B7/CD28 pathway will be prioritized by the Network. There is considerable evidence from animal models of both MS and SLE to indicate that this pathway plays an important role in autoreactivity in these diseases.

b) CTLA4Ig and CD40L combination treatment

Early stage clinical trials of combination CD40L and B7-blocking mAb therapy are a high priority for the Autoimmunity Subgroup. Submissions for Phase I-II trials in patients with Lupus, rheumatoid arthritis and multiple sclerosis are invited at this time.

3) SOLUBLE MEDIATOR-DIRECTED IMMUNOMODULATION

Studies from many different laboratories have demonstrated that animal models of multiple sclerosis and inflammatory bowel disease can be effectively treated with IL-4, IL-10, TGFb, anti-IL-12 antibodies, or anti-IFNg antibodies. Animal models of SLE can be effectively treated with TNFb or anti-IL-10 antibodies, and animal models of RA can be treated with anti-TNF antibodies or IL-10. Pharmaceutical companies are aggressively developing many of these agents for treatment of various autoimmune diseases. The ITN is actively seeking novel applications of these agents in clinical scenarios not currently duplicated by the pharmaceutical industry.

Furthermore, recent animal studies have indicated that gene transfer may offer potential for treatment of autoimmune diseases in animal models, as it may ameliorate several complicating factors in the use of soluble cytokines. The Network is interested in pursuing such strategies in cases where animal data strongly support the extension of studies into human clinical trials.

4) THERAPEUTIC VACCINE STRATEGIES (E.G. DISEASE-LINKED MHC ANTIGENS)

Therapeutic vaccine candidates employing both disease-linked HLA-alleles and TCR chain sub-groups are now in pharmaceutical industry-sponsored Phase II clinical trials. This approach is particularly attractive in the case of Rheumatoid Arthritis, where patients usually express one or more of a relatively small subset of HLA-DRB1 chain genes. Furthermore, a "universal" MHC class II peptide vaccine seems possible for RA since 17 of the 27 possible HLA-DR4 B1* chains, 3 of 4 HLA-DR1 molecules, 12 HLA-DR6 B1*, and several other class II B1* chains associated with susceptibility to RA all share a near-identical, 8 amino acid sequence at positions 67-74 in the third hypervariable region of their otherwise hypervariable b1-domain. This shared epitope is the core of a therapeutic peptide vaccine that represents one such approach for treatment of rheumatoid arthritis. Extensive pre-clinical studies have established the striking allele specificity of this approach and have indicated that such a vaccine is capable of inducing both antibodies and T cell reactivity specific for the HLA-derived peptide vaccine. The Network is seeking a collaborative effort with academic and industrial partners to design and conduct trials in these areas.