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off the inflammatory events in three separate preclinical animal models of autoimmune disease.

  • The alternative strategy of transferring huge numbers of fully activated Th1-type T-cells may simply overwhelm the immune system, when the goal is simply to restore homeostasis. More importantly, very few of the transferred T-cells would find their way to the CNS joints or beta cells. The transgene approach doesn’t allow for the restoration of homeostasis; for that, one needs immunoregulation.

  • An alternative approach is to develop preventive immunization that is harmless enough to use in genetically predisposed individuals. This approach has been used in thyroiditis, where the etiologic autoantigen is well known and studied. There is a long list of potential autoantigens in other diseases, however, and much remains to be learned about them.

  • Human studies have been limited. Chimpanzees with MS responded well to an extract of myelin sheath containing MBP and other peptides. Human trials of MBP were conducted in the 1970s, but the subcutaneous route proved to be disastrously wrong, and several patients died of fulminating encephalomyelitis. There will be Phase I clinical trials this fall using immunodominant determinants of myelin protein, as described above.

    Researchers do not know if the retrovirus will persist after homeostasis is restored.

  • There have been anecdotal reports of patients whose autoimmune diseases were cured when they received autologous bone marrow transplants for other reasons, such as cancer therapy, but this approach is far too radical to use pre-ventively—for example, in prediabetic children that aren’t yet sick. An alternative that may be much simpler is stem cell rescue: if the patient becomes heterozygous, this protects against diabetes, although it may allow other diseases to be induced. This approach has been successful in animal models, but humans will have to wait until the next century—at least 25 years—for well-thought-out strategies involving bone marrow transplantation or stem cell reconstitution to (1) induce chimerism and heterozygosity or (2) induce homozygosity for nonpermissive alleles.

  • Researchers got protection with IL-10, as well, and TGF-beta may be a good regulatory cytokine as well. They pursued IL-4 initially because they got the best results with it in early tests. Researchers will eventually look at a wider range of regulatory and counterregulatory inflammatory cytokines, alone and in combinations.

  • The genetics of human diabetes is similar to that of the NOD mouse. MHC typing reveals five genomic intervals related to the disease, none of which has been targeted. In NOD mice, there is a clear B-chain epitope on the MHC that, when used to immunize naive animals, does not cause inflammation. If this epitope is sufficiently conserved to be relevant to human disease, it will not cause harm there either. However, the targets include antigen processing and presentation, as well as MHC. Researchers know nothing about processing at present.

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