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nous IL-12 and IFN-gamma production to maintain a milieu that doesn’t lead to remission, but instead encourages inflammation to continue.

PEPTIDE-MEDIATED REGULATION OF AUTOIMMUNITY20

Unlike Jenner and Pasteur, who were trying to initiate a strong immune response in order to get rid of a pathogen, the problem in autoimmune diseases is to turn off a strong immune response against an autoantigen. And while there are many differences among autoimmune diseases, and a welter of potential autoantigens, it is nevertheless worth asking if there may not be some more generic form of treatment that would work for many or all of these conditions. It may be hard to envision a single antigen or a single T-cell receptor that could be used in a range of immunotherapies, but if there were a sufficient understanding of the mechanisms of the immune response, it might be possible to develop strategies that would deliver regulatory products—cytokines or other products—to the sites of inflammation.

Regulatory Peptides. Peptides or proteins delivered in nonaggregated form, in the absence of strong adjuvants, lead to a form of immune unresponsiveness that can be adapted for immunotherapeutic intervention. In at least three different animal models of autoimmune disease (EAE, diabetes, and type 2 collagen-induced arthritis), whether spontaneous or induced, it is possible to use peptides of major dominant autoantigens in a “tolerogenic” fashion to turn off the disease. This presentation focused on EAE, which had been discussed by several other speakers (see above).

The first step in developing vaccine strategies is to test the obvious sites of potential intervention in preclinical models, to ensure that the vaccine will not make the disease worse. This would be the worst possible outcome—to take a patient with a mild case of MS or arthritis and put them in a wheelchair. In the case of EAE, this intervention might come at two different stages in the development of the disease: (1) prior to the initiation of symptoms, and (2) during remission following the onset of disease.

Peptide Immunotherapy. In the first case, mice were given synthetic peptides of immunodominant determinants of myelin protein in a tolerizing regime to block the initiation of symptoms. Earlier studies had shown that mice tolerized prior to time zero with peptides of myelin sheath do not develop disease in response to MBP. More recent work has shown that a “cocktail” of peptides is more effective than either the major immunodominant (AC 1–11) or secondary immunodominant (AC35–47). Even AC 1–11 is a rather weak antigen, however, with very poor MHC binding. Researchers have determined that peptide substitution—using a tyrosine at the fourth position of the acetylated 11

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Based on a presentation by Garrison Fathman, M.D.



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