![]() ![]() Alternatively, the APCs may be provided with a means of synthesizing large quantities of the blocking peptides intracellularly. The peptides of the invention may be introduced into APCs directly, e.g., by intravenous injection of a solution containing one or more of the peptides. Because the blocking peptides of the invention are self peptides with the exact carboxy and amino termini tolerized during ontogeny, they are immunologically inert and will not induce an immune response which may complicate treatment using non-self blocking peptides. Once in the APC, a peptide binds to the class II molecules with high affinity, thereby blocking the binding of immunogenic peptides which are responsible for the immune reaction characteristic of the disease condition. It may be useful to employ a “cocktail” of peptides, where complete degeneracy is lacking for individual peptides, i.e., where peptides binds to fewer than all allotypes the cocktail provides overlapping binding specificity. Tissue typing to determine the particular class II alleles expressed by the patient may be unnecessary, as the peptides of the invention are bound by multiple class II isotypes. In the therapeutic methods of the invention, short peptides modelled on the high-affinity immunomodulating self peptides of the invention (which preferably are nonallelically restricted) are introduced into the APCs of a patient. In addition, such therapy could be used to reduce transplant rejection. These three characteristics-(1) self rather than foreign, (2) degeneracy, and (3) high affinity binding-suggest a novel means for therapeutic intervention in disease conditions characterized by autoreactivity, such as Type I diabetes, rheumatoid arthritis, and multiple sclerosis. Furthermore, many if not all of the self-peptides disclosed herein bind to the class II molecules with relatively high affinity. This observation runs counter to the widely-accepted view of MHC class II function, which dictates that each allotype binds a different set of peptides. ![]() ![]() Several self peptide families have been identified with the unexpected property of degenerate binding: that is, a given self-peptide will bind to a number of HLA-DR allotypes. ![]() These peptides were found to be predominantly derived from self proteins rather than foreign proteins. In the work disclosed herein, naturally processed peptides bound to six of the some 70 known human MHC class II DR allotypes (HLA-DR1, HLA-DR2, HLA-DR3, HLA-DR4, HLA-DR7, and HLA-DR8) have been characterized. The amount of each species of peptide which binds class II is determined by its local concentration and its relative binding affinity for the given class II binding groove, with the various allotypes displaying different peptide-binding specificities. Class II MHC molecules bind not only to peptides derived from exogenous (ingested) proteins, but also to those produced by degradation of endogenous (self) proteins. The class II/peptide complex is transported from the endosomes to the cell surface where it becomes accessible to T-cell recognition and subsequent activation of immune responses. In the endosomes, Ii is removed by a process involving proteolysis this exposes the peptide binding cleft, thus allowing peptides present in the endosome to bind to the MHC molecule. Association with Ii is proposed to block the premature acquisition of peptides (by blocking the peptide binding cleft of the MHC heterodimer), promote stable &agr /&bgr interaction, and direct subsequent intracellular trafficking of the complex to endosomal vesicles. Within the ER the class II &agr /&bgr chain complex associates with an lo additional protein termed the invariant chain (Ii). Termini which target them to the endoplasmic reticulum (ER). ![]()
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