HLA Peptide B27PD in EAU

The immunological properties of peptide B27PD were tested in vivo in the Lewis rat model of EAU (Figure 25.3). Following immunization with HLA peptide B27PD most rats develop a very mild uveitis, often only characterized by infiltrating lymphocytes without retinal destruction. In contrast, immunization with the retinal peptide PDSAg, which is highly uveitogenic with an incidence of more than 80%, gave rise to a severe, destructive form of uveitis. However, oral tolerance induction by feeding B27PD or PDSAg strongly suppresses uveitis caused by immunization with S-Ag or PDSAg (Wildner and Thurau, 1994).

The mechanism of oral tolerance (Mowat, 1987) is usually effective for nutritional proteins, preventing adverse reactions that potentially lead to food allergies. When autoantigens are fed, autoimmune reactions can be suppressed as well, indicating a potential for oral tolerance as a therapeutic approach for autoimmune diseases (Weiner, 1997). Tolerance is mediated by suppressor cells specific for the respective antigen; however, the exact mechanisms underlying orally induced suppression are not yet fully elucidated. It is assumed that suppressor T cells recognize the respective antigen and secrete suppressive cytokines, such as TGF-P (Miller et al, 1992), IL-10 (Rizzo et al, 1999; Slavin et al., 2001) (Th3, Tr type), or cytokines belonging to the respective antagonistic Th type of the pathogenic immune response (Weiner, 2001).

Figure 25.3. Immunological activities of mimicry peptides. (A) Pathogenicity was tested by immunization of rats with the respective peptides. B7PD (ALNEDLRSWTAADT), derived from HLA-B7, differs from B27PD in only one amino acid (131 S ^ R). Mean histological uveitis score + SE is shown. Numbers in percent indicate the incidence (positive eyes). (B) Rats were fed with the respective peptides to show suppression of PDSAg-induced uveitis. Asterisks indicate significant reduction of disease.

Figure 25.3. Immunological activities of mimicry peptides. (A) Pathogenicity was tested by immunization of rats with the respective peptides. B7PD (ALNEDLRSWTAADT), derived from HLA-B7, differs from B27PD in only one amino acid (131 S ^ R). Mean histological uveitis score + SE is shown. Numbers in percent indicate the incidence (positive eyes). (B) Rats were fed with the respective peptides to show suppression of PDSAg-induced uveitis. Asterisks indicate significant reduction of disease.

Even IRBP-induced uveitis can be significantly downregulated by oral application of peptide B27PD, but not by S-Ag or peptide PDSAg, which points to a not yet identified mimotope in the sequence of IRBP. This is supported by the findings of Deeg et al. (2002), who have established a new model of experimentally induced uveitis in horses. Following immunization with IRBP all horses developed uveitis. Peripheral blood lymphocytes proliferated in response to IRBP peptide R14 (bovine IRBP, aa 1169-1191) as well as to HLA peptide B27PD, but not to S-Ag peptide PDSAg.

The antigen specificity was confirmed by the failure of recognizing control peptide B7PD, which differs from the sequence of B27PD by only a single amino acid. B7PD is not uveitogenic and is unable to induce oral tolerance and to prevent uveitis (Wildner and Thurau, 1994) (Figure 25.3).

Gamma-delta T cells isolated from spleens of mucosally tolerized rats can transfer tolerance to naive animals (McMenamin et al., 1995). Rats can be protected from PDSAg-induced uveitis by preinoculation of y/8 TCR+ splenocytes from donor rats either fed with PDSAg itself or with B27PD, but not with B7PD (Wildner et al., 1996). These regulatory y/8 T cells are CD8+. They proliferate in vitro in response to the tolerizing antigen (PDSAg or B27PD) or its respective mimicry peptides, but not to control peptide B7PD, in coculture with antigen-specific activated a/p+ effector cells (Wildner et al., 2004). The respective mode of antigen recognition/presentation of y/8 and a/p T cells is still unknown, but our data suggest that there is a direct cell-cell contact between effector and suppressor cells. Although in our rat model effector and regulatory T cells are different with respect to type (CD4 vs. CD8) and TCR (a/p vs. y/8), they seem to similarly recognize the antigen peptides.

Nevertheless, retinal peptide PDSAg and HLA peptide B27PD differ with respect to pathogenicity and tolerogenicity: while PDSAg is both uveitogenic and orally tolerogenic, B27PD is predominantly tolerogenic. We thus attempted to define those amino acid residues that stimulate pathogenic effector cells versus those that confer tolerance (Wildner and Diedrichs-Mohring, 2003b).

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