A PEPTIDOMIMETIC THAT SPECIFICALLY INHIBITS HUMAN-LEUKOCYTE ANTIGEN DRB1-ASTERISK-0401-RESTRICTED T-CELL PROLIFERATION

The ability of a peptidomimetic (SC-67655) to block the peptide bindin g site of the rheumatoid arthritis-linked human leukocyte antigen enco ded by the DRB10401 allele was evaluated. The inhibitor bound to puri fied DRB10401 molecules with an affinity similar to that of the well- characterized peptide ligand HA307-319. Cell binding assays demonstrat ed that, in contrast to the promiscuous HA307-319 peptide, the peptido mimetic was highly specific for DRB10401. The inhibitor also blocked functional T cell responses to peptide antigens but did not block T ce ll proliferation in response to protein antigens. Furthermore, it did not appear to be taken up by cells. An analog of the peptidomimetic th at was conjugated to a signal peptide sequence did inhibit a T cell pr oliferative response to protein antigen. Thus, the peptidomimetic must be taken up by cells to block the presentation of peptides derived fr om protein antigens. These findings have implications for the rational development of inhibitors that block the class II peptide binding gro ove for the treatment of autoimmune diseases.