Disclosed herein are isolated major histocompatibility complex (MHC) class II α1 domain polypeptides and methods of use. In some embodiments, the isolated polypeptide comprises or consists of an MHC class II α1 domain polypeptide (or portion thereof) and does not include an MHC class II α2, &bgr;1, or &bgr;2 domain. The disclosed MHC class II α1 domain polypeptides are of use in treating or inhibiting disorders in a subject, such as inflammatory and/or autoimmune disorders. Also disclosed are methods of evaluating efficacy of treatment or optimizing treatment of a subject with a polypeptide including an MHC class II α1 domain polypeptide (or portion thereof) or a polypeptide including an MHC class II α1 domain and &bgr;1 domain (such as a &bgr;1α1 RTL).