The goal of this proposal is to identify HLA-linked immune response (Ir) genes in outbred human populations. This will be performed by measuring the proliferative response, in secondary cultures of T-cells primed in vitro to KLH, and to 5 synthetic amino acid polymers. Individuals identified as low responders to specific antigens will be further characterized with respect to segregation of low responsiveness and HLA haplotypes in informative families; and whether the low response is due to defective antigen recognition by T cells or to specific supressor cell activation. HLA-A, B, C and DR typed populations for study will include normal random donors, normal donors who are homozygous for D region specificities, and selected patient groups with diseases showing associations with HLA-D region specificities.