Epa-1 is a tissue-restricted, non-H-2 alloantigen defined on mouse epidermal cells by H-2-restricted cytotoxic T lymphocytes (CTL). The first long-term objective of this project is to further elucidate the immunogenetics and transplantation immunology of Epa alloantigens, including: (1) mapping the Epa-1 gene locus with a new set of recombinant-inbred strains; (2) using a newly developed Epa-1 congenic strain to determine the role of Epa-1 in the rejection of various tissues and organs and in graft-versus-host reactions and disease; (3) cellularly defining and characterizing other Epa antigens by cloning CTL directed against non-Epa-1 specificities; and (4) characterizing clonotype-specific reactions against Epa-specific CTL and using them to modulate Epa-specific transplantation immunity. The second objective is to characterize the tissue-destructive """"""""innocent bystander"""""""" reactions induced when target cells are admixed with CTL and the mixture is injected intradermally into host syngeneic to the CTL, including: (1) determining the genetic, immunologic, and cellular requirements for inducing destructive bystander reactions in normal and immunosuppressed hosts: (2) using cells other than classic CTL to evoke bystander reactions to determine whether the reactions are mediated via the T-cell receptor; (3) determining whether cells obtained from various transplantable organs other than the skin can function as targets for bystander reactions in the skin and other organs; (4) evaluating the apparent lack of MHC restriction in the bystander system and the putative control by immune-response genes; (5) histologically and immunohistologically characterizing bystander lesions evoked by CTL directed against Epa-1 and other histocompatibility, antigens, the hapten, trinitrophenyl, and influenza and CMV virus antigens in the skin, gut, kidney, and liver in normal and immunosuppressed hosts; (6) determining which host cells, such as helper T cells, NK cells, macrophages, Langerhans cells, neutrophils and mast cells, mediate and amplify bystander reactions; and (7) determining which cytokines are critically involved in the initiation and amplification of destructive bystander reactions in various antigen systems. These proposed studies in histocompatibility antigen, altered-self and virus--the encoded antigen system should help to determine the role of nonspecific tissue destruction in graft rejection, graft-versus- host disease and the histopathology of certain virus infections.
