ACUTE GRAFT-VERSUS-HOST REACTION CAN BE ABORTED BY BLOCKADE OF COSTIMULATORY MOLECULES

Injection of parental lymphocytes into an unirradiated adult F-1 host results in an acute GVH reaction characterized by immune deficiency, a ttack on host lymphohematopoietic tissues, and repopulation with donor -derived cells. All of these events result from the initial activation of donor lymphocytes by host alloantigens. Interaction of pairs of ho st and donor costimulatory molecules, in particular CD28/CTLA4 and B7- 1/B7-2, play a crucial role in this initial activation of donor T cell s. We demonstrate here that in vivo treatment of the host with high do ses of CTLA4-Ig solely during the initial period of donor alloactivati on can completely abort the subsequent development of GVH reaction. Al though donor T cells are retained, CTLA4-Ig treatment reduces the init ial endogenous cytokine production and arrests the subsequent expansio n of donor T cells, the differentiation of anti-host effecters, and th e development of severe immune deficiency. This result is consistent w ith the establishment of host-specific tolerance in the donor populati on, while maintaining host immune competence.