Interferon-gamma-mediated prevention of graft-versus-host disease: Development of immune competent and allo-tolerant T cells in chimeric mice

Recently it was shown that delayed graft-versus-host disease (GVHD) in mice can be completely prevented by repeated injections of interferon-gamma (IFN-gamma). The characteristics of this sustained IFN-gamma-induced chimerism were studied in more detail, First, the potency of IFN-gamma as a modulator of GVHD was tested in a fully H-2 mismatched murine bone marrow transplantation (BMT) model, Donor bone marrow cells (BMC; C57BL/Rij; H-2(b)) were mixed with increasing numbers of donor spleen cells (SC) and transplanted into lethally irradiated recipients (C3H/Law; H-2(k)). Secondly, BMC and SC of the IFN-gamma-induced chimeras (C3H/Law; H-2(b)) were tested on their immunological competence and GVHD inducing capacity, Repeated injections of the host with IFN-gamma were able to prevent GVHD even when up to 10(5) SC were added to the graft; adding higher numbers of SC resulted in a rapid increase in the frequency of lethal GVHD, Donor-derived lymphocytes (H-2(b)) obtained from chimeric animals were immuno-competent as concluded from Con A stimulation in vitro, Chimeric-derived BMC (H-2(b)) were mixed with up to 10(7) chimeric SC (H-2(b)) and transplanted into a new group of lethally irradiated C3H/Law (H-2(k)) recipients. All transplanted animals survived the latter treatment without any macroscopic signs or histological lesions typical of GVHD, We conclude that IFN-gamma treatment allows the development of mature donor-derived immunocompetent T cells, which are allo-tolerant for the recipient.