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

Abstract

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-2b) were mixed with increasing numbers of donor spleen cells (SC) and transplanted into lethally irradiated recipients (C3H/Law; H-2k). Secondly, BMC and SC of the IFN-gamma-induced chimeras (C3H/Law; H-2b) 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-2b) obtained from chimeric animals were immunocompetent as concluded from Con A stimulation in vitro. Chimeric-derived BMC (H-2b) were mixed with up to 10(7) chimeric SC (H-2b) and transplanted into a new group of lethally irradiated C3H/Law (H-2k) recipients. All transplanted animals survived the latter treatment without any macroscopic signs of 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.