Amelioration of acute GVHD disease and reestablishment of tolerance by short term treatment with anti TCR antibody

Abstract

We investigated whether tolerance can be reestablished in mice with graft-versus-host disease (GVHD) by using a short-term, T-celldepleting treatment with an anti-TCR-αβ mAb. GVHD was induced in 950-rad—irradiated AKR mice (H-2k, Mls-1a) by injecting 5 × 106 T celldepleted bone marrow cells together with either 107 or 2 × 106 lymph node (LN) cells from BALB/c mice (H-2d, and Mls-1b). AKR mice that received 107 LN cells exhibited a severe form of acute GVHD, in which all mice died by day 60. In this severe form of GVHD, treatment with anti-TCR-αβ-mAb completely ameliorated the induction of GVHD when initiated on day 0 (a total of 800 μg/mouse administered on days 0, 5, and 10). When the same protocol was begun on day 10, it had no therapeutic effect. However, this delayed treatment with anti-TCR-αβ mAb was very effective in reversing a less severe form of GVHD that was induced by the injection of 2 × 105 donor LN cells. Recipient mice given prophylactic antiTCR-αβ treatment achieved host-specific tolerance in association with clonal deletion of host Mls-1a-reactive Vβ+T cells. In contrast, spleen cells from recipient mice that recovered from the mild form of GVHD as a result of the delayed anti-TCR-αβ treatment contained a considerable proportion of Vβ6+T cells, despite the healthy appearance of these mice. A MLR assay showed that the spleen cells from these mice responded well to Mls-1a Ag but not to H-2k Ag, in contrast with the apparent responses of spleen cells from untreated GVHD controls to both Ags. In addition, cells from the anti-TCR-αβ treated mice exhibited a specific reduction in cytotoxicity against AKR blasts. Collectively, these data indicated that a short-term treatment of mice having GVHD with an anti-TCR-αβ mAb, starting even after disease onset, can re-establish host-specific tolerance, at least to the host-histocompatibility Ag. (Copyright 1994. The Journal of Immunology.)