Graft-versus-leukemia effect in minor antigen mismatched chimeras given delayed donor leucocyte infusion: immunoregulatory aspects and role of donor T and ASGM1-positive cells

Abstract

Background: Previous studies have demonstrated that delayed donor leukocyte infusion (DLI) can increase graft-versus-leukemia (GVL) without increasing graft-versus-host-disease (GVHD) in MHC mismatched bone marrow (BM) chimeras. In our report, the immune status of minor antigen mismatched BM chimeras given DLI was studied. Particularly the role of donor ASGM1 positive or T cells in the graft-versus-leukemia effect (GVL) was investigated.

Methods: AKR mice (H2k, Mls1a, Thy1.1) received TBI (9,5 Gy) and T cell-depleted (TCD) C3H (H2k, Mls2a, Thy1.2) BM alone (BM chimeras), or TCD BM together with immunocompetent C3H spleen cells at the time of BM transplantation (BM+SP chimeras), or TCD BM and 3 weeks later C3H spleen cells (DLI chimeras). Chimerism and T lymphocyte subsets were scored using FACS and anti-Thy, anti-Vbeta6, anti-IL2-beta receptor, anti-CD4, anti-CD3, and anti-CD8 mAbs. Leukemia challenge consisted of 5 x 10(6) AKR T cell lymphoma (BW4157) cells injected i.v. ASGM1 positive (ASGM1+) cells and T cells were depleted using anti-ASGM1 or anti-Thy1.2 antibodies, respectively. Immune tolerance was studied using MLR and CML tests.

Results: BM + SP chimeras developed acute and lethal GVHD, whereas DLI chimeras were totally free from GVHD. In DLI chimeras, host-reactive cytotoxic T cells (CTL) could not be induced and host-reactive CD8Vbeta6 cells were deleted whereas CD4Vbeta6 cells and MLR reactivity persisted temporarily. In contrast, in BM+SP chimeras, anti-host CTL were easily generated and an expansion of both host-reactive CD8Vbeta6 and CD4Vbeta6 T cells was found as well as high anti-host MLR reactivity. Depletion of either ASGM1 + cells or T cells from the DLI inoculum resulted in an abrogation of GVL reactivity, suggesting that both cell populations were involved in the protection against BW4157 leukemia. Three weeks after DLI, the GVL effect waned which correlated with the disappearance of host-reactive CD4 cells and MLR reactivity.

Conclusion: In minor antigen mismatched BM chimeras, anti-host reactivity after DLI is characterized by (1) an absence of clinical GVHD, (2) clonal deletion of host-reactive CD8 cells, (3) an absence of anti-host CTL induction, and ( 4) a temporary persistence of host-reactive CD4 T cells and of MLR reactivity. In addition, either donor ASGM1+ cells or an interaction between these cells and T cells contribute to the GVL effect.