Gaft-versus-leukemia activity after bone marrow transplantation does not require graft-versus-host disease

Abstract

Clinical data have suggested that graft-versus-host disease (GVHD) plays a crucial role in the antileukemic effects of bone marrow grafts. We investigated (a) whether bone marrow cells unable to induce GVHD can effect graft-versus-leukemia (GVL) activity and (b) whether such antileukemic capacity depends on the presence of T lymphocytes in the graft. Balb/c mice were inoculated with A20 cells, a B-cell lymphoma/leukemia of Balb/c origin. Four weeks after tumor inoculation the animals were lethally irradiated and received a bone marrow graft. Cells from (Balb/c x C57) F1 or (C3H x Balb/c) F1 hybrids were transplanted into parental-strain Balb/c mice. Since lymphocytes from F1 hybrids are unable to cause graft-versus-host reactivity against a parental-strain animal, we used this experimental setting to explore GVL effects in a GVHD-free system. In vitro incubation with monoclonal anti-Thy-1.2 antibody plus complement was used to eliminate Thy-1+ cells. After syngeneic transplantation, the death rate due to leukemia remained unchanged (91%) compared with that among untreated animals (86%). Following transplantation of F1 marrow cells of either (C57 x Balb/c) F1 or (C3H x Balb/c) F1 origin, death rates of 40% and 50% were observed; these were significantly lower. Depletion of Thy 1+ cells from bone marrow graft caused only a slight increase in the leukemic death rate after transplantation of bone marrow of (C57 x Balb/c) F1 hybrid origin (50%), but a high leukemic death rate was seen after transplantation of (C3H x Balb/c) F1 bone marrow (100%). Additional experiments with fully allogeneic, T-cell-depleted C57 bone marrow transplantation suggest an antileukemic effect that is comparable to that seen after transplantation of unmanipulated F1 bone marrow. Taken together, our results indicate that GVL activity can be dissociated from graft-versus-host reaction.

Early lymphocyte recovery post-allogeneic hematopoietic stem cell transplantation is associated with significant graft-versus-leukemia effect without increase in graft-versus-host disease in pediatric acute lymphoblastic leukemia

“…13,28 However, GVL effect is not entirely dependent on GVHD. 29 Evidence for GVL includes higher relapse rate after T cell-depleted transplants, 30 and remission induction after donor leukocyte infusion in patients with leukemia relapsing post transplantation. 6,14,15 The effector mechanism of GVL and GVHD are complex and incompletely understood.…”

“…CD4 þ , CD8 þ T lymphocytes and NK cells are considered major players. 29,31 The early post-transplantation period is the most critical as the disease burden is lowest at this time and chances of eliminating it completely through immune mechanism are highest. During the early post-transplantation period the majority of the peripheral blood mononuclear cells are NK cells that are capable of mediating cytotoxicity without prior sensitization and may be responsible for most of early antileukemic activity of allograft.…”

Definitive separation of graft-versus-leukemia- and graft-versus-host-specific CD4 + T cells by virtue of their receptor β loci sequences

“…In HLA-identical siblings, cytotoxic T lymphocytes that kill leukemic or nonleukemic targets have also been isolated (24). Furthermore, experiments in mice have demonstrated clearly that GVL and GVH reactivity are separable (25). In another study, clones with three different reactivities were identified: clones reacting only against normal PBMCs, clones reacting only against leukemic cells, and clones reacting against both (6).…”

Recognition of clonogenic leukemic cells, remission bone marrow and HLA-identical donor bone marrow by CD8+ or CD4+ minor histocompatibility antigen-specific cytotoxic T lymphocytes.

“…An association has been found between the occurrence of GVHD and GVL reactivity, although clinical observations and animal studies have indicated that GVL may exist in the absence of GVHD (2,(32)(33)(34)(35)(36). Several studies have suggested that both CD8+ and CD4+ T lymphocytes are involved in GVHD and GVL reactivity and may recognize polymorphic antigens in the context of HLAclass I and class II molecules, respectively, that are processed by the recipient cells (37)(38)(39)(40)(41)(42)(43)(44)(45)(46).…”