Characterization of effector cells of graft vs leukemia following allogeneic bone marrow transplantation in mice inoculated with murine B-cell leukemia

Abstract

It is now widely accepted that immunocompetent lymphocytes in allogeneic bone marrow grafts exert an antileukemic effect that contributes to the cure of leukemia. Graft vs leukemia (GVL) effects independent of graft vs host disease were investigated in allogeneic bone marrow chimeras tolerant of host and donor alloantigens. The role of Thy1.2, L3T4 and Lyt2 T lymphocytes as effector cells of GVL were investigated in (BALB/c x C57BL/6)F1 mice inoculated with murine B-cell leukemia and subsequently conditioned with total lymphoid irradiation and cyclophosphamide (200 mg/kg). Mice were reconstituted with C57BL/6 bone marrow cells depleted of well-defined T-cell subsets or enriched for stem cells by the soybean agglutination method. Detection of residual tumor cells, an indicator for efficacy of GVL, was carried out by adoptive transfer of peripheral blood or spleen cells obtained from treated chimeras into secondary naive BALB/c recipients at different time intervals following bone marrow transplantation. Treatment of the primary marrow inoculum with monoclonal anti-Thy1.2 or anti-Lyt2 abolished the GVL effects and all secondary BALB/c recipients developed leukemia within 60 days. On the other hand, the treatment with monoclonal anti-L3T4 did not influence the effect of GVL and all treated recipients remained without leukemia. The data suggest that T cells may mediate GVL effects in the absence of graft vs host disease and in circumstances where tolerance to conventional alloantigens is elicited. Effector cells of GVL across the major histocompatibility complex (MHC) in the murine B-cell leukemia tumor model system appear to be Thy1.2+ Lyt2+ L3T4-. Induction of GVL effects by allogeneic cells tolerant of host MHC suggests that these effects may be independent of graft vs host disease.

Allogeneic peripheral blood stem cell transplantation using a fludarabine-based low intensity conditioning regimen for malignant lymphoma

“…9,10 We have previously shown, in a murine model of B cell lymphoma (BCL 1 ), that it is possible to induce a potent graft-versus-lymphoma (GVLy) effect by allogeneic, but not syngeneic, transplantation. 11 Subsequently, we were able to induce a GVLy effect in the same murine model by administration of allogeneic lymphocytes following transplantation. 12,13 Recently, an allogeneic GVLy effect has been induced in malignant lymphoma (ML) patients by administration of donor lymphocyte infusion.…”

Towards Possible Cure of Cancer by Immunotherapy of Minimal Residual Disease

“…Interestingly, similarly to the data first reported in mice [14][15][16][17][18], GVL effects independently of GVHD were also confirmed in clinical practice either following BMT [11] or following donor lymphocyte infusion (DLI) given post transplantation to induce GVL effects to treat or prevent relapse when patients are off any post-transplant immunosuppressive agents [33][34][35][36][37][38][39][40].…”

“…The possibility that allogeneic lymphocytes administered in the course of BMT eliminate leukemia through immune-mediated GVL effects has been suggested ever since the earliest days of experimental [12][13][14][15][16][17][18][19] and clinical BMT [8][9][10][11]. Convincing direct correlation between acute and chronic GVHD and reduced rate of relapse of leukemia in clinical practice was first reported by Weiden et al [8,9].…”

Murine B-cell leukemia lymphoma (BCL1) cells as a target for NK cell-mediated immunotherapy

“…Inoculation of more than 10 cells results in typical B-cell leukemia/ lymphoma characterized by marked splenomegaly, extreme peripheral blood lymphocytosis (up to 200 000/mm 3 ) and death of all tumor-bearing mice.…”

“…Although there seems to be no question on the role of alloreactive T cells in induction and maintenance of GVL effects in experimental animals and man, [1][2][3][4] thus explaining the inseparable effects of GVL and graft-versushost disease (GVHD), the therapeutic role of NK cells, especially against lymphoid target cells, remains unclear. Recently, Ruggeri et al 5 demonstrated the pivotal role of NK cells in GVL.…”