A second prophylactic MHC-mismatched bone marrow transplantation protects against rat acute myeloid leukemia (BNML) without lethal graft-versus-host disease.
BACKGROUND
We have employed a rat model for human acute myeloid leukemia, a promyelocytic leukemia in the BN rat strain (BNML), to develop new protocols for immunotherapy in combination with allogeneic bone marrow transplantation (alloBMT). The status of mixed chimerism in allotransplanted rats provided an opportunity for immunotherapy using alloreactive donor cells. In addition to T or natural killer (NK) cells, we introduced a second infusion of bone marrow cells as prophylactic donor lymphocyte infusions (DLI) to test whether an effective graft-versus-leukemia (GVL) response could be obtained without clinical graft-versus-host disease (GVHD).


METHODS
BN rats were sublethally irradiated and transplanted with T-cell depleted bone marrow cells from either fully major histocompatibility complex (MHC)-mismatched (PVG) donor rats or MHC-matched (PVG.1N) as controls. Seven days after transplantation, rats were given 500 leukemic cells to mimic minimal residual disease. Additional cellular therapy was given at day +7. The efficiency of DLI was monitored by chimerism analysis in peripheral blood.


RESULTS
Rats receiving infusions of NK cells succumbed to leukemia. T-DLI induced complete donor T-cell chimerism and lethal GVHD. A second alloBMT protected against leukemia. This effect was dependent on an MHC incompatibility between the donor and host and also on the presence of alloreactive T cells in the second bone marrow inoculum, resulting in an increased, mixed donor T-cell chimerism.


CONCLUSIONS
A second prophylactic transplantation influenced the degree of T-cell chimerism to balance favorably between GVL and GVHD. If applicable to humans, repeated alloBMT may provide a novel approach to leukemia therapy.
Nestvold
Janne M
JM
Department of Anatomy, Institute of Basic Medical Sciences, University of Oslo, and Institute of Immunology, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway.
Omdal
Bente K
BK
Dai
Ke-Zheng
KZ
Martens
Anton
A
Benestad
Haakon B
HB
Vaage
John T
JT
Rolstad
Bent
B
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000379:methods* / Q000473:pathology; D046528:Chimerism; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D020544:Graft vs Leukemia Effect; D007167:Immunotherapy / Q000379:methods; D007694:Killer Cells, Natural / Q000276:immunology / Q000473:pathology / Q000502:physiology; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008285:Major Histocompatibility Complex / Q000276:immunology*; D008297:Male; D018365:Neoplasm, Residual / Q000276:immunology; D051381:Rats; D011914:Rats, Inbred BN; D011923:Rats, Nude; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000502:physiology