In treating of leukemia and controlling of minimal-residual disease (MRD), graft versus leukemia effect (GVL) plays a critical role, and complicated mechanisms are involved in this immunology process. When graft cells are infused into recipients, the evoked GVL effect must be inevitably influenced by many factors derived from allogeneic effect between donor and receptor. To utilize GVL more efficiently in future clinical practice and to improve the curative effect of allo-HSCT, it is necessary to recognize these factors. Some potential factors influencing GVL such as chimerism patterns, autocytotoxic cells, dynamics of immune cells in patients, the cytokines and so on are reviewed in this article.
Graft vs Leukemia Effect ; Hematopoietic Stem Cell Transplantation ; Humans ; Leukemia ; immunology ; surgery

Graft vs Host Disease ; prevention & control ; Graft vs Leukemia Effect ; Hematopoietic Stem Cell Transplantation ; methods ; Humans ; Transplantation, Homologous ; methods

OBJECTIVETo explore the dissociation of graft-versus-leukemia (GVL) effects from graft-versus-host disease (GVHD) in the patients who experienced GVHD during leukemia relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

METHODSThe primary disease, disease status, GVHD, response to donor lymphocyte infusion (DLI) and prognosis were analysed in 11 leukemia patients who relapsed with GVHD after allo-HSCT.

RESULTSOf the 11 relapsed, 5 were acute lymphoblastic leukemia and 6 acute myeloid leukemia. Five received DLI before relapse and all developed post-DLI GVHD, including 2 grade II acute GVHD (aGVHD), 1 limited chronic GVHD (cGVHD) plus grade II aGVHD, and 2 extensive cGVHD. After relapse of the 5 patients, 2 received Chemo-DLI, one achieved CR with extensive cGVHD and then relapsed again, the other didn't achieved CR. The other 6 patients didn't received DLI before relapse and also developed post-HSCT GVHD while relapsing, including 3 extensive cGVHD, 1 grade I aGVHD and 2 grade II-IV aGVHD. After relapse, these 6 patients received Chemo-DLI, 2 achieved CR and then relapsed again, 4 didn't achieved CR.

CONCLUSIONThe elicited GVHD after allo-HSCT may not accompany effective GVL effects inhibiting leukemic relapse.

Graft vs Host Disease ; Graft vs Leukemia Effect ; Hematopoietic Stem Cell Transplantation ; Humans ; Leukemia, Myeloid, Acute ; Precursor Cell Lymphoblastic Leukemia-Lymphoma

Hepatocyte growth factor (HGF) is a pleiotropic cytokine, its roles in the physiology and pathology of immune system, have been investigated thoroughly, great deal of data have been documented on its immunoregulatory activity. In this review, according to advance of study on HGF in recent years, the role of HGF in the immune regulation, such as immunoregulatory effects of HGF on T lymphocytes, B lymphocytes and dendritic cell, modulation of HGF on specific humoral and cellular immune response, control of acute GVHD and acceleration of myeloid and immunologic reconstitution in allogenetic bone marrow transplantation models, promotion of tissue repair and regeneration, and alleviation of immune rejection in allogeneic organ transplantation including the heart, liver and kidney transplantation, prevention of grafts from injury as well as applicably useful of HGF in the therapy of autoimmune disorders were summarized.
Animals ; Graft Rejection ; immunology ; prevention & control ; Graft vs Host Disease ; immunology ; prevention & control ; Graft vs Leukemia Effect ; immunology ; Hepatocyte Growth Factor ; physiology ; Humans ; Immunity, Cellular ; immunology

BACKGROUNDWe distinguished graft-versus-host disease (GVHD) from graft-versus-leukemia (GVL) effects and to investigate the distribution of T-cell receptor (TCR) V beta gene repertoire in individuals with leukemia before and after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

METHODSPeripheral blood mononuclear cells (PBMC) were obtained from 10 normal individuals, 8 donors and 11 patients with leukemia before and after transplantation. Polymerase chain reaction (PCR) amplification of complementarity-determining region 3 (CDR3) of 24 TCR V beta genes was used to examine serial samples of PBMC. The PCR products were further analyzed by genescan to evaluate clonality of T cells.

RESULTSThe 24 TCR V beta gene repertoire displayed highly diverse and polyclonal spectratypes in all normal individuals and 4 of 8 donors. Another 4 donors expressed part of the 24 TCR V beta subfamily and 1 donor had oligoclonality. The expressions of the 24 TCR V beta subfamilies were skewed and restricted in 11 leukemia patients before and after transplantation. Some absences of 24 TCR V beta subfamily expression were quite similar between the recipients pro-transplantation and related donors. The number of subfamilies expressed increased over time post-transplantation, but the restricted expressions of the subfamily could last 6 - 30 months after transplantation. All patients with GVHD and some without GVHD exhibited T cell clonal expansion. The expansive T cell clone was distributed in V beta 2-3, 16-17, 18-19, 21 and V beta 23 in patients with GVHD and in V beta 7, 9, 16 and 19 in patients without GVHD. One patient with syngeneic-HSCT (syn-HSCT) had V beta 15 and 16 T cell expansion after transplantation. One patient displayed V beta 18 T cell expansion after donor lymphocyte infusion (DLI).

CONCLUSIONSNormal individuals express the entire 24 TCR V beta gene repertoire and have polyclonal distribution. However, the TCR V beta gene repertoire is only partially expressed in some donors. The TCR V beta gene repertoire is restrictedly expressed in a skew fashion in patients with leukemia before and after transplantation. The number of TCR V beta gene subfamilies increases over time post-transplantation. GVHD and GVL effects may induce the proliferation of T cell clones. Clinical GVL response may be distinguished from GVHD alloreactivity through the host MHC antigen.

Graft vs Host Disease ; genetics ; Graft vs Leukemia Effect ; genetics ; Hematopoietic Stem Cell Transplantation ; Humans ; Leukemia ; genetics ; therapy ; Polymerase Chain Reaction ; Receptors, Antigen, T-Cell, alpha-beta ; genetics

OBJECTIVETo study if methoxy polyethylene glycol modification (mPEG) affects grafts versus leukemia (GVL) when donor bone marrow mononuclear cells are camouflaged with mPEG in murine bone marrow transplantation (BMT).

METHODSSixty (BALB/c(H-2d) x 615(H-2k))F(1) mice were divided into four groups randomly. Mice in group A were only irradiated with 8.0 Gy (60)Cogamma, and mice in the other groups were inoculated intraperitoneally with 1 x 10(6) L615 cells 3 days before irradiation with the same dose (60)Cogamma. BALB/c(H-2d) mice were sacrificed and bone marrow cells and spleen cells were collected. The bone marrow cells (1 x 10(7)) were mixed with the spleen cells (1 x 10(7)), which were camouflaged or not camouflaged with mPEG, were transplanted into irradiated leukemia mice in C and D groups. GVL effects were assessed by L615 cells proportion in peripheral blood, histopathological changes and survival time.

RESULTSSevere GVHD was observed in group C (without mPEG modification), and the mice rapidly died, the mean survival time was 6.9 days. The mice in irradiated group (group B) with leukemia cell died of leukemia. The average survival time of group D (with mPEG modification) was 24.2 days, which was longer than that of the other groups (P < 0.05), and the survival rate of group D (27%) was significantly higher than that of the others (P < 0.05), 11 mice (11/15) died of leukemia and the others were still alive.

CONCLUSIONThe camouflage with mPEG modification is capable of preserving GVL effect and preventing GVHD in mice BMT.

Animals ; Bone Marrow Transplantation ; Female ; Graft vs Host Disease ; prevention & control ; Graft vs Leukemia Effect ; Male ; Mice ; Mice, Inbred BALB C ; Polyethylene Glycols ; pharmacology

After allogeneic hematopoietic stem cell transplantation (allo-HSCT), the donor cells present a profound immunization therapy efficiency. Among these effector cells, allo-reactivity natural killer (NK) cell activation are concerned with the graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect. As known, GVHD is primarily a T-cell-mediated event but not initiated by NK cells. NK cells may significantly enhance GVL immune response by using an integration of activating and inhibitory receptors. Allo-reactivity NK cell infusion after allo-HSCT already transits from experiments to clinic. In this review the background on NK cells, and their clinical roles in Allo-HSCT were summarized.
Graft vs Host Disease ; immunology ; Graft vs Leukemia Effect ; immunology ; Hematopoietic Stem Cell Transplantation ; Humans ; Killer Cells, Natural ; immunology ; Transplantation Immunology

Despite significant recent advances in the applicability and outcome following unrelated cord blood transplantation (UCBT), infections remain a major cause of mortality associated with poor immune recovery in the first 6 months after UCBT. Enhanced immune reconstitution not only could improve survival by reduced transplant related mortality, but may also favorably impact on relapse incidence by improved graft-versus-leukemia effects. This review will summarize our current understanding of the biology of immune recovery post-UCBT with an emphasis on adaptive T cell dependent immunity. New efforts to boost immunity will be also highlighted including our own laboratory, where ex vivo T cell expansion is pursued towards adoptive immunotherapy.
Biology ; Cord Blood Stem Cell Transplantation ; Fetal Blood ; Graft vs Leukemia Effect ; Immunotherapy, Adoptive ; Incidence ; Opportunistic Infections ; Recurrence ; Transplants

Nonmyeloablative stem cell transplantation (NST) is increasingly used with beneficial effects because it can be applied to older patients with hematological malignancies and those with various complications who are not suitable for conventional myeloablative stem cell transplantation (CST). Various conditioning regimens differ in their myeloablative and immunosuppressive intensity. Regardless of the type of conditioning regimen, graft-versus- host disease (GVHD) in NST occurs almost equally in CST, although a slightly delayed development of acute GVHD is observed in NST. Although graft-versus-hematological malignancy effects (i.e., graft-versus-leukemia effect, graft-versus-lymphoma effect, and graft-versus-myeloma effect) also occur in NST, completely eradicating residual malignant cells through allogeneic immune responses is insufficient in cases with rapidly growing disease or uncontrolled progressive disease. Donor lymphocyte infusion (DLI) is sometimes combined to support engraftment and to augment the graft-versus-hematological malignancy effect, such as the graft-versus-leukemia effect. DLI is especially effective for controlling relapse in the chronic phase of chronic myelogenous leukemia, but not so effective against other diseases. Indeed, NST is a beneficial procedure for expanding the opportunity of allogeneic hematopoietic stem cell transplantation to many patients with hematological malignancies. However, a more sophisticated improvement in separating graft-versus-hematological malignancy effects from GVHD is required in the future.
Antigen-Presenting Cells/physiology ; Graft vs Host Disease/etiology ; *Graft vs Leukemia Effect ; Hematopoietic Stem Cell Transplantation/*adverse effects ; Humans ; Leukemia/therapy ; Lymphocyte Transfusion ; Lymphoma, Non-Hodgkin/therapy ; Multiple Myeloma/therapy ; *Transplantation Conditioning

OBJECTIVETo study the role of donor-derived NK cells in haploidentical bone marrow transplantation (BMT) in leukemic mice.

METHODSCB6F1(H-2b/d) mice model of EL9611 (H-2d) erythroleukemia was established by injection of EL9611 (H-2d) cells via tail vein. CB6F1(H-2b/d) mice were used as recipient, and C57BL/6(H-2b) mice as donor. Five days later, 70 CB6F1(H-2b/d) mice were randomly divided into 7 groups (10 mice per group) as follows: group 1: without treatment; group 2: simple-irradiated group; group 3: treated with cytarabine (Ara-C) at 50 mg/kg x6 d; group 4: simple BMT; group 5: haploidentical BMT with graft-versus-host disease (GVHD) that injected with bone marrow cells and spleen cells of C57BL/6(H-2b) mice 4 hours after irradiation; group 6: after irradiated with 9 Gy, mice were injected with C57BL/6(H-2b) NK cells (1 x 10(6)) and 4 hours later with BM cells, group 7: after irradiation of 9 Gy, mice were injected with C57BL/6(H-2b) NK cells (1 x 10(6)) and 4 hours later with BM cells and spleen cells. The blood routine test, survival time, body weight, and histopathology in the recipients were observed and compared among these group.

RESULTSThe survival time was (10.1 +/- 0.9), (9.8 +/- 0.9), (22.7 +/- 3.2) and (20.1 +/- 1.7) days in groups 1, 2, 3, and 5 respectively; was (30.1 +/- 16.0) days in group 4, out of which 2 mice survived for more than 30 days. The survival time was (39.1 +/- 18.1) and (49.3 +/- 17.2) days in groups 6 and 7 respectively, out of which 4 mice in group 6 and 7 mice in group 7 survived for more than 30 days. The survival time in group 6 was much longer than that in group 1, 2, 3 and 5 (P < 0.01). The survival time in group 7 was much longer than that in other groups (P < 0.05). The liver and spleen enlargement, organ destruction and infiltration with leukemic cells were observed in mice died from leukemia. The chimerism of Y chromosome appeared (80%-90%) in long-term survival mice in groups 6 and 7.

CONCLUSIONDonor-derived NK cells have the antileukemia ability and reduce GVHD in haploidentical BMT in erythroleukemia mice (EL9611, H-2d).

Animals ; Bone Marrow Transplantation ; immunology ; Disease Models, Animal ; Female ; Graft vs Host Disease ; prevention & control ; Graft vs Leukemia Effect ; Killer Cells, Natural ; immunology ; Leukemia, Erythroblastic, Acute ; surgery ; Lymphocyte Transfusion ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL