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©The Author(s) 2023.
World J Clin Cases. Jan 16, 2023; 11(2): 268-291
Published online Jan 16, 2023. doi: 10.12998/wjcc.v11.i2.268
Published online Jan 16, 2023. doi: 10.12998/wjcc.v11.i2.268
Table 1 Molecules that mediate hematopoietic stem and progenitor cell adhesion and chemotaxis during transplantation
HSPC receptor | Bone marrow ligands | Effect | Ref. |
PSGL-1/CD162 | Selectins (P and E) | Promote HSPC homing | [10] |
β1 integrin | Opn | Contribute to HSC trans-marrow migration toward the endosteal region | [17,18] |
VLA-4/α4 β1 | VCAM-1, fibronectin | Promote HSPC homing | [7,11] |
VLA-5/α5 β1 | Fibronectin | Promote HSPC homing and proliferation | [19,20] |
LFA-1/αL β2 | ICAM-1 | Promote HSPC homing | [7,11] |
LPAM-1/α4 β7 | MAdCAM-1 | Promote HSPC homing and engraftment | [21] |
Cx43 | Participate in the formation of intercellular transmembrane channels, facilitate the transportation of mitochondria or other substances, and promote bone marrow regeneration and HSPC engraftment | [22] | |
CXCR4 | SDF-1 | Promote HSPC homing and engraftment and participate in the regulation of HSPC survival and proliferation | [7] |
c-kit | SCF | The transmembrane isoform of SCF is critical in the lodgment and detainment of HSCs within the bone marrow niche | [23] |
c-MPL | TPO | TPO promotes the survival and proliferation of HSPCs and upregulates SDF-1 in the bone marrow niche, thereby contributing to HSPC homing and engraftment | [24,25] |
CD44/Pgp-1 | Selectins (P, E and L), HA | CD44 and HA play a key role in SDF-1-dependent transendothelial migration of HSPCs and their final anchorage within the bone marrow niche | [26] |
CD82/KAI1 | CD82 modulates HSPC bone marrow maintenance, homing, and engraftment | [27] | |
Anxa2r | Annexin II/Anxa2 | Regulate stem cell adhesion, homing, and engraftment | [28] |
CaR | Ca2+ | Enhance HSC lodgment and engraftment in the bone marrow niche | [29] |
N-cadherin | N-cadherin | N-cadherin-mediated cell adhesion is functionally required for the establishment of hematopoiesis in the bone marrow niche after bone marrow transplantation | [30] |
Table 2 Main factors for post-transplant immune reconstitution
Factors | Effect | Ref. |
Recipient age | Several studies show that immune reconstitution, especially the reconstitution of CD4+ T cells, is inversely related to age. However, some studies report that age has no effect on the reconstitution of any subgroup of lymphocytes | [63,90,91] |
Graft source | Immune reconstitution occurs faster after PBSCT than after BMT. This may be because PBSCT grafts are rich in mature lymphocytes. Delayed immune reconstitution after UCBT is related to low lymphocyte count and immature immune cells in umbilical cord blood | [61,92-95] |
HLA matching between donor and recipient | HLA mismatch causes delayed reconstitution of neutrophils and T cells | |
Intensity of preconditioning | Several studies show that compared with MA-SCT, RICSCT reduces thymus damage and promotes immune reconstitution. However, some studies show no significant difference in recipient immune reconstitution between these two transplantation methods | [60,96-98] |
GVHD | GVHD damages thymus structure and function and interferes with T cell differentiation at all stages, thereby affecting T cell reconstitution. GVHD also affects the recovery of B cell number and function | [84,99] |
GVHD prevention | Donor TCD reduces the risk of GVHD; however, the lack of T cells increases the risk of infection and delayed immune reconstitution | [100] |
The use of ATG or alemtuzumab has a negative effect on the reconstitution of T cells and B cells | [101-103] |
Table 3 Strategies to separate graft-versus-host disease and graft-versus-leukemia
Separation strategies | Approaches | Brief description | Ref. |
GVHD risk prediction | GVHD biomarker testing | Contributes to GVHD diagnosis and provides evidence for the early use of anti-GVHD drugs | [123] |
Cytokine gene polymorphism testing | Helps to identify patients with a high risk of severe GVHD and take preventive measures | [124] | |
Modification of donor graft cells | Donor T cell depletion | Donor T cell depletion reduces GVHD while increasing the risk of infections, graft rejection, and disease relapse | [109] |
Graft-specific cell population depletion | Removing specific cell populations such as naïve T cells in the graft that consistently cause severe GVHD | [118] | |
DLI to treat relapse | DLI is very effective in the treatment of relapsed slow-growing hematopoietic malignancies such as CML; however, the mechanism is unknown | [122] | |
Application of CAR T cell | The combination of scFv that identifies leukemia-specific antigens and the activating domain of T cells enhances specific identification and killing of leukemia cells | [125,126] | |
Suicide gene transduced donor lymphocyte infusion | A genetically modified suicide gene is introduced. Donor lymphocytes expressing this gene are sensitive to prodrugs, a feature that can be used when needed to regulate GVHD through the drug clearance of transduced cells | [127] | |
Selecting memory T cells | Memory T cells cause mild or no GVHD and have critical graft-versus-tumor functions | [118] | |
Enhancing activated γδ T cells | γδ T cells have the ability to kill leukemic blasts, and allogeneic TCR γδ T cells are not alloreactive and do not cause GVHD | [113] | |
Selecting Tregs | Tregs suppress the activation and proliferation of effector T cells and downregulate the body’s response to foreign antigens or autoantigens | [86] | |
Modifying/selecting other cells in the grafts | Selecting mesenchymal cells, NK cells, and manipulating dendritic cells and dendritic cell subsets | [79,122,129] | |
Drug intervention | Application of immunosuppressants | Various immunosuppressants suppress T cells and reduce GVHD via different mechanisms | [130] |
Application of HDACis | HDACis, such as vorinostat, downregulate inflammatory cytokines and increase the number of Tregs, thereby reducing the occurrence of GVHD, without effecting the GVL effect of donor CTLs | [131,132] | |
Suppression of cytokines related to the occurrence of GVHD | Th1 cytokines such as TNF-α, IFN-γ, and IL-6 are related to aGVHD; Th2 cytokines such as IL-4, IL-5, and IL-10 are related to cGVHD. Appropriate regulation of these cytokines facilitates GVHD management | [122] | |
Enhancing cytokines that suppress GVHD | Various cytokines such as IL-11 and keratinocyte growth factor reduce GVHD while preserving the GVL effect | [122] | |
Targeting MiHAs on hematopoietic cells | CTLs targeting MiHAs such as HA-1 and HA-2 (expressed on hematopoietic cells only) promote the GVL effect | [121] | |
Development and application of tumor vaccines | Vaccines targeting MiHAs on hematopoietic cells and leukemia-specific antigens improve GVL specificity | [133] |
Table 4 Main factors for post-hematopoietic stem cell transplantation relapse
Factors | Brief description | Ref. |
Disease type | The relapse rate is highest in ALL patients, followed by AML patients and CML patients | [161] |
Pretransplant disease status | The risk of relapse is significantly higher in nonremission patients and patients with a high level of residual leukemia cells before transplantation | [151] |
Risk stratification | The level of risk is positively correlated with the relapse rate and negatively correlated with the disease-free survival rate | [162] |
Stem cell source | Peripheral blood stem cells contain more lymphocytes with a more potent GVL effect; as a result, the relapse rate of BMT is higher than that of PBSCT | [163,164] |
Preconditioning | Myeloablative preconditioning is more effective in reducing post-transplant relapse than reduced intensity conditioning and nonmyeloablative preconditioning; T cell depletion is associated with increased relapse rates in CML and AML | [164,165] |
GVHD | Post-transplant GVHD, especially cGVHD, is associated with a significantly lower relapse rate and a higher survival rate | [166,167] |
- Citation: Chen YF, Li J, Xu LL, Găman MA, Zou ZY. Allogeneic stem cell transplantation in the treatment of acute myeloid leukemia: An overview of obstacles and opportunities. World J Clin Cases 2023; 11(2): 268-291
- URL: https://www.wjgnet.com/2307-8960/full/v11/i2/268.htm
- DOI: https://dx.doi.org/10.12998/wjcc.v11.i2.268