1. Introduction
Hematopoietic stem cell transplantation (HSCT) has evolved over the course of its history from a method that was declared ineffective and of limited applicability in the 1960s to a standard treatment for fatal malignant and benign blood diseases [ 1 ]. To date, approximately 1.5 million HSCTs have been performed in more than 1500 transplant centers worldwide. Timely restoration of the immune system after hematopoietic cell transplantation is a critical factor associated with the development of complications such as relapses or secondary tumor diseases and various infections, as well as graft-versus-host disease (GVHD) in allogeneic transplantation, which ultimately affects patient survival [ 2 , 3 ]. Protection against infectious agents and antitumor control primarily depend on the reconstitution of the T-cell component of the immune system.
Recovery of various immune cell subsets after HSCT occurs at distinct time intervals. [ 4 ]. After conditioning therapy, patients undergo an “aplastic phase” (severe neutropenia or pre-engraftment phase) until neutrophils are restored. The doses of total nucleated cells (TNCs) and CD34 + cells in the graft source are key factors influencing the engraftment rate and outcome following HSCT [ 5 , 6 ].
Myelopoiesis is restored first, followed by natural killer (NK) cell numbers within 21–100 days, while adaptive immunity takes longer to recover [ 7 , 8 ]. The process of T-cell pool restoration is divided into two independent pathways: thymus-dependent and thymus-independent [ 9 , 10 ], with the second pathway being predominantly restored by homeostatic proliferation of T-lymphocytes, which results in a contraction of T cell receptor repertoire diversity. In the early post-transplant period, lymphocyte restoration occurs by the thymus-independent pathway, that is, by mature donor T-cells that were transfused to the recipient along with hematopoietic stem cells during transplantation, and to a lesser extent by the expansion of previously existing naive T-cells and memory T-cells of the recipient that “survived” after the conditioning [ 9 ]. The thymus-dependent pathway involves the de novo formation of naive T cells in the thymus and the subsequent formation of a pool of memory T cells that implement the main immunological reactions—“graft versus tumor” and “graft versus host” [ 11 , 12 ]. Restoration of the T-cell link is key to protection against viral infections, which are a serious complication after GVHD.
The B cell compartment, which is involved in humoral immunity, is the slowest to recover [ 13 ] and can take as long as 5 years after allogeneic HSCT. Transient CD19 + CD21 low CD38 high B cells are the first B cells to migrate from the bone marrow, and their levels increase in the peripheral blood in the first months after HSCT, after which their percentage gradually declines, while the proportion of more mature B cell subsets increases [ 14 ]. The absence of CD19 + CD27 + memory B cells, reduced levels of circulating immunoglobulins, impaired immunoglobulin class switching, and loss of complexity in immunoglobulin gene rearrangement patterns make patients undergoing allogeneic HSCT susceptible to encapsulated bacteria like Streptococcus pneumoniae and Haemophilus influenzae .
A promising approach to accelerate immune reconstitution and reduce risks in HSCT is cell therapy. Currently, various types of cell therapy schemes used in HSCT are being considered, including the introduction of cells before this therapy, co-transplantation when introducing stem cells into the recipient’s body, as well as the adoptive transfer of various cells, both once and in the form of a course with different durations and the introduction, of cells at different stages of immune system restoration.
2. Platelet and Red Blood Cell Therapy and HSCT
After chemotherapy and radiation therapy to prepare the patient for hematopoietic stem cell transplantation, pancytopenia is observed. It is known that rapidly dividing cells are most sensitive to the effects of cytostatic therapy, but high doses of drugs in the conditioning mode significantly reduce the number of formed elements of the blood. Patients who have received a hematopoietic stem cell transplant require extensive transfusion support with formed blood elements until the graft is established [ 15 ].
Platelets and erythrocytes, in addition to their direct functions of hemostasis and oxygen delivery to tissues, respectively, have immunomodulatory functions. It has been established that platelets participate in anti-infective protection, recruitment and stimulation of innate cell functions, activation of dendritic cells, and enhancement of the antigen presentation and adaptive immune response [ 16 ]. Depending on the microenvironmental conditions, erythrocytes may either facilitate immune activation or preserve immune quiescence [ 17 ]. Thus, platelets and erythrocytes may play an important role in modulating post-transplant immunity.
Platelet and red blood cell transfusion support are positively correlated with plasma tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and soluble thrombomodulin levels [ 18 ] and do not increase the risk of developing aGVHD. The only predictable complication in the form of rejection reactions is the transfusion of red blood cells with platelets, incompatible according to the ABO system, to patients [ 19 ]. However, in the case of transplantation of certain organs rather than HSCT, the transfusion of red blood cells at an early stage is associated with the risk of developing rejection reactions [ 18 ]. Platelet accumulation in grafts contributes to the development of vasculopathy and is associated with the risks of acute and chronic graft rejection. This is facilitated by platelet-derived humoral factors and the expression of surface markers such as CD39 and CD154 and secreted chemokines such as PF4 and β-thromboglobulin (β-TG), which recruit neutrophils, and regulated on activation, normal T cell expressed and secreted (RANTES), which in addition to recruiting monocytes, also recruits T cells [ 20 ]. It should be noted that such a negative side of immunomodulation with these cells is associated with the transplantation of parenchymatous organs. And in patients with allotransplantation of stem cells in the early post-transplantation period, platelet transfusion did not cause transplant rejection reactions [ 21 ].
We summarized the various data on the side effects of red blood cell and platelet transfusion after HSCT ( Table 1 ). Transfusion support for HSCT is an essential part of supportive care, and platelets and red blood cells should be transfused into recipients. Transfusion support is necessary to prevent the development of bleeding and anemia. The formation of red blood cells and megakaryocytes as a result of de novo hematopoiesis plays an important role in creating a microenvironment for stem cells and, consequently, better engraftment of the cells.
3. Granulocyte Transfusion
The granulocyte group includes neutrophils, basophils, eosinophils, and mast cells [ 26 ]. Neutrophils are the largest type of leukocytes in the blood of adult humans and are part of the innate immune system, helping to eliminate fungi and bacteria. Neutrophils, like other granulocytes, are formed quite quickly and have a short lifespan [ 27 ], due to which their pool is renewed faster than other white blood cell compartments. Because their numbers are easily restored, neutrophils have time to recover after HSCT within the week.
Neutrophils are also instrumental in regenerating the injured vascular niche and may provide strategies to accelerate regeneration of patients undergoing HSCT [ 28 ]. Newly generated neutrophils may promote regeneration of the sinusoidal network, which in turn facilitates the engraftment of hematopoietic progenitors. This positive vicious cycle continues until the vascular niche is restored and the bone marrow returns to homeostasis [ 29 ]. Depletion of mature neutrophils from the initial graft or genetic ablation of donor-derived neutrophils delayed regeneration of the vasculature in the bone marrow. Currently, there is evidence of the heterogeneity of neutrophil populations and their active participation in many processes associated with the activation of innate and adaptive immunity after HSCT [ 29 ].
It can be noted that granulocyte transfusion after HSCT may be effective in case of delayed recovery of neutrophil numbers. When evaluating the effectiveness of this type of cell therapy, ambiguous results were obtained [ 26 ]. This may be due to the insufficient number of patients in the study or the heterogeneity of the neutrophil pool. In a retrospective analysis, patients who received a mean transfusion dose ≥ 0.6 × 10 9 granulocytes per kilogram tended to have better outcomes than those who received a lower dose [ 30 ]. Another study also showed that granulocyte transfusion was effective in only a small part of patients [ 31 ].
Since granulocytes are difficult to separate from erythrocytes, they contain a large number of donor red blood cells, and therefore cells for transfusion must be ABO-compatible with the recipient plasma to avoid hemolytic reactions [ 32 ]. In addition, the product must be irradiated to prevent acute graft-versus-host disease. Cellular products from donors must be transfused within 24 h. It is important to note that granulocyte infusions are associated with fever and may cause more serious reactions such as acute lung injury. Thus, the question of the necessity of using donor granulocyte transfusions and methods of increasing the safety and effectiveness of the procedure remains open.
4. Adoptive Transfer of Lymphocytes
4.1. Depletion of αβT-Lymphocytes and CD19
Due to the decreased ability of the body to resist infectious processes after HSCT, a number of studies have been conducted on the effectiveness of the adoptive transfer of donor lymphocytes [ 33 , 34 , 35 , 36 ]. As a result of αβ T and CD19 depletion, a cellular product with a high content of stem cells, committed myeloid precursors, NK cells, and γδ T lymphocytes is formed. This type of depletion prevents the possible presence of adaptive immune cells, which is safe and associated with a minimal risk of GVHD, as well as other immune and toxic complications. The use of low-dose infusions of CD45RA-depleted donor lymphocytes correlates with a decrease in the cumulative probability of transplant mortality and an increase in the overall survival of allogeneic HSCT recipients with αβ T and CD19 depletion of the graft, which is apparently associated with a reduced risk of severe viral infections. However, reliable data confirming a reduction in the risk of recurrence of oncohematological diseases and transplant rejection events have not been obtained. Of interest is also the use of individual populations of lymphocytes that are part of TCRαβ/CD19 cell–depleted cells, such as NK cells, helper ILCs, gamma-delta T cells, etc.
4.2. NK Cells
NK cells are one of the populations of immune system cells that perform immunological surveillance of the tumor and are responsible for killing tumor cells [ 37 ]. At the same time, NK cells recognize the absence of “self” MHC molecules and, as a result, have alloreactivity, participating in the GVHD reaction in alloHSCT. Tolerance of NK cells to their own tissues is formed in the process of the interaction of inhibitory killer-cell immunoglobulin-like receptor (KIR) with their own HLA I molecules, which excludes the development of autoreactivity [ 38 ]. In contrast, when the expression of HLA I molecules is impaired, for example, on cells damaged due to infection or tumor cells, signals activating KIR prevail, and the mechanism of destruction of these cells is launched. This property of NK cells formed the basis of the “missing-self” hypothesis [ 37 ].
After allo-HSCT, most NK cells have on their cell membrane a donor repertoire of KIR molecules, which differs significantly from the repertoire of recipient NK cells before allo-HSCT [ 38 ]. Therefore, NK cells expressing donor KIRs may exhibit alloreactive properties in recipients. However, an increase in the pool of alloreactive NK cells in the peripheral blood of recipients allows the development of graft-versus-tumor disease early after allo-HSCT [ 39 ]. One possible explanation for the occurrence of graft-versus-tumor disease is that transfusion of donor HSCT may create a transient dominant environment of donor HLA in the recipient bone marrow, and donor NK cells expressing KIRs may be “educated” by donor HLA, which affects their functions [ 40 ]. After leaving the bone marrow and migrating into a recipient-dominated environment, NK cells eventually lose their ability to respond to recipient HLA I molecules.
A study in mice showed that adoptive transfer of IL-2-activated natural killers together with donor hematopoietic stem cells promotes effective graft engraftment and reduces the risk of severe GVHD [ 38 , 41 , 42 ]. Moreover, transfusion of mice with Ly49 + NK cells from MHC I-incompatible animals (Ly49 receptors in mice are similar to KIR in humans and recognize MHC class I molecules) promotes the elimination of residual host tumor cells and protects against GVHD by depleting host APCs [ 43 ]. In contrast, mice that received bone marrow transplantation without NK cell transfusion died from GVHD, and transfusion of NK cells from MHC I-compatible donors did not provide protection against GVHD. Subsequent studies also showed that donor alloreactive NK cells suppressed the development of GVHD by inhibiting T cell proliferation and activation [ 42 , 44 ]. A study in patients showed that patients with refractory AML who underwent haploidentical donor allo-HSCT (haplo-HSCT) followed by donor NK cell transfusion had a lower risk of developing GVHD than patients without NK cell transfusion [ 45 ]. The “protective” role of NK cells in the pathogenesis of GVHD has been questioned; in another study [ 46 ], patients who received transfusion of donor IL-15/4-1BBL-activated NK cells after haplo-HSCT with T cell depletion had a higher risk of GVHD. However, in phase I clinical trials, IL-2-activated NK cells from haploidentical donors demonstrated their safety and association with a low risk of developing GVHD [ 47 ].
Unlike alloreactive NK cells, autologous NK administration is not associated with the risk of GVHD, allowing for long-term infusion of these cells into patients without immunosuppressive conditioning [ 48 ]. Potential limitations of autologous NK cell-based products include the apparent lack of finished products and the ongoing manufacturing costs of producing the cell product. It has been suggested that autologous NK cell-based therapy may be particularly suitable for patients with low tumor burden, such as minimal residual disease. This is based on earlier studies in experimental model systems demonstrating the ability of NK cells to preferentially target small tumors [ 49 ].
An interesting option for cell therapy after auto-HSCT is the introduction of NK cells obtained from the umbilical cord blood of donors who do not match either the MHC I or KIR receptors [ 50 ]. A pilot study showed the safety of the therapy and a reduced risk of relapse in patients compared to the control group.
Thus, NK cell therapy after HSCT is primarily aimed at reducing the risk of tumor recurrence in both allo- and auto-HSCT ( Table 2 ). In the case of GVHD prevention in allo-HSCT, the role of NK cells is controversial and requires further research.
4.3. Innate Lymphoid Cells (ILC)
ILCs were originally considered T-cell analogues, and non-cytotoxic ILCs were largely mirroring functions of T helper (Th) subsets, subdivided into ILC1, ILC2, and ILC3, and duplicating the functions of Th1, Th2, and Th17 cells, respectively [ 51 ]. However, it is now believed that ILCs are not only innate T-helper cell analogues but also participate as a link between sensory cells that monitor any changes in the cell environment that are not necessarily pathogenic and instruct effector cells that act to maintain tissue homeostasis [ 52 ]. Therefore, restoration of the ILC pool after HSCT is essential for immune system function. It was found that, unlike NK cells, helper-like ILCs recovered slowly, mirroring the pattern observed for T cells, with normalization achieved at 1 year [ 53 , 54 ]. Interestingly, the total absence of ILCs was not linked to an increased susceptibility to diseases, suggesting that in the context of modern medical care and hygiene, along with the presence of a functional adaptive immune system, ILCs may be redundant [ 55 ].
The mechanisms behind ILC reconstitution following depletion remain unclear. Hematopoietic stem and progenitor cell (HSPC) grafts comprise both progenitor and mature ILC [ 56 ]. It is likely that circulating ILCs originate from common lymphoid progenitor (CLP) cells in the bone marrow, as well as from mature ILCs that were co-transfused with the graft. ILCs are generally considered to be tissue-resident cells reliant on local self-renewal. However, since donor-derived ILCs have been observed in non-lymphoid tissues following allogeneic HSCT, it is plausible that the seeding of ILCs from the circulation also contributes to this process. Lastly, environmental factors can influence ILC plasticity.
Allo-HSCT, sourced from the blood of G-CSF-mobilized healthy donors, exhibited a frequency of ILC closely resembling that found in the peripheral blood of healthy individuals [ 57 ]. The composition of ILC subsets was also comparable to that in the blood of donors, with the notable exception of NKp44 + ILC3, which were significantly more prevalent in the HSCT grafts. Furthermore, the relative ILC content in the graft showed a tendency to correlate with ILC reconstitution following allogeneic HSCT, indicating that the peripheral expansion of transplanted mature ILC may play a role in the early reconstitution of ILC post-transplantation. Patients who received a graft with a relatively low ILC content faced a significantly higher risk of developing acute GVHD compared to those who received allogeneic HCT grafts that were relatively high in ILC [ 58 ]. In another study it was found that graft-versus-host disease (GVHD) correlated with reduced levels of activated and gut-homing NKp44 + innate lymphoid cell progenitors (ILCPs), which supports the notion that this specific ILC subset plays a crucial and non-redundant role in preventing this life-threatening condition under lymphopenic circumstances [ 54 ].
Donor ILC2 infusion successfully reduced the lethality associated with aGVHD and effectively treated lower gastrointestinal tract disease in murine models of allogeneic HSCT [ 58 , 59 ]. However, another study demonstrated that ILC2 may change their phenotype following transplantation due to plasticity, which is one of several possible mechanisms behind the poor reconstitution of these important cells following allo-HSCT [ 60 ].
In the case of ILC, there is a shortage of cells after transplantation, but this does not lead to an increase in the incidence of infectious complications or the risk of relapse but increases the chances of developing GVHD. ILC infusions have reduced the risk of developing GVHD in mouse models of allo-HSCT.
4.4. γδ T Cells
γδ T-lymphocytes are T cells, but unlike conventional αβ T-cells, they occupy an intermediate position between innate and adaptive immunity [ 61 ]. γδ T cells are known to have antitumor activity and are capable of antigen presentation and clonal expansion but have no MHC restrictions. According to the literature, γδ T cell reconstitution occurs within the first few weeks after HSCT [ 62 , 63 , 64 , 65 ]. In children with haploidentical HSCT who received αβ T cell-depleted grafts, γδ T cells rapidly expand to reach up to 90% of the initial T cell pool and subsequently decline as αβ T cells begin to reconstitute [ 66 ]. Further characterization of γδ T cell composition one month after therapy revealed that the γδ T cell composition was not significantly different from that present in the peripheral blood of donors or healthy adults [ 66 ]. Similarly, studies of γδ T cell reconstitution at the clonal level showed that the reconstituted γδ T cell repertoire in blood remained highly stable over time after HSCT [ 65 ].
Clinical trials assessing the use of γδ T cells for targeting hematologic malignancies can be categorized into three distinct groups: (a) in vivo stimulation of autologous γδ T cells, (b) adoptive transfer of ex vivo expanded autologous γδ T cells, and (c) adoptive transfer of ex vivo expanded allogeneic γδ T cells [ 67 ]. As a result, an increase in survival and a decrease in the risk of GVHD were observed in most studies. However, Pabst et al. showed that patients who received higher levels of donor γδ T-lymphocytes experienced a higher incidence of acute GVHD (66% versus 40%, p = 0.02) [ 68 ]. Presumably, differences in cell effects may be due to different γδ T cell subsets, which must be taken into account when conducting therapy.
4.5. T Regulatory Cells (Treg)
It is known that Tregs provide tolerance to both auto- and alloantigens [ 69 , 70 , 71 ]. A significant decrease in the Treg:Th cell ratio at 2 weeks after allo-HSCT transplantation is associated with the development of acute GVHD [ 72 ], and a high probability of developing acute GVHD was also observed in patients with a low number of granzyme B + Treg [ 73 ]. During autologous HSCT, an increased content of CD4 + Foxp3 + cells (6.7%) in the peripheral blood of patients with multiple myeloma on the day of graft engraftment led to a relapse or progression of the tumor disease within 12 months after transplantation [ 74 ], which is possibly associated with the suppression of T-effector cell expansion at an early stage of immune reconstitution, while no cases of acute and chronic GVHD were recorded. The development of GVHD is also affected by the number of Tregs in the graft: a significant decrease in the likelihood of developing GVHD after allo-HSCT is observed with a Treg content of 10 × 10 6 /kg or more [ 75 , 76 ].
The suppressive effect of Tregs on GVHD is provided by contact-dependent and contact-independent mechanisms: cytolysis of effector cells (secretion of perforin and granzyme B); secretion of IL-10, TGF-β, and IL-35 immunosuppressive cytokines; depletion of IL-2 due to its greater consumption by Tregs due to high expression of CD25; induction of enzymatic breakdown of adenosine triphosphoric acid to adenosine; modulation of DC function both at the maturation stage and during the implementation of the antigen-presenting function [ 77 ].
It has been shown in animal models that the infusion of freshly isolated or ex vivo-obtained Tregs in various modes (prophylactically—before HSCT; therapeutically—simultaneously with the transplant or the day after transplantation) can restrain the development of GVHD or even prevent its development and ensure early immunoreconstitution [ 78 , 79 ]. The duration of the effect in preventing GVHD is directly related to the expansion and survival of Tregs in the recipient’s body [ 78 ]. The adoptive transfer of even low doses of Tregs can prevent the development of GVHD while maintaining the cytotoxic activity of conventional T cells in the graft-versus-tumor reaction [ 78 ]. However, there is evidence that the infusion of induced Tregs can reduce the effectiveness of the antitumor response after transplantation and lead to a short-term relapse of leukemia [ 80 , 81 ].
Most clinical trials involving adoptive transfer of Tregs in patients with hematological malignancies are aimed at reducing the incidence or severity of GVHD after allogeneic HSCT. The effect in preventing GVHD was confirmed using freshly isolated donor Tregs [ 82 , 83 ], which were administered to patients 4 days before HSCT. Repeated administration of in vitro expanded cord blood Tregs (0.1–30 × 10 5 cells), starting from the day after transplantation and until the absolute neutrophil count was above 2500/μL, reduced the incidence of acute GVHD (43% versus 61% in the historical control without Tregs) and did not increase the risks of infections, disease relapse, or early mortality [ 84 ]. Administration of ex vivo expanded CD4 + CD25 + CD127 − Tregs to patients with chronic GVHD significantly alleviated symptoms and reduced immunosuppressive pharmacotherapy [ 85 ]. However, no convincing effect of adoptive Treg therapy in the treatment of acute GVHD was demonstrated [ 86 ]. In 4 out of 5 patients with chronic GVHD refractory to treatment and receiving Tregs from HLA-matched donors after transplantation, an increase in Treg in the peripheral blood was observed against the background of a decrease in the amount of immunosuppressive therapy received, and 2 out of 5 patients achieved relief of GVHD symptoms [ 87 ]. However, the use of Tregs for the treatment of GVHD cannot be called successful, since skin cancer was diagnosed in 2 patients several months after the therapy [ 87 ].
Adoptive therapy uses not only Tregs but also added conventional donor T cells, which allows for greater success in preventing GVHD. Thus, within the HLA-haploidentical HSCT protocol, including the introduction of donor Tregs and infusion of donor T lymphocytes, the probability of relapse-free/moderate/severe chronic GVHD was 75% with a median follow-up of 29 months [ 88 ]. Patients with acute myeloid leukemia (50 people) received an infusion of 2 × 10 6 /kg donor Tregs on day −4, then 1 × 10 6 /kg donor T cells on day −1, and an average of 10.7 × 10 6 ± 3.4 × 10 6 /kg CD34 + HSCs on day 0. Moreover, after transplantation, leukemia relapse was observed in 4% of patients (2 people); 33% of patients (15 people) developed acute GVHD without transition to chronic, 2 of 15 patients died from acute GVHD, and 1 of 15 patients died from leukemia relapse [ 88 ].
In addition to classical CD4 + CD25 + Foxp3 + Treg, Tr1 cells (CD4 + Foxp3 − LAG3 + CD49b + ) that produce high levels of IL-10 are capable of supporting the restoration of immune cells and preventing the development of GVHD [ 89 ]. In 4 out of 12 patients with hemoblastoses, after the introduction of alloantigen-specific donor IL-10-anergized T cells (IL10-DLI) containing Tr1 (on average 35 days after haplo-HSCT), GVHD did not develop, and disease remission was maintained for a long time [ 90 ].
Thus, Tregs play an important role in limiting immune responses associated with alloantigen recognition and in preventing GVHD while maintaining an antitumor response against residual tumor clones and without increasing the risks of disease relapse and post-transplant infections. However, the use of Tregs is associated with a number of difficulties. The number of Treg populations in the body is small and, according to various estimates, is 4–10% of CD4 + T lymphocytes in peripheral blood; to ensure the required number for transplantation, it is necessary to resort to ex vivo Treg expansion [ 91 ], which in turn can affect the functional state of the cells. When introduced into the body, the question arises about the stability of Tregs, especially induced Tregs, which are highly plastic. Tregs are capable of acquiring various transcriptional programs in response to changing environmental conditions, in particular through cytokine signaling [ 92 ], and losing their immunosuppressive function. A solution to this problem may be Treg cells modified using genetic engineering approaches that maintain stable expression of Foxp3, IL-10, the ability to induce tolerance to alloantigens, and even antitumor activity [ 93 , 94 , 95 , 96 , 97 ]. Results of Treg cell therapy are presented in Table 3 .
5. Co-Transplantation of Mesenchymal Stem Cells
Mesenchymal stem cells (MSCs) are fibroblast-like cells capable of differentiating into various cell types, such as osteoblasts, chondrocytes, adipocytes, and others [ 98 ]. Characteristic features of MSCs are their adhesive ability to plastic and the expression of CD73, CD90, and CD105. MSCs can be obtained and efficiently collected from various tissue sources without significant ethical concerns, which determines their convenience for use in cell therapy [ 99 ].
A number of functional properties of MSCs suggest beneficial effects from the co-transplantation of these cells in HSCT. First, as key players in the bone marrow niche, MSCs support hematopoietic stem cell (HSC) function by secreting multiple factors (SCF, angiopontin, VCAM1, osteopontin, and extracellular matrix components) and expressing CXCL12 [ 100 , 101 ]. Second, MSCs do not stimulate alloreactivity and are not lysed by cytotoxic T cells and natural killers. Third, MSCs exhibit strong immunosuppressive properties, such as inhibition of activated T cell proliferation; downregulation of IL-2, TNF-α, IL-1β, and IFN-γ secretion; and stimulation of regulatory transcriptional complex expression, which supports Treg formation [ 99 ]. This suppressive activity has been shown to underlie the reduction in the risk of alloreactivity development during MSC co-transplantation in the context of HSCT [ 102 ]. Thus, the ability to modulate the bone marrow microenvironment, safety, low immunogenicity, and immunosuppressive properties of MSCs make them an interesting candidate for improving HSCT outcomes. Indeed, clinical studies demonstrate the effects of MSC co-transplantation in the form of a reduced risk of GvHD development and rapid restoration of hematopoiesis in the treatment of pathologies of various origins, including blood cancer [ 101 , 103 , 104 ].
Interestingly, MSCs, in the case of hematological malignancies, are involved in enhancing the engraftment efficiency of both myeloid and lymphoid lineages. In a study investigating the effect of co-transplantation of autologous MSCs on the early and late (homeostatic proliferation and thymopoiesis, respectively) stages of restoration of different T-cell subsets in patients with hematological malignancies, an improvement in the early restoration of both naive and memory cells was demonstrated, with a more pronounced effect on CD4 + lymphocytes in the MSCs(+) group compared to MSCs(-). The authors of the study emphasize that despite their immunosuppressive properties, under certain conditions, namely a small number of MSCs or a low basal level of T-lymphocyte proliferation, MSCs are capable of stimulating T-lymphocytes. At the same time, according to the results of the experiments, the restoration of CD4 + in the early post-transplant period was associated with the anti-apoptotic effect of MSCs. In addition, it was shown that patients from the MSCs(+) group were distinguished by more effective restoration of early thymic migrants (RTEs) [ 105 , 106 ]. Other studies by the same group of authors also showed earlier and more effective restoration of lymphocytes for patients with co-transplantation of auto-MSCs [ 107 ]. Thus, it is obvious that co-transplantation of auto-MSCs has an advantage in more pronounced restoration of the T-lymphocyte link compared to standard HSCT, both at the early and late post-transplantation stages.
Promising results were also obtained in a study of myeloid lineage cell regeneration during co-transplantation of auto-MSCs together with HSCs for blood cancer therapy. A significant reduction in the period of neutropenia and thrombocytopenia was shown. Interestingly, this result did not depend on the number of administered MSCs [ 108 ]. The above data are consistent with the results of other phase I/II clinical studies, which demonstrated a higher frequency of neutrophil and platelet engraftment in groups with pre-incubation of HSCs with allo-MSCs before administration. The authors associate these results with the ability of MSCs to repeat some signals of the bone marrow niche, which increases the proliferation and survival of progenitor cells in vitro before administration [ 109 , 110 ]. Thus, the use of MSC co-transplantation in both allo- and autotransplantation demonstrates positive effects for the engraftment of both myeloid and lymphoid lineage cells, indicating the prospects for their use in the context of HSC transplantation for hematological malignancies.
However, there is evidence of negative effects of MSCs in this context. Thus, in a clinical study assessing the effect of MSCs co-transplantation in allo-HSCT for people with hematological malignancies, an increased incidence and rate of relapse was shown for the MSCs(+) group compared to the MSCs(-) group. This was explained by the suppression of the graft-versus-tumor (GvT) response due to the immunosuppressive properties of MSCs. Moreover, the results of this study did not confirm the role of MSCs in improving the restoration of hematopoiesis parameters. In this regard, the authors suggest that MSC co-transplantation in allo-HSCT is more applicable in the treatment of non-malignant diseases, but not malignant hematopoietic diseases [ 111 ]. This example demonstrates that despite the numerous advantages of MSCs, there are certain risks associated with their use. Perhaps the discrepancies in the results may be associated with the protocol of the procedure and the characteristics of the presented sample. Indeed, some preclinical studies demonstrate that the results of cell therapy are affected by such parameters as the mode of radiation or chemotherapy, the dose of administered MSCs, and the conditions of administration of both MSCs and HSCs [ 112 ].
To summarize the above, it is necessary to pay attention to the remarkable prospects for the use of MSC co-transplantation in HSCT for leukemia treatment. Nevertheless, such studies require a certain degree of caution and the development of optimal therapy protocols.
6. Effect of Cell Therapy on Risks That Reduce the Effectiveness of HSCT
6.1. Transplant Failure
HSCT is associated with many complications, including those associated with post-transplant pancytopenia. Recent studies defined poor graft function (PGF) as at least bilinear severe cytopenia, which is characterized by the following: (1) ANC ≤ 0.5 × 10 9 /L, (2) platelet count ≤ 20 × 10 9 /L, and (3) hemoglobin ≤ 70 g/L for at least 3 consecutive days beyond day +28 after HSCT or the requirement of transfusion with full chimerism and a hypoplastic-aplastic bone marrow, while severe graft versus host disease (GVHD) and relapse were excluded [ 113 ]. Therefore, the rate of recovery is directly related to the development of complications and survival after HSCT. The co-transplantation of mesenchymal stem cells can increase the rate of hematopoiesis recovery [ 114 ]. However, the introduction of a number of other cells, such as erythrocytes [ 18 ], platelets [ 21 ], and neutrophils [ 28 ], helps to fill empty niches and ensures the maintenance of the immune system in the periphery during the period of pancytopenia.
6.2. Relapse of Cancer
Relapse is the most common cause of treatment failure after HSCT [ 115 ]. Antitumor activity is predominantly exerted by cytotoxic T-lymphocytes and NK cells; infusions of killer cells can be used in the relapse of leukemia [ 34 , 35 , 36 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 ]. However, the use of these cells is associated with a number of complications, including the development of GVHD. It is also possible to use γδT cells to enhance the antitumor response [ 67 ]. Cell therapy is still facing challenges regarding the difficulties in its expansion and the standardization of protocols.
6.3. Graft-Versus-Host Disease (GVHD)
GVHD is one of the most common complications in allo-HSCT [ 116 ]. The main drugs for its prevention remain calcineurin inhibitors (cyclosporine A and tacrolimus), methotrexate, and mycophenolate mofetil. With the spread of low-intensity conditioning regimens, antithymocyte globulin has become widely used. However, a “negative” effect on the reconstitution of the T-cell link of immunity was noted, which increases the risk of severe infectious complications and relapse of the disease. With the increasing number of alternative (partially matched and haploidentical) donor transplants, cyclophosphamide (CP) has been widely used as a prophylactic agent. Adoptive transfer of NK cells, γδT cells, ILCs, and T-regulatory cells may be considered additional cell therapy.
6.4. Infections
First of all are viral infections such as cytomegalovirus (CMV) and Epstein–Barr virus (EBV), with viral reactivation thought to reflect the status of T cell recovery [ 117 ]. Memory CD8 + T cell populations seem to play a crucial role in providing protection against CMV and EBV or in their elimination, while for other herpes viruses like adenovirus and HHV-6, the count of CD4 + T cells is the primary predictor of both reactivation and outcomes. Additionally, CD4 + T cell count is a key predictor of long-term immunity against CMV. The reactivation of CMV significantly stimulates overall T cell recovery, with the most pronounced effect observed six months after HSCT. In contrast, reactivation of HHV-6 may lead to reduced T cell counts in patients at both six months and one year following HSCT. The adoptive transfer of antigen-specific T cells is anticipated to become more common in the near future, as this approach directly addresses the mechanisms of viral reactivation.
7. Conclusions and Future Perspectives
Cell therapy, both in the form of co-transplantation with HSCT and in the form of cell infusions before and after HSCT, is an important addition to this type of therapy. The use of various cell therapy options can prevent various types of complications observed in both auto-HSCT and alloHSCT. An important advantage of cell therapy in HSCT is the ability to combine various methods of both introducing different types of cells and conventional therapy, which is standardly used to reduce the risk of complications. We assume that in order to increase the effectiveness of HSCT, it is necessary to develop complex therapy based on infusions of different types of cells, carried out individually depending on the parameters of the recipient. The basis for a personalized approach can be information about the diagnosis, the presence of minimal residual disease, indicators of the immune system and cellular composition before therapy, the pattern of leukocyte recovery, parameters of immune reconstitution in dynamics after HSCT, etc.
One of the important areas of further research is the combination of HSCT with concomitant cell therapy and various modern methods of antitumor therapy, including monoclonal antibodies and cell therapy. An equally promising direction is the creation of cell products in which the genes of the main histocompatibility complex molecules I and II would be switched off, but at the same time, there would be signals for inhibiting the recognition of “lack of self”, which would allow avoiding a number of complications. It should also be noted that it is necessary to improve technologies that allow producing the necessary cells ex vivo, which will make this type of therapy more accessible.
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Author Contributions
Conceptualization, V.D. and E.P.; writing—original draft preparation, E.P., E.B., M.B. and A.A.; writing—review and editing, E.P. and V.D.; funding acquisition, E.P. All authors have read and agreed to the published version of the manuscript.
Institutional Review Board Statement
Not applicable.
Data Availability Statement
No new data were created or analyzed in this study.
Conflicts of Interest
The authors declare no conflicts of interest.
References
1. Granot N. Storb R. History of hematopoietic cell transplantation: Challenges and progress Haematologica 2020 105 2716 2729 10.3324/haematol.2019.245688 33054108 PMC7716373
2. Roeker L.E. Dreger P. Brown J.R. Lahoud O.B. Eyre T.A. Brander D.M. Skarbnik A. Coombs C.C. Kim H.T. Davids M. Allogeneic stem cell transplantation for chronic lymphocytic leukemia in the era of novel agents Blood Adv. 2020 4 3977 3989 10.1182/bloodadvances.2020001956 32841336 PMC7448605
3. Pockley A.G. Lindsay J.O. Foulds G.A. Rutella S. Gribben J.G. Alexander T. Snowden J.A. Immune Reconstitution After Autologous Hematopoietic Stem Cell Transplantation in Crohn’s Disease: Current Status and Future Directions. A Review on Behalf of the EBMT Autoimmune Diseases Working Party and the Autologous Stem Cell Transplantation in Refractory CD-Low Intensity Therapy Evaluation Study Investigators Front. Immunol. 2018 9 646 10.3389/fimmu.2018.00646 29670622 PMC5893785
4. Cichocki F. Verneris M.R. Cooley S. Bachanova V. Brunstein C.G. Blazar B.R. Wagner J. Schlums H. Bryceson Y.T. Weisdorf D.J. The Past, Present, and Future of NK Cells in Hematopoietic Cell Transplantation and Adoptive Transfer Curr. Top. Microbiol. Immunol. 2016 395 225 243 10.1007/82_2015_445 26037048 PMC5870762
5. Remberger M. Törlén J. Ringdén O. Engström M. Watz E. Uhlin M. Mattsson J. Effect of Total Nucleated and CD34 + Cell Dose on Outcome after Allogeneic Hematopoietic Stem Cell Transplantation Biol. Blood Marrow Transplant. 2015 21 889 893 10.1016/j.bbmt.2015.01.025 25662230
6. Kupeli S. Inan G. Ozkan A. Sezgin G. Bayram I. Tanyeli A. Total nucleated cell dose in graft is a better prognostic factor for survival in pediatric patients transplanted with bone marrow compared to CD34+, CD3+, or total mononuclear cell count J. Clin. Apher. 2022 37 19 24 10.1002/jca.21946 34694023
7. Orrantia A. Terrén I. Astarloa-Pando G. González C. Uranga A. Mateos-Mazón J.J. García-Ruiz J.C. Riñón M. Rey M. Pérez-Fernandez S. NK Cell Reconstitution After Autologous Hematopoietic Stem Cell Transplantation: Association Between NK Cell Maturation Stage and Outcome in Multiple Myeloma Front. Immunol. 2021 12 748207 10.3389/fimmu.2021.748207 34675932 PMC8524090
8. Davison G.M. Opie J.J. Davids S.F.G. Mohammed R. Novitzky N. Early recovery of natural killer cells post T-cell depleted allogeneic stem cell transplantation using alemtuzumab “in the bag” Transpl. Immunol. 2024 84 102045 10.1016/j.trim.2024.102045 38641148
9. Popova N.N. Savchenko V.G. Reconstitution of T-cell-mediated immunity in patients after allogeneic stem cell transplantation Russ. J. Hematol. Transfusiol. 2020 65 24 38 (In Russian) 10.35754/0234-5730-2020-65-1-24-38
10. Velardi E. Tsai J.J. van den Brink M.R.M. T cell regeneration after immunological injury Nat. Rev. Immunol. 2021 21 277 291 10.1038/s41577-020-00457-z 33097917 PMC7583557
11. Gao X. Xu C. Li B. Zhao L. Yu Y. Su Y. Wang J. Liu N. Chen J. Hu J. Quantitative Analysis of Thymus-Independent Donor-Derived T Cell Expansion in Transplant Patients Biol. Blood Marrow Transplant. 2020 26 242 253 10.1016/j.bbmt.2019.10.026 31682978
12. Gaballa A. Clave E. Uhlin M. Toubert A. Arruda L.C.M. Evaluating Thymic Function After Human Hematopoietic Stem Cell Transplantation in the Personalized Medicine Era Front. Immunol. 2020 11 1341 10.3389/fimmu.2020.01341 32849495 PMC7412601
13. van der Maas N.G. Berghuis D. van der Burg M. Lankester A.C. B Cell Reconstitution and Influencing Factors After Hematopoietic Stem Cell Transplantation in Children Front. Immunol. 2019 10 782 10.3389/fimmu.2019.00782 31031769 PMC6473193
14. Ogonek J. Kralj Juric M. Ghimire S. Varanasi P.R. Holler E. Greinix H. Weissinger E. Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation Front. Immunol. 2016 7 507 10.3389/fimmu.2016.00507 27909435 PMC5112259
15. Jekarl D.W. Kim J.K. Han J.H. Lee H. Yoo J. Lim J. Kim Y. Transfusion support in hematopoietic stem cell transplantation Blood Res. 2023 58 S1 S7 10.5045/br.2023.2023004 36843378 PMC10133853
16. Ali R.A. Wuescher L.M. Worth R.G. Platelets: Essential components of the immune system Curr. Trends Immunol. 2015 16 65 78 27818580 PMC5096834
17. Anderson H.L. Brodsky I.E. Mangalmurti N.S. The Evolving Erythrocyte: Red Blood Cells as Modulators of Innate Immunity J. Immunol. 2018 201 1343 1351 10.4049/jimmunol.1800565 30127064 PMC6108441
18. Gaiffe E. Vernerey D. Bardiaux L. Leroux F. Meurisse A. Bamoulid J. Courivaud C. Saas P. Tiberghien P. Ducloux D. Early Post-Transplant Red Blood Cell Transfusion Is Associated with an Increased Risk of Transplant Failure: A Nationwide French Study Front. Immunol. 2022 13 854850 10.3389/fimmu.2022.854850 35711440 PMC9197232
19. Cohn C.S. Transfusion support issues in hematopoietic stem cell transplantation Cancer Control 2015 22 52 59 10.1177/107327481502200108 25504279
20. Morrell C.N. Sun H. Swaim A.M. Baldwin W.M. 3rd Platelets an inflammatory force in transplantation Am. J. Transplant. 2007 7 2447 2454 10.1111/j.1600-6143.2007.01958.x 17927608
21. Wandt H. Schaefer-Eckart K. Frank M. Birkmann J. Wilhelm M. A therapeutic platelet transfusion strategy is safe and feasible in patients after autologous peripheral blood stem cell transplantation Bone Marrow Transplant. 2006 37 387 392 10.1038/sj.bmt.1705246 16400342
22. Hosoba S. Waller E.K. Shenvi N. Graiser M. Easley K.A. Al-Kadhimi Z. Andoh A. Antun A.G. Barclay S. Josephson C.D. Peritransplantation Red Blood Cell Transfusion Is Associated with Increased Risk of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation Biol. Blood Marrow Transplant. 2018 24 973 982 10.1016/j.bbmt.2018.01.003 29307717 PMC5953791
23. Christou G. Kekre N. Petrcich W. Tokessy M. Neurath D. Giulivi A. Saidenberg E. McDiarmid S. Atkins H. Bence-Bruckler I. Impact of platelet transfusion on toxicity and mortality after hematopoietic progenitor cell transplantation Transfusion 2015 55 253 258 10.1111/trf.12817 25125085
24. Gjærde L.K. Sørensen A.L.T. von Stemann J.H. Fischer-Nielsen A. Hansen M.B. Sengeløv H. Ostrowski S.R. Platelet and Red Blood Cell Transfusions and Risk of Acute Graft-versus-Host Disease after Myeloablative Allogeneic Hematopoietic Cell Transplantation Transplant. Cell Ther. 2021 27 866.e1 866.e9 10.1016/j.jtct.2021.07.001 34252580
25. Yuan S. Yang D. Nakamura R. Al Malki M.M. Salhotra A. Afkhami M. Wang S. Lack of RBC transfusion independence by Day 30 following allogeneic hematopoietic stem cell transplant strongly predicts inferior survival and high non-relapse mortality in acute myeloid leukemia patients Transfusion 2024 64 255 280 10.1111/trf.17714 38225215
26. Meng Y. Sun J. Qv N. Zhang G. Yu T. Piao H. Application of molecular imaging technology in tumor immunotherapy Cell Immunol. 2020 348 104039 10.1016/j.cellimm.2020.104039 32007223
27. Potts J.R. Farahi N. Heard S. Chilvers E.R. Verma S. Peters A.M. Circulating granulocyte lifespan in compensated alcohol-related cirrhosis: A pilot study Physiol. Rep. 2016 4 e12836 10.14814/phy2.12836 27613822 PMC5027336
28. Cossío I. Lucas D. Hidalgo A. Neutrophils as regulators of the hematopoietic niche Blood 2019 133 2140 2148 10.1182/blood-2018-10-844571 30898859 PMC6524561
29. Tecchio C. Cassatella M.A. Uncovering the multifaceted roles played by neutrophils in allogeneic hematopoietic stem cell transplantation Cell Mol. Immunol. 2021 18 905 918 10.1038/s41423-020-00581-9 33203938 PMC8115169
30. Price T.H. Boeckh M. Harrison R.W. McCullough J. Ness P.M. Strauss R.G. Nichols W.G. Hamza T.H. Cushing M.M. King K.E. Efficacy of transfusion with granulocytes from G-CSF/dexamethasone-treated donors in neutropenic patients with infection Blood 2015 126 2153 2161 10.1182/blood-2015-05-645986 26333778 PMC4626256
31. Özkan S.G. Kimiaei A. Safaei S. Sönmezoğlu M. Özkan H.A. Granulocyte Transfusions in Neutropenic Infections: Insights from a Single-Center Study Cureus 2024 16 e55953 10.7759/cureus.55953 38601410 PMC11005880
32. Adkins B.D. Jacobs J.W. Booth G.S. Savani B.N. Stephens L.D. Transfusion Support in Hematopoietic Stem Cell Transplantation: A Contemporary Narrative Review Clin. Hematol. Int. 2024 6 128 140 10.46989/001c.94135 38817704 PMC11086996
33. Riddell S.R. Watanabe K.S. Goodrich J.M. Li C.R. Agha M.E. Greenberg P.D. Restoration of viral immunity in immunodeficient humans by the adoptive transfer of T cell clones Science 1992 257 238 241 10.1126/science.1352912 1352912
34. Li Pira G. Malaspina D. Girolami E. Biagini S. Cicchetti E. Conflitti G. Broglia M. Ceccarelli S. Lazzaro S. Pagliara D. Selective Depletion of αβ T Cells and B Cells for Human Leukocyte Antigen-Haploidentical Hematopoietic Stem Cell Transplantation. A Three-Year Follow-Up of Procedure Efficiency Biol. Blood Marrow Transplant. 2016 22 2056 2064 10.1016/j.bbmt.2016.08.006 27519279
35. Sahasrabudhe K. Otto M. Hematti P. Kenkre V. TCR αβ+/CD19+ cell depletion in haploidentical hematopoietic allogeneic stem cell transplantation: A review of current data Leuk. Lymphoma 2019 60 598 609 10.1080/10428194.2018.1485905 30187806 PMC6764418
36. Merli P. Algeri M. Galaverna F. Bertaina V. Lucarelli B. Boccieri E. Becilli M. Quagliarella F. Rosignoli C. Biagini S. TCRαβ/CD19 cell-depleted HLA-haploidentical transplantation to treat pediatric acute leukemia: Updated final analysis Blood 2024 143 279 289 10.1182/blood.2023021336 37738655
37. Abel A.M. Yang C. Thakar M.S. Malarkannan S. Natural Killer Cells: Development, Maturation, and Clinical Utilization Front. Immunol. 2018 9 1869 10.3389/fimmu.2018.01869 30150991 PMC6099181
38. Konova Z.V. Parovichnikova E.N. Galtseva I.V. Khamaganova E.G. Impact of natural killer cell’s functional reconstruction on the results of allogeneic hematopoietic stem cell transplantation Gematol. I Transfuziol. 2022 67 551 569 (In Russian) 10.35754/0234-5730-2022-67-4-551-569
39. Rathmann S. Glatzel S. Schönberg K. Uhrberg M. Follo M. Schulz-Huotari C. Kaymer M. Veelken H. Finke J. Fisch P. Expansion of NKG2A-LIR1-natural killer cells in HLA-matched, killer cell immunoglobulin-like receptors/HLA-ligand mismatched patients following hematopoietic cell transplantation Biol. Blood Marrow Transplant. 2010 16 469 481 10.1016/j.bbmt.2009.12.008 20044012
40. Moretta L. Locatelli F. Pende D. Marcenaro E. Mingari M.C. Moretta A. Killer Ig-like receptor-mediated control of natural killer cell alloreactivity in haploidentical hematopoietic stem cell transplantation Blood 2011 117 764 771 10.1182/blood-2010-08-264085 20889923
41. Asai O. Longo D.L. Tian Z.G. Hornung R.L. Taub D.D. Ruscetti F.W. Murphy W.J. Suppression of graft-versus-host disease and amplification of graft-versus-tumor effects by activated natural killer cells after allogeneic bone marrow transplantation J. Clin. Investig. 1998 101 1835 1842 10.1172/JCI1268 9576746 PMC508768
42. Olson J.A. Leveson-Gower D.B. Gill S. Baker J. Beilhack A. Negrin R.S. NK cells mediate reduction of GVHD by inhibiting activated, alloreactive T cells while retaining GVT effects Blood 2010 115 4293 4301 10.1182/blood-2009-05-222190 20233969 PMC2879101
43. Ruggeri L. Capanni M. Urbani E. Perruccio K. Shlomchik W.D. Tosti A. Posati S. Rogaia D. Frassoni F. Aversa F. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants Science 2002 295 2097 2100 10.1126/science.1068440 11896281
44. Hüber C.M. Doisne J.M. Colucci F. IL-12/15/18-preactivated NK cells suppress GvHD in a mouse model of mismatched hematopoietic cell transplantation Eur. J. Immunol. 2015 45 1727 1735 10.1002/eji.201445200 25778912 PMC4687420
45. Jaiswal S.R. Zaman S. Nedunchezhian M. Chakrabarti A. Bhakuni P. Ahmed M. Sharma K. Rawat S. O’Donnell P. Chakrabarti S. CD56-enriched donor cell infusion after post-transplantation cyclophosphamide for haploidentical transplantation of advanced myeloid malignancies is associated with prompt reconstitution of mature natural killer cells and regulatory T cells with reduced incidence of acute graft versus host disease: A pilot study Cytotherapy 2017 19 531 542 10.1016/j.jcyt.2016.12.006 28131632
46. Shah N.N. Baird K. Delbrook C.P. Fleisher T.A. Kohler M.E. Rampertaap S. Lemberg K. Hurley C.K. Kleiner D.E. Merchant M.S. Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell-depleted stem cell transplantation Blood 2015 125 784 792 10.1182/blood-2014-07-592881 25452614 PMC4311226
47. Devillier R. Calmels B. Guia S. Taha M. Fauriat C. Mfarrej B. Venton G. Vivier E. Olive D. Chabannon C. Phase I Trial of Prophylactic Donor-Derived IL-2-Activated NK Cell Infusion after Allogeneic Hematopoietic Stem Cell Transplantation from a Matched Sibling Donor Cancers 2021 13 2673 10.3390/cancers13112673 34071607 PMC8198961
48. Nahi H. Chrobok M. Meinke S. Gran C. Marquardt N. Afram G. Sutlu T. Gilljam M. Stellan B. Wagner A.K. Autologous NK cells as consolidation therapy following stem cell transplantation in multiple myeloma Cell Rep. Med. 2022 3 100508 10.1016/j.xcrm.2022.100508 35243416 PMC8861830
49. Ljunggren H.G. Kärre K. Host resistance directed selectively against H-2-deficient lymphoma variants. Analysis of the mechanism J. Exp. Med. 1985 162 1745 1759 10.1084/jem.162.6.1745 3877776 PMC2187973
50. Wu Y. Wang Y. Ji J. Kuang P. Chen X. Liu Z. Li J. Dong T. Li X. Chen Q. A pilot study of cord blood-derived natural killer cells as maintenance therapy after autologous hematopoietic stem cell transplantation Ann. Hematol. 2023 102 3229 3237 10.1007/s00277-023-05471-4 37775597
51. Vivier E. The discovery of innate lymphoid cells Nat. Rev. Immunol. 2021 21 616 10.1038/s41577-021-00595-y 34580448
52. Xiong L. Nutt S.L. Seillet C. Innate lymphoid cells: More than just immune cells Front. Immunol. 2022 13 1033904 10.3389/fimmu.2022.1033904 36389661 PMC9643152
53. Munneke J.M. Björklund A.T. Mjösberg J.M. Garming-Legert K. Bernink J.H. Blom B. Huisman C. van Oers M.H.J. Spits H. Malmberg K.-J. Activated innate lymphoid cells are associated with a reduced susceptibility to graft-versus-host disease Blood 2014 124 812 821 10.1182/blood-2013-11-536888 24855210
54. Piperoglou C. Larid G. Vallentin B. Balligand L. Crinier A. Banzet N. Farnarier C. Gomez-Massa E. Adalia A.C. CRYOSTEM Consortium Innate lymphoid cell recovery and occurrence of GvHD after hematopoietic stem cell transplantation J. Leukoc. Biol. 2022 111 161 172 10.1002/JLB.5A1019-522RR 33847423
55. Vély F. Barlogis V. Vallentin B. Neven B. Piperoglou C. Ebbo M. Perchet T. Petit M. Yessaad N. Touzot F. Evidence of innate lymphoid cell redundancy in humans Nat. Immunol. 2016 17 1291 1299 Erratum in Nat. Immunol. 2016 , 17 , 1479 10.1038/ni1216-1479b 27618553 PMC5074366
56. Blom B. van Hoeven V. Hazenberg M.D. ILCs in hematologic malignancies: Tumor cell killers and tissue healers Semin. Immunol. 2019 41 101279 10.1016/j.smim.2019.06.002 31200953
57. Kroeze A. van Hoeven V. Verheij M.W. Turksma A.W. Weterings N. van Gassen S. Zeerleder S.S. Blom B. Voermans C. Hazenberg M.D. Presence of innate lymphoid cells in allogeneic hematopoietic grafts correlates with reduced graft-versus-host disease Cytotherapy 2022 24 302 310 10.1016/j.jcyt.2021.10.011 35058143
58. Bruce D.W. Stefanski H.E. Vincent B.G. Dant T.A. Reisdorf S. Bommiasamy H. Serody D.A. Wilson J.E. McKinnon K.P. Shlomchik W.D. Type 2 innate lymphoid cells treat and prevent acute gastrointestinal graft-versus-host disease J. Clin. Investig. 2017 127 1813 1825 10.1172/JCI91816 28375154 PMC5409787
59. Bruce D.W. Kolupaev O. Laurie S.J. Bommiasamy H. Stefanski H. Blazar B.R. Coghill J.M. Serody J.S. Third-party type 2 innate lymphoid cells prevent and treat GI tract GvHD Blood Adv. 2021 5 4578 4589 10.1182/bloodadvances.2020001514 34619767 PMC8759141
60. Laurie S.J. Foster J.P. Bruce D.W. Bommiasamy H. Kolupaev O.V. Yazdimamaghani M. Pattenden S.G. Chao N.J. Sarantopoulos S. Parker J.S. Type II innate lymphoid cell plasticity contributes to impaired reconstitution after allogeneic hematopoietic stem cell transplantation Nat. Commun. 2024 15 6000 10.1038/s41467-024-50263-7 39019846 PMC11255294
61. Latha T.S. Reddy M.C. Durbaka P.V. Rachamallu A. Pallu R. Lomada D. γδ T Cell-Mediated Immune Responses in Disease and Therapy Front. Immunol. 2014 5 571 10.3389/fimmu.2014.00571 25426120 PMC4225745
62. Chaudhry M.S. Velardi E. Malard F. van den Brink M.R. Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation: Time to T up the Thymus J. Immunol. 2017 198 40 46 10.4049/jimmunol.1601100 27994167
63. Dekker L. de Koning C. Lindemans C. Nierkens S. Reconstitution of T Cell Subsets Following Allogeneic Hematopoietic Cell Transplantation Cancers 2020 12 1974 10.3390/cancers12071974 32698396 PMC7409323
64. de Witte M.A. Sarhan D. Davis Z. Felices M. Vallera D.A. Hinderlie P. Curtsinger J. Cooley S. Wagner J. Kuball J. Early Reconstitution of NK and γδ T Cells and Its Implication for the Design of Post-Transplant Immunotherapy Biol. Blood Marrow Transplant. 2018 24 1152 1162 10.1016/j.bbmt.2018.02.023 29505821 PMC5993609
65. Gaballa A. Arruda L.C.M. Uhlin M. Gamma delta T-cell reconstitution after allogeneic HCT: A platform for cell therapy Front. Immunol. 2022 13 971709 10.3389/fimmu.2022.971709 36105821 PMC9465162
66. Airoldi I. Bertaina A. Prigione I. Zorzoli A. Pagliara D. Cocco C. Meazza R. Loiacono F. Lucarelli B. Bernardo M.E. γδ T-cell reconstitution after HLA-haploidentical hematopoietic transplantation depleted of TCR-αβ+/CD19+ lymphocytes Blood 2015 125 2349 2358 10.1182/blood-2014-09-599423 25612623 PMC4440890
67. Jhita N. Raikar S.S. Allogeneic gamma delta T cells as adoptive cellular therapy for hematologic malignancies Explor. Immunol. 2022 2 334 350 10.37349/ei.2022.00054 35783107 PMC9249101
68. Pabst C. Schirutschke H. Ehninger G. Bornhäuser M. Platzbecker U. The graft content of donor T cells expressing gamma delta TCR+ and CD4+foxp3+ predicts the risk of acute graft versus host disease after transplantation of allogeneic peripheral blood stem cells from unrelated donors Clin. Cancer Res. 2007 13 2916 2922 10.1158/1078-0432.CCR-06-2602 17504991
69. Sakaguchi S. Sakaguchi N. Shimizu J. Yamazaki S. Sakihama T. Itoh M. Kuniyasu Y. Nomura T. Toda M. Takahashi T. Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: Their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance Immunol. Rev. 2001 182 18 32 10.1034/j.1600-065X.2001.1820102.x 11722621
70. Taylor P.A. Noelle R.J. Blazar B.R. CD4(+)CD25(+) immune regulatory cells are required for induction of tolerance to alloantigen via costimulatory blockade J. Exp. Med. 2001 193 1311 1318 10.1084/jem.193.11.1311 11390438 PMC2193378
71. Hara M. Kingsley C. Niimi M. IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo J. Immunol. 2001 166 3789 10.4049/jimmunol.166.6.3789 11238621
72. Fujioka T. Tamaki H. Ikegame K. Yoshihara S. Taniguchi K. Kaida K. Kato R. Inoue T. Nakata J. Ishii S. Frequency of CD4(+)FOXP3(+) regulatory T-cells at early stages after HLA-mismatched allogeneic hematopoietic SCT predicts the incidence of acute GVHD Bone Marrow Transplant. 2013 48 859 864 10.1038/bmt.2012.232 23165499
73. Drokov M.Y. Davydova J.O. Kuzmina L.A. Galtseva I.V. Kapranov N.M. Vasilyeva V.A. Dubnyak D.S. Koroleva O.M. Mikhalcova E.D. Popova N.N. Level of Granzyme B-positive T-regulatory cells is a strong predictor biomarker of acute Graft-versus-host disease after day + 30 after allo-HSCT Leuk. Res. 2017 54 25 29 10.1016/j.leukres.2017.01.014 28095351
74. Batorov E.V. Tikhonova M.A. Pronkina N.V. Kryuchkova I.V. Sergeevicheva V.V. Sizikova S.A. Ushakova G.Y. Aristova T.A. Batorova D.S. Menyaeva E.V. Increased circulating CD4+FOXP3+ T cells associate with early relapse following autologous hematopoietic stem cell transplantation in multiple myeloma patients Oncotarget 2018 9 27305 27317 10.18632/oncotarget.25553 29930767 PMC6007464
75. Rezvani K. Mielke S. Ahmadzadeh M. Kilical Y. Savani B.N. Zeilah J. Keyvanfar K. Montero A. Hensel N. Kurlander R. High donor FOXP3-positive regulatory T-cell (Treg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT Blood 2006 108 1291 1297 10.1182/blood-2006-02-003996 16627754 PMC1895877
76. Yang K. Fan Z.P. Liu Q.F. Zhang Y. Effect of donor CD4+CD25+ regulatory T cells on hematopoietic and immune reconstitution, GVHD and disease-free survival after allogeneic hematopoietic stem cell transplantation Nan Fang Yi Ke Da Xue Xue Bao = J. S. Med. Univ. 2008 28 537 541 (In Chinese) 10.1182/blood.V108.11.2910.2910 18495584
77. Guo W.W. Su X.H. Wang M.Y. Han M.Z. Feng X.M. Jiang E.L. Regulatory T Cells in GVHD Therapy Front. Immunol. 2021 12 697854 10.3389/fimmu.2021.697854 34220860 PMC8250864
78. Nguyen V.H. Zeiser R. Dasilva D.L. Chang D.S. Beilhack A. Contag C.H. Negrin R.S. In vivo dynamics of regulatory T-cell trafficking and survival predict effective strategies to control graft-versus-host disease following allogeneic transplantation Blood 2007 109 2649 2656 10.1182/blood-2006-08-044529 17095616
79. Riegel C. Boeld T.J. Doser K. Huber E. Hoffmann P. Edinger M. Efficient treatment of murine acute GvHD by in vitro expanded donor regulatory T cells Leukemia 2020 34 895 908 10.1038/s41375-019-0625-3 31719679 PMC7214258
80. Zhang P. Tey S.K. Koyama M. Kuns R.D. Olver S.D. Lineburg K.E. Lor M. Teal B.E. Raffelt N.C. Raju J. Induced regulatory T cells promote tolerance when stabilized by rapamycin and IL-2 in vivo J. Immunol. 2013 191 5291 5303 10.4049/jimmunol.1301181 24123683
81. Heinrichs J. Li J. Nguyen H. Wu Y. Bastian D. Daethanasanmak A. Sofi M.H. Schutt S. Liu C. Jin J. CD8(+) Tregs promote GVHD prevention and overcome the impaired GVL effect mediated by CD4(+) Tregs in mice Oncoimmunology 2016 5 e1146842 10.1080/2162402X.2016.1146842 27471614 PMC4938369
82. Di Ianni M. Falzetti F. Carotti A. Terenzi A. Castellino F. Bonifacio E. Del Papa B. Zei T. Ostini R.I. Cecchini D. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation Blood 2011 117 3921 3928 10.1182/blood-2010-10-311894 21292771
83. Di Ianni M. Falzetti F. Carotti A. Terenzi A. Del Papa B. Perruccio K. Ruggeri L. Sportoletti P. Rosati E. Marconi P. Immunoselection and clinical use of T regulatory cells in HLA-haploidentical stem cell transplantation Best Pract. Res. Clin. Haematol. 2011 24 459 466 10.1016/j.beha.2011.05.005 21925099
84. Brunstein C.G. Miller J.S. Cao Q. McKenna D.H. Hippen K.L. Curtsinger J. Defor T. Levine B.L. June C.H. Rubinstein P. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: Safety profile and detection kinetics Blood 2011 117 1061 1070 10.1182/blood-2010-07-293795 20952687 PMC3035067
85. Brunstein C.G. Miller J.S. McKenna D.H. Hippen K.L. DeFor T.E. Sumstad D. Curtsinger J. Verneris M.R. MacMillan M.L. Levine B.L. Umbilical cord blood-derived T regulatory cells to prevent GVHD: Kinetics, toxicity profile, and clinical effect Blood 2016 127 1044 1051 10.1182/blood-2015-06-653667 26563133 PMC4768428
86. Trzonkowski P. Bieniaszewska M. Juścińska J. Dobyszuk A. Krzystyniak A. Marek N. Myśliwska J. Hellmann A. First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127− T regulatory cells Clin. Immunol. 2009 133 22 26 10.1016/j.clim.2009.06.001 19559653
87. Theil A. Tuve S. Oelschlägel U. Maiwald A. Döhler D. Oßmann D. Zenkel A. Wilhelm C. Middeke J.M. Shayegi N. Adoptive transfer of allogeneic regulatory T cells into patients with chronic graft-versus-host disease Cytotherapy 2015 17 473 486 10.1016/j.jcyt.2014.11.005 25573333
88. Pierini A. Ruggeri L. Carotti A. Falzetti F. Saldi S. Terenzi A. Zucchetti C. Ingrosso G. Zei T. Iacucci Ostini R. Haploidentical age-adapted myeloablative transplant and regulatory and effector T cells for acute myeloid leukemia Blood Adv. 2021 5 1199 1208 10.1182/bloodadvances.2020003739 33646302 PMC7948281
89. Sayitoglu E.C. Freeborn R.A. Roncarolo M.G. The Yin and Yang of Type 1 Regulatory T Cells: From Discovery to Clinical Application Front. Immunol. 2021 12 693105 10.3389/fimmu.2021.693105 34177953 PMC8222711
90. Bacchetta R. Lucarelli B. Sartirana C. Gregori S. Lupo Stanghellini M.T. Miqueu P. Tomiuk S. Hernandez-Fuentes M. Gianolini M.E. Greco R. Immunological Outcome in Haploidentical-HSC Transplanted Patients Treated with IL-10-Anergized Donor T Cells Front. Immunol. 2014 5 16 10.3389/fimmu.2014.00016 24550909 PMC3907718
91. Marín Morales J.M. Münch N. Peter K. Freund D. Oelschlägel U. Hölig K. Böhm T. Flach A.C. Keßler J. Bonifacio E. Automated Clinical Grade Expansion of Regulatory T Cells in a Fully Closed System Front. Immunol. 2019 10 38 10.3389/fimmu.2019.00038 30778344 PMC6369367
92. DuPage M. Bluestone J.A. Harnessing the plasticity of CD4(+) T cells to treat immune-mediated disease Nat. Rev. Immunol. 2016 16 149 163 10.1038/nri.2015.18 26875830
93. Andersen K.G. Butcher T. Betz A.G. Specific immunosuppression with inducible Foxp3-transduced polyclonal T cells PLoS Biol. 2008 6 e276 10.1371/journal.pbio.0060276 18998771 PMC2581628
94. MacDonald K.G. Hoeppli R.E. Huang Q. Gillies J. Luciani D.S. Orban P.C. Broady R. Levings M.K. Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor J. Clin. Investig. 2016 126 1413 1424 10.1172/JCI82771 26999600 PMC4811124
95. Locafaro G. Andolfi G. Russo F. Cesana L. Spinelli A. Camisa B. Ciceri F. Lombardo A. Bondanza A. Roncarolo M.G. IL-10-Engineered Human CD4+ Tr1 Cells Eliminate Myeloid Leukemia in an HLA Class I-Dependent Mechanism Mol. Ther. 2017 25 2254 2269 10.1016/j.ymthe.2017.06.029 28807569 PMC5628869
96. Noyan F. Zimmermann K. Hardtke-Wolenski M. Knoefel A. Schulde E. Geffers R. Hust M. Huehn J. Galla M. Morgan M. Prevention of Allograft Rejection by Use of Regulatory T Cells with an MHC-Specific Chimeric Antigen Receptor Am. J. Transplant. 2017 17 917 930 10.1111/ajt.14175 27997080
97. Cieniewicz B. Uyeda M.J. Chen P.P. Sayitoglu E.C. Liu J.M. Andolfi G. Greenthal K. Bertaina A. Gregori S. Bacchetta R. Engineered type 1 regulatory T cells designed for clinical use kill primary pediatric acute myeloid leukemia cells Haematologica 2021 106 2588 2597 10.3324/haematol.2020.263129 33054128 PMC8485690
98. Bianco P. “Mesenchymal” stem cells Annu. Rev. Cell Dev. Biol. 2014 30 677 704 10.1146/annurev-cellbio-100913-013132 25150008
99. Zhong X. Chen J. Wen B. Wu X. Li M. Du F. Chen Y. Deng S. Zhao Y. Shen J. Potential role of mesenchymal stem cells in T cell aging J. Mol. Med. 2023 101 1365 1378 10.1007/s00109-023-02371-y 37750918
100. Ehninger A. Trumpp A. The bone marrow stem cell niche grows up: Mesenchymal stem cells and macrophages move in J. Exp. Med. 2011 208 421 428 10.1084/jem.20110132 21402747 PMC3058583
101. Crippa S. Bernardo M.E. Mesenchymal stromal cells: Role in the BM niche and in the support of hematopoietic stem cell transplantation Hemasphere 2018 2 e151 10.1097/HS9.0000000000000151 31723790 PMC6745957
102. Le Blanc K. Immunomodulatory effects of fetal and adult mesenchymal stem cells Cytotherapy 2003 5 485 489 10.1080/14653240310003611 14660044
103. Le Blanc K. Samuelsson H. Gustafsson B. Remberger M. Sundberg B. Arvidson J. Ringden O. Transplantation of mesenchymal stem cells to enhance engraftment of hematopoietic stem cells Leukemia 2007 21 1733 1738 10.1038/sj.leu.2404777 17541394
104. Ball L.M. Bernardo M.E. Roelofs H. Lankester A. Cometa A. Egeler R.M. Locatelli F. Fibbe W.E. Cotransplantation of ex vivo–expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation Blood J. Am. Soc. Hematol. 2007 110 2764 2767 10.1182/blood-2007-04-087056 17638847
105. Batorov E.V. Shevela E.Y. Tikhonova M.A. Batorova D.S. Ushakova G.Y. Sizikova S.A. Sergeevicheva V.V. Gilevich A.V. Kryuchkova I.V. Ostanin A.A. Mesenchymal stromal cells improve early lymphocyte recovery and T cell reconstitution after autologous hematopoietic stem cell transplantation in patients with malignant lymphomas Cell. Immunol. 2015 297 80 86 10.1016/j.cellimm.2015.07.001 26227214
106. Batorov E.V. Shevela E.Y. Tikhonova M.A. Pronkina N.V. Batorova D.S. Kryuchkova I.V. Pospelova T.I. Ostanin A.A. Chernykh E.R. Possible mechanisms of stimulatory effects of mesenchymal stromal cells upon t cell recovery during chemotherapy-induced lymphopenia Med. Immunol. 2014 16 139 148 10.15789/1563-0625-2014-2-139-148
107. Chernykh E.R. Batorov E.V. Shevela E.Y. Pronkina N.V. Kryuchkova I.V. Sergeevicheva V.V. Gilevich A.V. Baranova D.S. Kozhevnikov V.S. Ostanin A.A. Effect of mesenchymal stromal cells on the early reconstitution of T-lymphocytes in malignant lymphoma patients with autologous hematopoietic stem cell transplantation Immunology 2013 34 202 207
108. Sergeevicheva V.V. Shevela E.Y. Sizikova S.A. Kulagin A.D. Kruchkova I.V. Gilevich A.V. Lisukov I.A. Kozlov V.A. Ostanin A.A. Chernykh E.R. Autologous mesenchymal stromal cells of hemoblastosis patients efficiently support hematopoietic recovery after stem cell transplantation Cell. Ther. Transplant. 2010 1 8
109. De Lima M. McNiece I. Robinson S.N. Munsell M. Eapen M. Horowitz M. Alousi A. Saliba R. McMannis J.D. Kaur I. Cord-blood engraftment with ex vivo mesenchymal-cell coculture N. Engl. J. Med. 2012 367 2305 2315 10.1056/NEJMoa1207285 23234514 PMC3805360
110. Mehta R.S. Saliba R.M. Cao K. Kaur I. Rezvani K. Chen J. Olson A. Parmar S. Shah N. Marin D. Ex vivo mesenchymal precursor cell–expanded cord blood transplantation after reduced-intensity conditioning regimens improves time to neutrophil recovery Biol. Blood Marrow Transplant. 2017 23 1359 1366 10.1016/j.bbmt.2017.05.002 28506845 PMC6453532
111. Ning H. Yang F. Jiang M. Hu L. Feng K. Zhang J. Yu Z. Li B. Xu C. Li Y. The correlation between cotransplantation of mesenchymal stem cells and higher recurrence rate in hematologic malignancy patients: Outcome of a pilot clinical study Leukemia 2008 22 593 599 10.1038/sj.leu.2405090 18185520
112. Fernández-García M. Yañez R.M. Sánchez-Domínguez R. Hernando-Rodriguez M. Peces-Barba M. Herrera G. O’connor J.E. Segovia J.C. Bueren J.A. Lamana M.L. Mesenchymal stromal cells enhance the engraftment of hematopoietic stem cells in an autologous mouse transplantation model Stem Cell Res. Ther. 2015 6 165 10.1186/s13287-015-0155-5 26345192 PMC4562358
113. Chen J. Pang A. Zhao Y. Liu L. Ma R. Wei J. Chen X. He Y. Yang D. Zhang R. Primary graft failure following allogeneic hematopoietic stem cell transplantation: Risk factors, treatment and outcomes Hematology 2022 27 293 299 10.1080/16078454.2022.2042064 35192779
114. Stenger E.O. Krishnamurti L. Galipeau J. Mesenchymal stromal cells to modulate immune reconstitution early post-hematopoietic cell transplantation BMC Immunol. 2015 16 74 10.1186/s12865-015-0135-7 26674007 PMC4681052
115. Roshandel E. Tavakoli F. Parkhideh S. Akhlaghi S.S. Ardakani M.T. Soleimani M. Post-hematopoietic stem cell transplantation relapse: Role of checkpoint inhibitors Health Sci. Rep. 2022 5 e536 10.1002/hsr2.536 35284650 PMC8905133
116. Mikhaltsova E.D. Popova N.N. Drokov M.Y. Kapranov N.M. Davydova Y.U.O. Vasilieva V.A. Dubnyak D.S. Maslikova U.V. Galtseva I.V. Kuzmina L.A. Impact of graft-versus-host disease prophylaxis on immune reconstitution in patients after allogeneic hematopoietic stem cell transplantation Med. Immunol. 2021 23 1125 1136 (In Russian) 10.15789/1563-0625-IOG-2167
117. Yanir A. Schulz A. Lawitschka A. Nierkens S. Eyrich M. Immune Reconstitution After Allogeneic Haematopoietic Cell Transplantation: From Observational Studies to Targeted Interventions Front. Pediatr. 2022 9 786017 10.3389/fped.2021.786017 35087775 PMC8789272