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0Unmanipulated HLA-Mismatched/Haploidentical Blood and Marrow Hematopoietic Stem Cell Transplantation
Xiao-Jun Huang, Ying-Jun Chang
Extensive ex vivo T cell-depleted or unmanipulated haploidentical transplantation provides benefits of rapid and near universal donor availability for patients without HLA-identical sibling donors or those who urgently need transplant. However, CD34 selected haplotype mismatched transplantation was limited by delayed immune reconstitution (IR), although this protocol has now been an acceptable approach. Recently, Peking University researchers developed a novel approach to HLA-mismatched/haploidentical blood and marrow transplantation without in vitro T cell depletion (GIAC protocol). This review summarizes transplant outcomes, and factors correlating with transplant outcomes following the GIAC protocol. Moreover, future challenges in improving posttransplant IRand finding the best approach reducing the incidence and severity of GVHD, whereas preserving graft-versus-leukemia effect to prevent the recurrence of underlying malignancy, are also discussed. Biol Blood Marrow Transplant 17: 197-204 (2011) © 2011 American Society for Blood and Marrow Transplantation
KEY WORDS: Unmanipulated haploidentical transplantation, Granulocyte colony-stimulating factor, Transplant outcome, Donor lymphocyte infusion
INTRODUCTION
During the past 2 decades, substantial progress has been made in the field of human leukocyte antigen (HLA)-mismatched/haploidentical hematopoietic stem cell transplantation (HSCT). Several transplant protocols has been established worldwide [1-8]. In Perugia, Italy, Aversa et al. [7-9] employed extensive ex vivo T cell depletion and megadose stem cells that had successfully overcome the HLA barrier to engraftment in mice and humans. By this technique, engraftment was improved and graft-versus-host disease (GVHD) was reduced following haploidentical transplantation. However, graft manipulation is associated with prolonged immune deficiencies and increased risks of infectious complication [4]. To overcome these shortcomings, unmanipulated allografts and posttransplant immune suppression were focused on by researchers from Johns Hopkins University [10,11], Osaka University [12], and other transplant centers [13,14]. Currently, the clinical outcomes of unmanipulated
From the Peking University People's Hospital, Peking University
Institute of Hematology, Beijing, People's Republic of China. Financiald disclosure: See Acknowledgments on page 202. Correspondence and reprint requests: Xiao-Jun. Huang, MD, Peking University Institute of Hematology, Peking University, People's Hospital No. 11, Xizhimen South Street, Beijing 100044, People's Republic of China (e-mail: xjhrm@medmail. com.cn).
Received September 28, 2009; accepted March 7, 2010
© 2011 American Society for Blood and Marrow Transplantation
1083-8791/$36.00
doi:10.1016/j.bbmt.2010.03.006
haploidentical transplantation are encouraging, although more patients and a longer follow-up are needed for confirmation [10-15]. In recent years, Peking University researchers developed a novel approach to HLA-mismatched/haploidentical blood and marrow transplantation without in vitro T cell depletion (the GIAC protocol) [6,15,16]. The protocol entails the following: treating donors with granulocyte colony-stimulating factor (G-CSF) to induce donor immune tolerance, intensified immuno-logic suppression to both promote engraftment and to prevent GVHD, antithymocyte globulin (ATG) was included for the prophylaxis of GVHD and graft rejection, and combination of G-CSF-primed bone marrow harvest (G-BM) and G-CSF-mobilized peripheral blood stem cell harvest (G-PB) as the source of stem cell grafts. Via this GIAC protocol, promising results have been achieved (Table 1) [5,6,15,17]. Currently, the status of haploidentical HSCT in Europe Japan, and the United States has been reviewed by other researchers [2,9,18-23]. Therefore, this review examined the basic and clinical research on unmanipulated haploidentical blood and marrow transplantation in China [6,24-27], especially at Peking University [5,6,15-17,27-38].
IMMUNE TOLERANCE BASIS FOR UNMANIPULATED HAPLOIDENTICAL BLOOD AND MARROW HSCT
The use of G-BM and G-PB may play a critical role in the GIAC protocol, although several
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Table 1. Studies on HLA-Mismatched/Haploidentical Hematopoietic Stem Cell Transplantation
Patients (n) Disease Conditioning GVHD Prophylaxis GR aGHVD cGVHD Limited Extensive TRM Relapse LFS Reference
35 AML/ALL/CML/ Standard intensity ± TBI Tacrolimus based 0 56% 19% II pt 9 pt 40% Ichinohe et al. (2004)
DLBCL/ATL Reduced intensity ± 64%
171 ALL/AMIL/CMIL/MDS Bu/Cy/Ara-C/ CsA/MTX/MMF 0 55% 21.3% 19% SR @ 2 years SR 12% SR 68% @ 2 years Huang et al. (2006)
MeCCNU+ATG 23.3% 31% HR @ 2 years HR 39% HR 42% @ 2 years
135 ALL/AMIL/CMIL/MDS Bu/Cy/Ara-C/ CsA/MTX/MMF 1.5% (II-IV) 55% 22% 18% 64% @ years Lu et al. (2006)
MeCCNU+ATG 40%
68 AMIL/ALL/CMIL/MDS/ TBI/Cy/Flu Cy/MMF/Tacrolimus 13% (II-IV) 5% * 4% @ 100 days 51% @ 1 year 34% @ I year Luznik et al. (2008)
CLL/HIL/NHIL/MM/ PNH 34% 25% 15% @ 1 year 58% @ 2 years 26% @ 2 years
29 AMIL/ALIL/CMIL/NHL/ Flu/Mel/OKT3/ CD3/CDI9 depletion 1 pt (II-IV) 3 pt 20% @ 100 days 12 pt 35% @ I year Bethge et al. (2008)
MM thiotepa 48%
42 AML/ALL/CML Bu/Cy/Ara-C/ CsA/MTX/MMF 0 57.2% 27.2% 20.4 ± 6.5% @ 1 year 21.43% 57.3±8% @ 3 years Liu et al. (2008)
MeCCNU+ATG 29.5%
93 CML Bu/Cy/Ara-C/ CsA/MTX/MMF 0 64.25% 27.16% 28.3% @ 1 year CPI 3.77% 76.5% @ I year Huang et al. (2008)
MeCCNU+ATG 22.22% 16.92% @ 1 year CP2 0% 74.5% @ 4 years
13.33% @ 1 year AP 13.94%
7.69% @ 1 year BC 38.46%
45 AML/ALIL/CMIL/NHL TBI/Cy/Ara-C/ATG CsA/MTX/MMF/ATG 2 pt (II-IV) 9 pt 3 pt II pt 24 pt Wang et al. (2009)
5 pt 3 pt
46 AML/CML/ALL TBI/Cy/Ara-C/ATG CsA/MTX/MMF 0 (I-II) 10.9% 8.7% @ 2 years 23.9% @ 2 years 70.6% @ 2 years Chen et al. (2009)
Bu/Cy/Ara-C/ 43.5%
MeCCNU+ATG
250 AML/ALL Bu/Cy/Ara-C/ CsA/MTX/MMF 0 45.8% 31.3% SR SR SR Huang et al. (2009)
MeCCNU+ATG 22.6% AML 11.9% @ 3 years AML I9.4% @ 3 years AML70.7% @ 3 years
ALL 24.3% @ 3 years ALL 2I.2% @ 3 years ALL 59.7% @ 3 years
HR HR HR
AML 20.2% @ 3 years AML 29.4% @ 3 years AML 55.9% @ 3 years
ALL 48.5% @ 3 years ALL 50.8% @ 3 years ALL 24.8% @ 3 years
HLA indicates human leukocyte antigen; AML, acute myelogenous leukemia; ALL, acute lymphoblastic leukemia; CML, chronic myelogenous leukemia; DLBCL, diffuse large B cell lymphoma; ATL, adult T cell leukemia/ lymphoma; MDS, myelodysplastic syndrome; TBI, total body irradiation; pt, patient; ATG, anti thymocyte globulin; Bu, busulfan; Cy, cyclophosphamide; GVHD, graft-versus-host diease; CsA, cyclosporine A; MMF, mycophenolate mofetil; Flu, fludrabine; SR, standard risk; HR, high risk; GR, graft failure; aGVHD, acute GVHD; cGVHD, chronic GVHD; TRM, treatment-related mortality; LFS, leukemia-free survival; CP, chronic phase; AP, accelerated phase; BC, blast crisis.
* indicates the incidence of extensive cGVHD at 1 year in the patients who received 2 doses of posttransplantation Cy.
Q 3 Q.
mechanism involving in the overcome of HLA barrier [6,27,39-42]. Initial studies showed that G-CSF leads to T cell hyporesponsiveness and modulates the balance between Th1 and Th2 immune responses (Figure 1) [39,41-44]. The effect of G-CSF on T cells is originally believed to be mediated exclusively through other effector cells, such as monocytes, CD401 GM cells, and type 2 dendritic cells (DC2, plasmacytoid DCs) [39,41,43]. Franzke et al. [45] reported that G-CSF can directly modulate T cell immune responses via G-CSF receptor. Morris et al. [46] suggest that 3 key immunomodulatory effects after treating healthy donors with G-CSF may lead to the attenuation of GVHD. First, donor T cells upregulate GATA-3 expression and are biased toward Th2 differentiation, limiting Th1-dependent monocyte activation after stem cell transplantation (SCT). Second, G-CSF induces the generation of Tr1 regulatory cells through interleukin-10 (IL-10) production. Third, G-CSF expands regulatory antigen-presenting cells (APCs) within the donor (immature myeloid precursors and plasmacytoid DCs) which, after transplantation, promote the generation of classical CD41 CD251 IL-10-producing regulatory T cells (Tregs). The generation of IL-10 and transforming growth factor-b (TGF-b) from Tr1 and Treg serve to further inhibit the inflammatory effector phase of GVHD, limiting target tissue damage [46].
In human and mice studies, the effects of G-CSF on immune characteristics of BM grafts were demonstrated by other researchers and us [41,44]. Our data suggest that in vivo administration of G-CSF might alter the composition of BM grafts, polarize Th1 to Th2, and induce hyporesponsiveness of T cells [41]. More recently, we found that G-CSF treament significantly decreased the expression of VLA-4, ICAM-1,
L-selectin, and LFA-1 on naive CD41 and CD81 T cells in BM grafts. G-CSF also polarized BM-naive CD41 and CD81 T cells from Th1 to Th2 phenotype [44]. Our findings also suggest that lower T cell hypo-responsiveness and easier polarization of T cells from Th1 to Th2 are found in G-BM compared with G-PB [42].
To clarify the mechanism on clinical use of G-BM and G-PB, these 2 grafts were mixed in vitro according to the proportions of G-PB:G-BM equal to 2:1, 1:1, and 1:2, respectively [40]. This match the clinical data, in which the median ratio of G-PB:G-BM was 1.16 (range: 0.15-5.73). Our results suggest that T cell hyporesponsiveness and polarization of T cell from Th1 to Th2 could be maintained after in vitro mixture of G-PB and G-BM. Although the relevance of this highly simplified in vitro system with phytohe-magglutinin to the complex situation of in vivo allor-eactivity cannot be completely established, we think that our data might partly explain the comparable incidence of GVHD beween HLA-mismatched/ haploidentical blood and marrow transplantation and HLA-identical sibling transplant (Figure 1) [5,6,40]. Other factors contributing to the overcoming of HLA barriers includes: (1) the use of ATG before transplantation, which may induce depletion of infused donor T lymphocytes in vivo and thus lower the incidence of GVHD [47]; (2) possible effect of combination of cyclosporine A (CsA), methotrexate (MTX), and mycophenolate mofetil (MMF) as postgrafting immunosuppression [48]; (3) the application of G-CSF day 15 posttransplant, which may further regulate T cell function [5,15]; (4) the immunomodulatory effect of mesenchymal stem cells (MSCs)/mesenchymal (stroma) progenitor cells (MPCs) from the G-CSF stimulated BM and peripheral blood stem cells (PBSCs), respectively [5,6].
Figure 1. Immunoregulatory effects after G-CSF administration to healthy donors. The G-CSF-induced alteration of immune cells, T cell polarization, and regulatory T cell (Treg) functional profile is depicted schematically. G-CSF can skrewthe phenotype of T cells from Thl to Th2, expand myeloid precursors, and induce tolerogenic dendritic cells (DCs). The numbers of monocyte and plasmacytoid DCs (DC2) were selectively increased. *Indicates the effects of G-CSF were observed both in peripheral blood and bone marrow grafts.
CLINICAL RESULTS OF HLA-MISMATCHED/ HAPLOIDENTICAL HSCT
Engraftment
In the GIAC protocol, the median time for myelogenous engraftment was 12 days (range: 9-26 days) and for platelet 15 days (range: 8-151 days) [5]. There was no significant association between the extent of HLA disparity and the time of myeloid or platelet recovery following HLA-mismatched/haploidentical transplantation [5,6,17,29]. Chang et al. [29] showed that low number of CD341 cells (<2.19 x 106/kg) in allografts, and advanced disease stage were independently associated with an increased risk of platelet engraftment. Although in pediatric patients [28], only infused CD341 cells/kg of recipient weight were significantly associated with an increased risk of platelet engraftment. These results suggest that a higher number of CD341 cells in allografts should be preferred to ensure rapid platelet engraftment, especially in patients with advanced stage disease because the latter is also associated with delayed platelet recovery in our transplant setting [28,29]. In the Italy series, primary engraftment was achieved in 94 of 101 assessable patients. Six of the 7 patients who rejected the primary graft engrafted after a second transplantation. Neutrophils reached a mean of 1000/mm3 at a median of 11 days (range: 9-30 days). Platelets reached 25,000/mm3 and 50,000/ mm3 at medians of 15 and 16 days, respectively (range: 11-45 days, and 11-110 days, respectively) [8]. Bethge et al. [49,50] demonstrated that engraftment was rapid with a median time to >500 granulocytes/mL of 12 (range: 10-21) days and >20,000 platelets/mL of 11 (range: 7-38) days following haploidentical transplantation in adults using CD3/CD19 depletion and reduced-intensity conditioning (RIC).
Our initial study showed that, at 100 days posttransplantation, the cumulative incidence was 55.0% for grade II-IV acute GVHD (aGVHD), and 23.1% for grade III-IV aGVHD. The incidence of chronic GVHD (cGVHD) was 44.67%, with 21.3% for limited and 23.3% for extensive, respectively [5]. Similar incidence of aGVHD and cGVHD was observed in subgroups of patients, including pediatrics and those with chronic myelogenous leukemia (CML) or acute leukemia [15-17]. Factors associated with a significantly increased risk of aGVHD include a higher CD4/CD8 cell ratio (more than 1.16) in G-BM [35,51] and CD56bright NK cells (more than 41.9 x 106/kg) in allografts [36]. Although a higher CD56dim/CD56bri NK cell ratio (more than 8.0) in al-lografts was correlated with a decreased risk of III-IV
aGVHD [36], further study showed that a high cell dose of CD4+CD45RA+CD62L+ cells in allografts increase the incidence of grades II-IV aGVHD after unmanipulated blood and marrow transplantation [52]. This finding is interesting and important because selectively depletion of CD4+CD62L+ naive cells in allografts might decrease the development of GVHD in the "GIAC" transplant settings if our preliminary results could be confirmed in future studies.
Other studies demonstrated that severe aGVHD and extensive cGVHD were largely prevented using CD3/CD19 depletion or positive selection CD341 cells from leukapheresis [8,49,50]. In this unmanipulated haploidentical transplant setting the incidence of grade III-IV aGVHD and extensive cGVHD were acceptable, although the T cell dose in grafts was more than 100 x 106/kg [5,6,15,27]. Moreover, comparable incidences of GVHD were found between patients who underwent haploidentical transplantion and those after HLA-identical sibling or unrelated HSCT [6,25,27]. These findings may be related to several factors (please see the section: immune tolerance basis for unmanipulated haploidentical blood and marrow HSCT).
In our transplant protocol [5,6,15-17,27], no effect of noninherited maternal antigen (NIMA)-mismatched siblings on GVHD was found as previously described by Ichinohe et al. [13] and von Rood et al. [14]. Several reasons may account for this different result: (1) all patients, except for 1 who receive bone marrow plus peripheral blood grafts, in Ichinohe or van Rood's studies received peripheral blood grafts or bone marrow grafts only [13,14]; (2) the application of G-CSF on day 5 posttransplant may contribute to the different result; (3) the GIAC protocol was different from those reported by Ichinohe et al. [13] and van Rood et al. [14]; especially, that no ATG was included in their transplant settings.
Relapse and Management
The Peking University study evaluated 250 GIAC recipients (acute myelogenous leukemia [AML] 108; acute lymphoblastic leukemia [ALL] 142). Of the 250 patients, 45 (AML, 13; ALL, 32) relapsed after transplantation; of these, 22 (AML, 6; ALL, 16) were from the high-risk group. The 3-year probability of relapse in the standard-risk group was 11.9% and 24.3% for AML and ALL, respectively, and that in high-risk group was 20.2% and 48.5% for AML and ALL, respectively [15]. Comparison analysis showed that there were no differences in relapse rate between patients who underwent unmanipulated haploidentical transplantation and those who received HLA-identical or unrelated HSCT [6,25,27]. Three factors, including advanced disease status [5,6,15,16], higher CD4/
CD8 in G-BM [35,51], and delayed lymphocyte reovery at day 30 posttransplantation [31], are correlated with increased relapse rates, whereas a higher CD56dim/CD56bri NK cell ratio (more than 8.0) was correlated with a decreased rate of relapse in the GIAC protocol [36].
In contrast to other authors' reports [53,54], we found that the 3-year probability of relapse was 24.3% and 48.5% for ALL in the standard-risk and high-risk group, respectively, following unmanipu-lated haploidentical transplantation. It seems that the relapse rate of ALL patients after unmanipulated haploidentical transplant is lower than those who underwent CD34 selected haplotype identical transplantation, although there is deficient in comparability. Several factors may be related to the result: (1) some differences, including compositions in allogafts and conditioning regimen, exist between CD34 selected haplotype identical transplant [53,54] and the GIAC protocol [6,16,27,55]; (2) kinetics of NK cell recovery and the role of NK cell alloreactivity of are also different between these 2 haploidentical transplant protocols [30,37,38,56,57]; and (3) the use of modified donor lymphocyte infusion (DLI) for prophylaxis of relapse in some patients following GIAC protocol [33].
In HLA-matched, related, or unrelated HSCT settings, DLI has been shown to exert a graft-versus-leukemia (GVL) effect and has been successfully used for treatment of leukemia relapse, although DLI could be followed by a high rate of severe GVHD and, sometimes, pancytopenia and infection [58]. To overcome these shortcomings, a modified DLI strategy was adopted in our center [32,33]. Considering the higher relapse rate of high-risk leukemia even after unmanipulated HLA-mismatched/hapolidentical HSCT, we explored the possibility and demonstrated the feasibility of applying the modified DLI strategy against leukemia recurrence from therapeutic DLI to prophylaxis DLI for patients with advanced hema-tologic malignancies [32-34].
Treatment-Related Mortality (TRM) and Survival
Under the "GIAC" protocol, Huang et al. [5] found that 39 of the 171 patients died from TRM. The causes of nonrelapse death included GVHD in 13 cases, infection in 21 cases, and other causes in 5 cases such as heart failure and hepatic failure. The TRM was also demonstrated in pediatric patients and those with CML or acute leukemia (Table 1) [17]. For CML patients, the 1-year TRM of patients in CP1, CP2/CR2, AP, and BC are 28.3%, 16.92%, 13.33%, and 7.69%, respectively [16]. In a recent report, 250 acute leukemia patients received allografts from related donors. The 3-year TRM in standard-risk
and high-risk groups was 19.4% and 29.4% for AML and 21.2% and 50.8% for ALL, respectively [15]. Four factors, including advanced disease status [5,15], higher CD4/CD8 in G-BM [35], time from diagnosis to transplant (>450 day for CML patients) [16], and lower absolute counts of lymphocytes (#300/mL) are correlated with increased TRM following unmanipulated haploidentical transplantation [31]. Zhao et al. [36] found that a higher CD56dim/CD56bri NK cell ratio (more than 8.0) in allografts was correlated with a decrease risk of TRM (P = .012).
As detailed in Table 1, the 2-year or 3-year probability of leukemia-free survival (LFS) for patients with hematologic maliganancies ranged from 24.8% to 74.5% [5,6,15-17]. Superior LFS after unmanipulated haploidentical transplantation is closely correlated with early disease status [5,15,16], higher numbers of CD56brig t cells reconstituted day 14 posttransplant [30], lower CD4/CD8 in G-BM [35], short time from diagnosis to transplant (#450 days) for CML patients [16], and higher absolute counts of lymphocytes (>300/mL) day 30 posttransplant [31]. Similar LFS were achieved using the GIAC protocol compared with HLA-matched sibling transplantation or unrelated donor transplantation [6,25,27]. A preliminary study from the Tübingen group showed that overall survival (OS) is 9 of 29 patients with a median follow-up of 241 days (range: 112-1217) [50]. Rizzieri etal. [59] demonstrated that the 1 -year survival rate of 49 patients with hematologic malignancies or marrow failure was 31% (95% confidence interval [CI], 18%-44%) after nomye-loablative therapy using haploidentical family member donors.
Posttransplant Immune Reconstitution
At Peking University, the immune reconstitution (IR) of natural killer (NK) cells in 43 patients were first investigated [30]. Our results showed that the absolute number of CD56bright NK subset in white blood cells and number of CD56bright NK subset had recovered to the donor's level by day 14, and continuously increased up to their highest levels by day 60 in those [16] who never developed GVHD or by day 120 in all 43 patients, which were higher compared with those of healthy controls. The ratio of CD56dim/CD56bright NK subsets in patients eventually reached the level similar to that of healthy controls by day 120 in those [16] who never developed GVHD, or by day 180 in all 43 patients. Patients with more CD56brightNK cells in the recovery stage had a higher survival rate and the patients with a higher ratio of T/NK had a higher chance of getting aGVHD and cGVHD [30].
In contrast to Ruggeri's et al. results [53,54], our findings showed that KIR ligand mismatch is associated with higher aGVHD, a greater relapse rate, and inferior survival [56]. The cumulative incidence of 3-year LFS, OS, and TRM were best
predicted by the number of KIR ligands carried by patients (P = .002 for LFS; P = .014 for OS; P = .030 for TRM). We also found that the KIR ligand-ligand mismatch model is a good predictor of aGVHD (P = .002) 38. Meanwhile, the presence of donor-activating KIR2DS3 also contributed significantly to aGVHD and cGVHD. These data suggest that prognosis after transplantation is associated with the numbers of KIR ligands in recipients and T cell alloreaction may play a predominant role in the "GIAC" model. Zhao et al. [37] also demonstrated that high levels of CD94 expression in donors or in recipients by day 60 after transplantation might be a good predictor for poor prognosis. Collectively, our results suggest that the role of NK cell alloreactivity could be covered by a large numbers of T cells in the GIAC protocol [30,37,38].
A retrospective study suggest that the IR, especially CD41 cells, and CD4+CD45RA+ cells, during the first 6 months following HLA-mismatched/ haploidentical transplantation without in vitro T cell depletion was somewhat delayed compared with those after HLA-matched sibling transplant [60]. Currently, a prospective study is being carried out in our center to investigate the kinetics of T cell, dendritic cells, and regulatory T cells after unmanipulated HLA-mismatched/haploidentical transplantation.
FUTURE DIRECTIONS
Several Chinese groups have confirmed the effeci-acy and feasibility of HLA-mismatched/haploidentical transplantation using an unmanipulated graft [24-26]. More recently, Huang et al. [27] showed that for every major HSCT end point, including relapse, nonrelapse mortality, and survival, partially matched-related and -unrelated HSCT, are not significantly different. This sudy provides better donor choice at experienced transplant centers, especially under certain specialized circumstances, and an opportunity for patients to benefit from HSCT when a HLA matched donor is not available. However, infection, relapse, and GVHD are still the main complications leading to mortality and morbidity after unmanipulated transplant. Based on previous studies [16,17,27-38,51,52,56], there are several novel approaches that may be promising in the future: (1) selective but effective allodepletion of CD4+CD62L+ naïve cells [52], which may facilitate successful donor engraftment, improve posttransplant IR, and maximally reduce the indidence of GVHD; (2) determining the patients who will benefit from immune-modulation therapy posttransplantation using prognosis index, such as Wilms' tumour suppressor gene (WT1), and day +30 absolute lymphocyte counts [31]; (3) improving DLI, to acquire GVL effect without or limiting GVHD; (4) further reducing in
TRM after unmanipulated HLA-mismatched/ haploidentical transplantation should aim at poor prognosis index [30,35,37,38] by hastening posttransplant IR, using G/GM test and fungal PCR for early diagnosis of fungal infection, and improving antifungal efficancy with preemptive management strategy; and (5) using adoptive cellular immunotherapy, such as Tregs, NK/Tregs, MSCs, and donor-derived NK subsets, as well as the third-party cells infusion.
ACKNOWLEDGMENTS
This work is supported by the National Outstanding Young Scientist's Foundation of China (Grant No. 30725038), and Program for Innovative Research Team in University (IRT0702).
Financial disclosure: The authors have nothing to disclose.
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