Immune cell reconstitution after allogeneic hematopoietic stem cell transplantation in children with β-thalassemia major

Introduction

Beta-thalassemia is the most common inherited blood disorder worldwide, and patients suffering from this disease primarily exhibit abnormal accumulation of α-hemoglobin chains and defective erythropoiesis in hemolytic anemia, which is the result of absent or reduced β-pearl protein formation (1). Despite the presence of various comorbidities and a heavy disease burden, conservative treatment with blood transfusions and iron chelation has transformed the natural course of β-thalassemia into a chronic disease with a prolonged life expectancy. β-thalassemia has been classified into three main subgroups based on the severity of the clinical phenotype: severe, intermediate, and mild. To date, in addition to regular blood transfusions, iron chelation therapy, and allogeneic hematopoietic stem cell transplantation (allo-HSCT), gene therapy for patients with β-thalassemia major (TM) has been rapidly developing, with several clinical trials underway in many countries, and is expected to be applied in the clinic in the near future (2-4).

Unlike supportive transfusions, allo-HSCT offers the hope of an eventual cure for patients with TM (5). Improvements in transplantation techniques and advances in supportive care strategies have led to significant improvements in the survival of patients receiving allo-HSCT. However, the speed and level of post-transplant immune reconstitution are closely related to clinical outcomes, and the outcome of transplantation is largely dependent on the hematopoietic engraftment and immune reconstitution capabilities that the donor’s hematopoietic stem cells have in the recipient’s body (6). There are more reports on TM in adults undergoing allo-HSCT and fewer reports on immune reconstitution, especially immune cell reconstitution, in children with TM who have undergone allo-HSCT. Data on immune cell reconstitution in children with TM transplants are important for summarizing the transplantation experience; therefore, the research analyzed and investigated the patterns of post-transplantation immune cell reconstitution in children with TM at our center in order to better understand and enhance the process of immune reconstitution and to find strategies to further optimize these transplantation procedures. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-325/rc).

Methods

Cases

In order to review the characteristics of immune reconstitution after allo-HSCT in patients with TM, 77 children who underwent allo-HSCT at the Department of Hematology and Oncology, Children’s Hospital of Chongqing Medical University during September 2014–December 2020 were enrolled in the study, of which 3 children were not included in the study due to their deaths during preconditioning or due to serious post-transplantation complications, and the remaining 74 patients all achieved post-transplant hematopoietic and immune reconstitution and survived to date. This study was approved by the Children’s Hospital of Chongqing Medical University Research Ethics Committee (No. 01/2024.02.27), and was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patients’ parents. Therefore, this study mainly summarized the absolute cell counts of various lymphocyte subpopulations in 74 children with TM on days 15, 30, 100, 180, and 360 after undergoing transplantation and analyzed the donor-recipient gender, blood type, age at transplantation, type of donor, type of graft, acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD), post-transplantation cytomegalovirus (CMV), and Epstein-Barr virus (EBV) infections in terms of the factors influencing immune cell reconstitution.

Definition

The date of stem cell infusion was defined as day zero, and lymphocyte reconstitution refers to absolute cell counts that meet the criteria for reconstitution. Immunophenotyping of peripheral blood was performed using flow cytometry to assess changes in lymphocyte subpopulations on days 15, 30, 100, 180, and 360 after allo-HSCT, including absolute counts of CD3⁺ T cells, CD4⁺ T cells, CD8⁺ T cells, natural killer (NK) cells (CD56⁺), and B cells (CD19⁺).

Implantation in the peripheral blood included the recovery of neutrophil and platelet counts. Neutrophil implantation was defined as 3 consecutive days of neutrophils over 0.5×10⁹/L, and platelet implantation was defined as 7 consecutive days of platelets not less than 20×10⁹/L and off platelet transfusion. Screening for CMV and EBV surveillance using DNA quantitative polymerase chain reaction (PCR) assays. CMV or EBV infection was defined as reactivation and infection, and CMV/EBV reactivation and infection (in the context of negative serostatus prior to HSCT) were defined as a level of CMV/EBV DNA in whole blood greater than or equal to 400 copies/mL. aGVHD and cGVHD were defined using standard clinical and laboratory criteria, with aGVHD classified as grades 1 to 4, and only aGVHD ≥2 was considered clinically significant.

Statistical analysis

SPSS 26.0 was used for statistical processing. In analyzing the factors affecting the reconstruction of lymphocyte subpopulations in children with TM, an independent sample Student’s t-test was used for data that met or approximated normal distribution in the one-way analysis, and a multiple linear regression model was used in the multifactorial analysis, in which the dichotomous and numerical independent variables were used in the general multiple linear regression analysis, and the unordered categorical independent variables were used in the multiple linear regression analysis after the setup of the dummy variables, and statistical descriptions were performed using median and interquartile spacing from Q25 to Q75, and the various types of lymphocyte counts were expressed as mean ± standard deviation, and plots were processed using GraphPad Prism 10. P<0.05 (two-sided) was considered a statistically significant difference.

Results

Inclusion of study participants

Between September 2014 and December 2020, 77 children with TM underwent allo-HSCT at the Department of Hematology and Oncology, Children’s Hospital of Chongqing Medical University. Among them, one child was excluded due to death from respiratory-circulatory failure during pretreatment, one child was excluded due to hematopoiesis that did not reach the reconstruction level after transplantation, and one child was excluded due to death from post-transplantation heart failure. Finally, 74 children were included in the study cohort. Inclusion criteria: (I) having a documented immune reconstitution process on day 100 post-transplantation or after day 100 post-transplantation; (II) receiving non-depleted T cells as a pretreatment regimen; (III) hematopoietic reconstitution. Exclusion criteria: (I) children with failed transplantation, failure to achieve hematopoietic reconstitution, or death within 3 months after transplantation; (II) no record of the immune reconstitution process on or after day 100 post-transplantation.

The mean follow-up of this study cohort was 24.5 months (range, 19.2–40.8 months). The median time of neutrophil implantation in the study was 11 days (range, 10–12 days) and platelet implantation was 13 days (range, 11–20 days) after transplantation. We summarized the transplantation characteristics related to age at transplantation, donor-recipient blood group, donor type, graft MNC content, graft CD34⁺ cell count, post-transplantation infections, and aGVHD in this cohort of children and obtained absolute cell counts of various lymphocyte subpopulations on days 15, 30, 100, 180, and 360 after these children underwent transplantation.

Basic information and transplant characteristics of the child

The basic characteristics of the 75 children are shown in Table 1. The study cohort consisted of 59% male and 41% female children with a median age at transplantation of 31.8 months (range, 22.4–50.2 months). The proportion of donor-recipient human leukocyte antigen (HLA) 10/10 compatible transplants was 64% (47/74). The proportion of donor-recipient blood group compatible transplants was 36% (27/74). The proportion of peripheral blood stem cell transplants received was 93% (69/74), and the proportion of cord blood + bone marrow combination transplants was 7% (5/74). The proportion of transplants received from unrelated donors was 69% (51/74), from sibling donors was 27% (20/74), and from related (father or mother) donors was 4% (3/74). The rate of aGVHD after transplantation was 53% and the rate of cGVHD was 24%.

Multifactorial and unifactorial analysis

Multiple linear regression analysis

Firstly, we selected 12 variables as independent variables, including age at transplantation, body weight at transplantation, presence of anemic heart disease before transplantation, type of graft, whether HLA is 10/10 compatible or not, whether blood group is compatible or not, MNC content of graft, CD34⁺ cell content of graft, presence or absence of aGVHD, presence or absence of cGVHD, presence or absence of CMV infection after transplantation, presence or absence of EBV infection after transplantation, etc., and multiple multivariate linear regressions were conducted on days 15, 30, 100, 180, and 360 after transplantation, respectively, as dependent variables to obtain the results. The absolute counts of various types of lymphocytes on days 15, 30, 100, 180, and 360 after transplantation were used as dependent variables in multiple linear regressions, and the results showed that post-transplantation CMV infection, the content of MNCs in the grafts, and the type of donor could affect the reconstruction level of various types of immune cells in TM children after allo-HSCT.

The results of multifactorial linear regression analysis showed that: (I) the level of post-transplant T-cell reconstitution was higher in children with positive post-transplant CMV infection than in those with negative post-transplant CMV infection, and the value of post-transplant B-cells was higher in those with negative post-transplant CMV infection than in those with positive post-transplant CMV infection; (II) the value of post-transplant immune cell reconstitution was significantly positively correlated with the graft CD34⁺ cell content of the graft showed a significant positive correlation; (III) children transplanted from sibling donors had higher levels of post-transplant immune cell reconstitution than children transplanted from unrelated donors.

One-way analysis of variance(s)

In order to study the effect of recipient gender, anemic heart disease, donor-recipient HLA is 10/10 compatible or not, donor blood type, aGVHD, cGVHD, CMV infection after transplantation and EBV infection after transplantation on immune cell reconstitution after underwent transplantation for TM, We divided the children included in the study into two groups based on the above characteristics, and statistically analyzed the absolute numbers of CD3⁺ T cells, CD4⁺ T cells, CD8⁺ T cells, B cells, and NK cells at different time points after underwent transplantation in the different groups by using the independent samples t-test.

The effect of recipient gender on immune cell reconstitution after transplantation in children with TM

The results showed that there was no statistical difference in the effect of gender on the reconstructed levels of lymphocyte subpopulations in children with TM after transplantation.

Effect of the presence or absence of anemic heart disease in recipients before transplantation on immune cell reconstitution after transplantation in children with TM (Table 2)

On day 15 after transplantation, the level of B cells reconstitution was higher in pre-transplanted children without anemic heart disease than in those with anemic heart disease. On day 100 after transplantation, the level of CD8⁺ T cells reconstitution was higher in pre-transplanted children without anemic heart disease than in those with anemic heart disease. On day 360 after transplantation, the level of CD4⁺ T cells and NK cells reconstitution was higher in pre-transplanted children without anemic heart disease than in those with anemic heart disease.

The effect of whether donor-recipient HLA is fully compatible on immune cell reconstitution after transplantation in children with TM (Figure 1A)

Figure 1 Immune cell reconstitution at different time points following transplantation in children with TM. (A) Comparison of absolute B-cell counts between the HLA-matched group and HLA-mismatched group at 15, 30, 100,180, and 360 days post-transplantation. (B) Comparison of T cells, B cells and NK cells between the ABO-matched and the ABO-mismatched groups on day 360 after allo-HSCT. (C) Comparison of absolute B-cell counts between the aGVHD (+) group and the aGVHD (−) group at 15, 30, 100,180, and 360 days post-transplantation. (D) Comparison of absolute CD8⁺ T-cell counts between the CMV (+) group and the CMV (−) group at 15, 30, 100,180, and 360 days post-transplantation. (E) Comparison of T cells, B cells and NK cells between the EBV (+) and the EBV (−) groups on day l00 after allo-HSCT. *, P<0.05; **, P<0.01. aGVHD, acute graft-versus-host disease; allo-HSCT, allogeneic hematopoietic stem cell transplantation; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HLA, human leukocyte antigen; NK, natural killer; TM, β-thalassemia major.

On days 100, 180 and 360 after transplantation, the level of post-transplantation B cells reconstitution in the children with HLA 10/10 fully compatible transplants was higher than that in the children with HLA 10/10 non-fully compatible transplants. On day 100 after transplantation, the level of post-transplantation CD8⁺ T cells reconstitution in the children HLA 10/10 fully compatible transplants was higher than that in the children with HLA 10/10 non-fully compatible transplants.

Influence of donor blood type on immune cell reconstitution after transplantation in children with TM (Figure 1B)

On day 360 after transplantation, the level of post-transplant CD3⁺ T cells, CD4⁺ T cells, and B cells reconstitution was higher in the children with compatible donor blood type transplants than in the children with incompatible donor blood type transplants.

Effect of whether aGVHD occurred after transplantation on immune cell reconstitution after transplantation in children with TM (Figure 1C)

On day 15 after transplantation, the level of post-transplant NK cells reconstitution in children who did not develop aGVHD after transplantation was higher than that of children who developed aGVHD. On days 100, 180 and 360 after transplantation, the level of post-transplant B cells reconstitution in children who did not develop aGVHD after transplantation was higher than that of children who developed aGVHD (Figure 1C).

Effect of whether cGVHD occurred after transplantation on immune cell reconstitution after transplantation in children with TM (Table 3)

On day 360 after transplantation, the post-transplantation B cells immune reconstitution in children who did not develop cGVHD after transplantation levels were higher than those of children who developed cGVHD.

The effect of the presence of CMV infection after transplantation on post-transplant immune cell reconstitution in children with TM (Figure 1D)

On day 15 after transplantation, children without CMV infection after transplantation had a higher level of NK cells reconstitution than those with CMV infection. On days 30, 100 and 360 after transplantation, children with CMV infection after transplantation had a higher level of CD3⁺ T cells reconstitution than those without CMV infection. On days 30, 100, 180 and 360 after transplantation, children with CMV infection after transplantation had a higher level of CD8⁺ T cells reconstitution than those without CMV infection (Figure 1D); on day 100 after transplantation, children with CMV infection after transplantation had a lower level of B cells reconstitution than those without CMV infection.

Effect of the presence of EBV infection after transplantation on post-transplant immune cell reconstitution in children with TM (Figure 1E)

On day 100 after transplantation, the level of CD3⁺ T cells and CD8⁺ T cells reconstitution in children with post-transplant EBV infection was higher than that in children without EBV infection.

The effect of the presence or absence of post-transplant organ damage on post-transplant immune cell reconstitution in children with TM

The results showed no statistically significant difference in the effect of whether or not organ function damage occurred on the level of reconstruction of lymphocyte subpopulations after transplantation in children with TM.

Effect of different groups in the pretreatment regimen on immune cell reconstitution after transplantation in children with TM (Tables 4,5)

TM children can be categorized into group I, group II and group III according to age, ferritin and hepatomegaly before allo-HSCT (7), and in this study, we also compared the effect of different groups in the pretreatment regimen on the post-transplantation immune cell reconstitution in TM children. The results of our analysis showed that at day 360 post-transplantation, children in group I had faster levels of CD4⁺ T-cell and NK-cell reconstitution than those in group II or group III.

Seventy-nine percent (15/19) of children with pre-transplant anemic heart disease were in group II or III and only 21% (4/19) were in group I at the time of pretreatment subgrouping, whereas 61% (34/56) of children without pre-transplant anemic heart disease were in group I and only 22% (22/56) were in group II or III at the time of pretreatment subgrouping.

Discussion

Immune reconstitution after allo-HSCT is divided into several phases, with nonspecific immunity being the first to regain function, whereas specific immune reconstitution may take several years due to the different schedules of immune reconstitution of different cell subpopulations. Successful donor-derived immune reconstitution is known to be influenced by a variety of factors, including the recipient’s thymic degeneration, donor age, pretreatment regimen, graft type, stem cell dose, donor-host differences, graft versus host disease (GVHD) prophylaxis, and the presence of GVHD or infection (8,9). In the present study, the influencing factors related to immune cell reconstitution after transplantation in children with TM who underwent allo-HSCT in a single center were investigated in depth. Among them, the results of multifactorial analysis showed that post-transplant CMV infection, CD34⁺ cell content in the graft, and donor type were independent influences on the level of immune cell reconstitution after underwent transplantation in children with TM. The results of univariate analysis also showed that the level of T cell reconstitution was higher in children with positive post-transplant CMV infection than in those with negative CMV infection, whereas the level of reconstitution of NK cells and B cells was higher in children with negative post-transplant CMV infection than in those with positive CMV infection.

Viral infections have a complex relationship with lymphocyte reconstitution, as opportunistic infections are associated with both the cause and outcome of delayed immune reconstitution. Previous literature has shown that impaired early reconstitution of CD3⁺CD8⁺ T cells leads to CMV reactivation (10). However, after infection, clonal expansion of CD3⁺CD8⁺ T lymphocytes stimulated by CMV antigen also leads to oligoclonal pooling of memory T cells (11). In addition, the presence of CMV-specific CD8⁺ effector memory T cells in seropositive CMV recipients has been associated with a rapid recovery of CD8⁺ T cells, and immune reconstitution is significantly faster in recipients who have received grafts from seropositive CMV donors (11-13). Our findings confirm the positive impact of CMV seropositivity on post-transplant T cell reconstitution in children with TM, which may reflect the fact that CMV-specific immunity is adequately maintained post-transplantation, with low levels of CMV reactivation in the blood and/or tissues being controlled immediately prior to detection by standard laboratory tests, while still providing CMV-specific CD8⁺ T-cell expansion with sufficient antigenic stimulation, leading to clonal expansion of CMV-specific CD8⁺ effector memory T cells (12).

Although CMV may play a dominant role, the numerical reconstitution of lymphocyte subpopulations after transplantation may also be driven by other pathogens, including EBV. The results of a retrospective study demonstrated an opposite-directional effect of post-transplantation CMV and EBV infections on the rate of immune reconstitution of lymphocyte subpopulations: reactivation of CMV within the first 100 days after allo-HSCT had a positive effect on the reconstitution of the immune reconstitution of CD3, CD4, and CD8 lymphocyte subsets, whereas EBV reactivation delayed the reconstitution of CD19 lymphocytes (14). Currently, there is disagreement between the relationship between CMV infection and the reconstitution of NK cells, with one study suggesting that post-transplantation CMV reactivation can drive the ongoing regulation and expansion of the NK cell repertoire (15), and others suggesting that rapid reconstitution of NK cells is associated with a lower incidence of CMV reactivation (16,17). In contrast, the results of our study showed that children who were CMV seronegative had faster levels of NK cell reconstitution. In addition, the results of the present study also showed that EBV infection promotes T-cell reconstitution, and these controversial points need to be confirmed by more and more in-depth studies to be conducted in the future.

At present, it is widely recognized by many experts and scholars that aGVHD is associated with significantly impaired immune reconstitution, but which is the cause and which is the effect? This question is still unclear. One study reported that the number of NK cells in patients without signs of aGVHD was significantly higher than that in patients who developed aGVHD during the observation period of 200 days after allo-HSCT, and it is noteworthy that the reconstruction of NK cells was also associated with the severity of aGVHD (18). In general, GVHD is associated with the reconstitution of functionally and numerically poorer B cells (19,20). In terms of pathophysiology, although it is generally accepted that aGVHD is mainly mediated by T cells, donor B cells may play an important role in the immunopathology of cGVHD (21,22). It has also been suggested that high levels of CD8⁺ T cell counts after transplantation are associated with the chance of developing GVHD (23). And our results showed that the level of immune cell reconstitution was higher in children with TM who did not develop aGVHD and cGVHD after transplantation than in those who developed aGVHD and cGVHD. It can be seen that numerous studies have not yet been conclusive about the cause and effect of GVHD and immune reconstitution.

Higher doses of CD34⁺ cells in the grafts promote early reconstitution of NK cells (16), which is in agreement with our findings, which show that increasing the dose of stem cells promotes immune cell reconstitution after transplantation (24,25). Our findings also showed that the level of immune cell reconstitution was higher in children with TM without anemic heart disease prior to transplantation than in those with anemic heart disease prior to transplantation, could this be related to the different strengths of the conditioning regimens? Firstly, we compared the reconstitution of immune cells after underwent transplantation in children in subgroup I and subgroup II/III (Table 4), which showed that at day 360 post-transplantation, children in group I had faster levels of CD4⁺ T-cell and NK-cell reconstitution than those in group II or group III. Subsequently, we compared children with/without pre-transplant cardiac disease in group I and group II/III of the conditioning regimen, and the results showed that seventy-nine percent (15/19) of children with pre-transplant anemic heart disease were in group II or III and only 21% (4/19) were in group I at the time of pretreatment subgrouping, whereas 61% (34/56) of children without pre-transplant anemic heart disease were in group I and only 22% (22/56) were in group II or III at the time of pretreatment subgrouping (Table 5). Most of the children without anemic heart disease prior to transplantation were in subgroup I in the conditioning regimen, while most of the children with heart disease prior to transplantation were in subgroup II/subgroup III in the conditioning regimen. When we developed the conditioning regimen with different intensities, children in subgroup I received the conditioning regimen at a stronger intensity, whereas children in subgroup II/subgroup III received the conditioning regimen at a lower intensity. Therefore, we speculated that the higher level of immune cell reconstitution in TM children without anemic heart disease prior to transplantation who underwent transplantation may be due to the fact that most of the children without anemic heart disease were in subgroup I at the time of the preconditioning regimen and thus underwent a more intense preconditioning regimen, which was more conducive to the implantation of donor stem cells.

The level of immune cell reconstitution was higher in TM transplanted by sibling donors than in those transplanted by unrelated donors, that the level of immune cell reconstitution was higher in TM transplanted by blood group compatible than in those transplanted by blood groups that were incompatible, and that the level of immune cell reconstitution was higher in TM transplanted by HLA all-incompatible B-cell reconstitution was also higher in children with heavy beta-TM transplantation than in children with HLA-incompatible transplantation. The results of a recent Meta-analysis showed that unrelated donor transplants with HLA 9/10 compatibility had worse overall survival compared with unrelated donor transplants with HLA 10/10 compatibility, and specified the negative impact of single HLA allele mismatch survival (26). Whether the slower immune cell reconstitution in children with TM who underwent HLA non-10/10 compatibility transplantation in the study was also associated with a single HLA allele mismatch? It is unclear and needs further study. Donor-recipient blood group compatibility and differences in immune reconstruction between sibling and unrelated donor transplants are all important factors in the present study. The differences in immune reconstitution between sibling donors and unrelated donors are all new findings in this study and will require more in-depth basic research to confirm them in the future.

Reconstruction of the donor-derived immune system is essential to achieve optimal post-transplant outcomes in children with TM, and the timing and degree of restoration of immune cell numbers and function has a direct impact on infection-related complications, the development and treatment of GVHD, and long-term survival. Reestablishment of innate immunity is rapidly achieved after transplantation and is usually only slightly affected by transplant-related variables. In contrast, reconstitution of adaptive immunity follows highly variable kinetics, and our study points out that these kinetics are influenced by CD34⁺ cell content in the graft, donor type, post-transplant CMV infection, post-transplant EBV infection, aGVHD, cGVHD, anemic heart disease, and donor-recipient blood type. Therefore, the timing of post-transplant immune cell reconstitution in children with TM can be modified by altering these factors. Operative strategies such as controlling the dose of CD34⁺ cells in the graft, early intervention of CMV and EBV infections, and active prevention and treatment of aGVHD and cGVHD will greatly influence the recovery of immune function after transplantation in children with TM.

Conclusions

In summary, this study not only reveals the characteristics of immune cell reconstitution following transplantation in children with TM but also identifies key factors influencing this process, laying a crucial theoretical foundation for future clinical applications. These findings offer novel insights for accelerating immune reconstitution after transplantation in children with TM, demonstrating significant potential for clinical translation.

Acknowledgments

We would like to thank the medical staff of the Department of Hematology and Oncology, Children’s Hospital of Chongqing Medical University for their support in data collection for this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-325/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-325/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-325/prf

Funding: This study was supported by funds from the Program for Youth Innovation in Future Medicine, Chongqing Medical University (grant No. W0132) and Chongqing Natural Science Foundation (No. CSTB2023NSCQ-MSX0212).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-325/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approved by the Children’s Hospital of Chongqing Medical University Research Ethics Committee (01/2024.02.27), and was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patients’ parents.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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