Mucus-degrading Bacteroides link carbapenems to aggravated graft-versus-host disease.

The intestinal microbiota is an important modulator of graft-versus-host disease (GVHD), which often complicates allogeneic hematopoietic stem cell transplantation (allo-HSCT). Broad-spectrum antibiotics such as carbapenems increase the risk for intestinal GVHD, but mechanisms are not well understood. In this study, we found that treatment with meropenem, a commonly used carbapenem, aggravates colonic GVHD in mice via the expansion of Bacteroides thetaiotaomicron (BT). BT has a broad ability to degrade dietary polysaccharides and host mucin glycans. BT in meropenem-treated allogeneic mice demonstrated upregulated expression of enzymes involved in the degradation of mucin glycans. These mice also had thinning of the colonic mucus layer and decreased levels of xylose in colonic luminal contents. Interestingly, oral xylose supplementation significantly prevented thinning of the colonic mucus layer in meropenem-treated mice. Specific nutritional supplementation strategies, including xylose supplementation, may combat antibiotic-mediated microbiome injury to reduce the risk for intestinal GVHD in allo-HSCT patients.

Graft-versus-host disease is locally maintained in target tissues by resident progenitor-like T cells.

In allogeneic hematopoietic stem cell transplantation, donor αß T cells attack recipient tissues, causing graft-versus-host disease (GVHD), a major cause of morbidity and mortality. A central question has been how GVHD is sustained despite T cell exhaustion from chronic antigen stimulation. The current model for GVHD holds that disease is maintained through the continued recruitment of alloreactive effectors from blood into affected tissues. Here, we show, using multiple approaches including parabiosis of mice with GVHD, that GVHD is instead primarily maintained locally within diseased tissues. By tracking 1,203 alloreactive T cell clones, we fitted a mathematical model predicting that within each tissue a small number of progenitor T cells maintain a larger effector pool. Consistent with this, we identified a tissue-resident TCF-1+ subpopulation that preferentially engrafted, expanded, and differentiated into effectors upon adoptive transfer. These results suggest that therapies targeting affected tissues and progenitor T cells within them would be effective.

Gene therapy for adenosine deaminase severe combined immune deficiency-An unexpected journey of four decades.

Severe combined immune deficiency due to adenosine deaminase deficiency (ADA SCID) is an inborn error of immunity with pan-lymphopenia, due to accumulated cytotoxic adenine metabolites. ADA SCID has been treated using gene therapy with a normal human ADA gene added to autologous hematopoietic stem cells (HSC) for over 30 years. Iterative improvements in vector design, HSC processing methods, and clinical HSC transplant procedures have led nearly all ADA SCID gene therapy patients to achieve consistently beneficial immune restoration with stable engraftment of ADA gene-corrected HSC over the duration of observation (as long as 20 years). One gene therapy for ADA SCID is approved by the European Medicines Agency (EMA) in the European Union (EU) and another is being advanced to licensure in the U.S. and U.K. Despite the clear-cut benefits and safety of this curative gene and cell therapy, it remains challenging to achieve sustained availability and access, especially for rare disorders like ADA SCID.

Correcting inborn errors of immunity: From viral mediated gene addition to gene editing.

Allogeneic hematopoietic stem cell transplantation is an effective treatment to cure inborn errors of immunity. Remarkable progress has been achieved thanks to the development and optimization of effective combination of advanced conditioning regimens and use of immunoablative/suppressive agents preventing rejection as well as graft versus host disease. Despite these tremendous advances, autologous hematopoietic stem/progenitor cell therapy based on ex vivo gene addition exploiting integrating γ-retro- or lenti-viral vectors, has demonstrated to be an innovative and safe therapeutic strategy providing proof of correction without the complications of the allogeneic approach. The recent advent of targeted gene editing able to precisely correct genomic variants in an intended locus of the genome, by introducing deletions, insertions, nucleotide substitutions or introducing a corrective cassette, is emerging in the clinical setting, further extending the therapeutic armamentarium and offering a cure to inherited immune defects not approachable by conventional gene addition. In this review, we will analyze the current state-of-the art of conventional gene therapy and innovative protocols of genome editing in various primary immunodeficiencies, describing preclinical models and clinical data obtained from different trials, highlighting potential advantages and limits of gene correction.

Silencing endomucin in bone marrow sinusoids improves hematopoietic stem and progenitor cell homing during transplantation.

Efficient homing of infused hematopoietic stem and progenitor cells (HSPCs) into the bone marrow (BM) is the prerequisite for successful hematopoietic stem cell transplantation. However, only a small part of infused HSPCs find their way to the BM niche. A better understanding of the mechanisms that facilitate HSPC homing will help to develop strategies to improve the initial HSPC engraftment and subsequent hematopoietic regeneration. Here, we show that irradiation upregulates the endomucin expression of endothelial cells in vivo and in vitro. Furthermore, depletion of endomucin in irradiated endothelial cells with short interfering RNA (siRNA) increases the HSPC-endothelial cell adhesion in vitro. To abrogate the endomucin of BM sinusoidal endothelial cells (BM-SECs) in vivo, we develop a siRNA-loaded bovine serum albumin nanoparticle for targeted delivery. Nanoparticle-mediated siRNA delivery successfully silences endomucin expression in BM-SECs and improves HSPC homing during transplantation. These results reveal that endomucin plays a critical role in HSPC homing during transplantation and that gene-based manipulation of BM-SEC endomucin in vivo can be exploited to improve the efficacy of HSPC transplantation.

Combination HSCT and intravenous AAV-mediated gene therapy in a canine model proves pivotal for translation of Krabbe disease therapy.

Hematopoietic stem cell transplantation (HSCT) is the only approved treatment for presymptomatic infantile globoid cell leukodystrophy (GLD [Krabbe disease]). However, correction of disease is not complete, and outcomes remain poor. Herein we evaluated HSCT, intravenous (IV) adeno-associated virus rh10 vector (AAVrh10) gene therapy, and combination HSCT + IV AAVrh10 in the canine model of GLD. While HSCT alone resulted in no increase in survival as compared with untreated GLD dogs (∼16 weeks of age), combination HSCT + IV AAVrh10 at a dose of 4E13 genome copies (gc)/kg resulted in delayed disease progression and increased survival beyond 1 year of age. A 5-fold increase in AAVrh10 dose to 2E14 gc/kg, in combination with HSCT, normalized neurological dysfunction up to 2 years of age. IV AAVrh10 alone resulted in an average survival to 41.2 weeks of age. In the peripheral nervous system, IV AAVrh10 alone or in addition to HSCT normalized nerve conduction velocity, improved ultrastructure, and normalized GALC enzyme activity and psychosine concentration. In the central nervous system, only combination therapy at the highest dose was able to restore galactosylceramidase activity and psychosine concentrations to within the normal range. These data have now guided clinical translation of systemic AAV gene therapy as an addition to HSCT (NCT04693598, NCT05739643).

Outcomes in Critically Ill Allogeneic Hematopoietic Stem-Cell Transplantation Recipients.

RATIONALE: Allogeneic hematopoietic stem-cell transplantation (Allo-HSCT) recipients are still believed to be poor candidates for intensive care unit (ICU) management. OBJECTIVES AND METHODS: We investigated outcomes and determinants of mortality in a large multicenter retrospective cohort of Allo-HSCT patients admitted between January 1, 2015 and December 31, 2020 to 14 French ICUs. MEASUREMENTS AND MAIN RESULTS: One thousand one hundred and sixty-four patients were admitted throughout the study period. At the time of ICU admission, 765 (66%) patients presented multiple organ dysfunction, including acute respiratory failure in 40% (n=461). Median SOFA was 6 (4-8). Invasive mechanical ventilation, renal replacement therapy and vasopressors were required in 438 (38%), 221 (19%) and 468 (41%) patients respectively. ICU mortality was 26% (302 deaths). Day-90, 1-year and 3-year mortality rates were 48%, 63%, and 70%, respectively. By multivariable analysis, age >56 years (OR 2·0 [1·53-2·60], p<0·001), time from Allo-HSCT to ICU admission between 30 and 90 days (OR 1·68 [1·17-2·40], p=0·005), corticosteroid-refractory acute graft-versus-host disease (OR 1·63 [1·38-1·93], p<0·001), need for vasopressors (OR 1·9 [1·42-2·55], p<0·001), and mechanical ventilation (OR 3·1 [2·29-4·18], p<0·001) were independently associated with day-90 mortality. In patients requiring mechanical ventilation, mortality rates ranged from 39% (no other risk factors for mortality) to 100% (4 associated risk factors for mortality). CONCLUSIONS: Most critically ill Allo-HSCT recipients survive their ICU stay, including those requiring mechanical ventilation, with an overall day-90 survival rate reaching 51.8%. A careful assessment of goals of care is required in patients with ≥ 2 risk factors for mortality.

Lung Injury Prediction Model in Bone Marrow Transplantation: A Multicenter Cohort Study.

Rationale: Pulmonary complications contribute significantly to nonrelapse mortality following hematopoietic stem cell transplantation (HCT). Identifying patients at high risk can help enroll such patients into clinical studies to better understand, prevent, and treat posttransplantation respiratory failure syndromes. Objectives: To develop and validate a prediction model to identify those at increased risk of acute respiratory failure after HCT. Methods: Patients underwent HCT between January 1, 2019, and December 31, 2021, at one of three institutions. Those treated in Rochester, MN, formed the derivation cohort, and those treated in Scottsdale, AZ, or Jacksonville, FL, formed the validation cohort. The primary outcome was the development of acute respiratory distress syndrome (ARDS), with secondary outcomes including the need for invasive mechanical ventilation (IMV) and/or noninvasive ventilation (NIV). Predictors were based on prior case-control studies. Measurements and Main Results: Of 2,450 patients undergoing stem cell transplantation, there were 1,718 hospitalizations (888 patients) in the training cohort and 1,005 hospitalizations (470 patients) in the test cohort. A 22-point model was developed, with 11 points from prehospital predictors and 11 points from posttransplantation or early (<24-h) in-hospital predictors. The model performed well in predicting ARDS (C-statistic, 0.905; 95% confidence interval [CI], 0.870-0.941) and the need for IMV and/or NIV (C-statistic, 0.863; 95% CI, 0.828-0.898). The test cohort differed markedly in demographic, medical, and hematologic characteristics. The model also performed well in this setting in predicting ARDS (C-statistic, 0.841; 95% CI, 0.782-0.900) and the need for IMV and/or NIV (C-statistic, 0.872; 95% CI, 0.831-0.914). Conclusions: A novel prediction model incorporating data elements from the pretransplantation, posttransplantation, and early in-hospital domains can reliably predict the development of post-HCT acute respiratory failure.

Reactive granulopoiesis depends on T-cell production of IL-17A and neutropenia-associated alteration of gut microbiota.

Granulopoiesis in the bone marrow adjusts cellular output as demand for neutrophils changes. Reactive granulopoiesis is induced by profound neutropenia, but its mechanism remains to be clarified. We herein explored its mechanisms using mouse models of syngeneic hematopoietic stem cell transplantation (SCT) and 5-fluorouracil-induced neutropenia. After SCT, T cell production of IL-17A was up-regulated. Neutrophil recovery was significantly delayed in IL-17A-deficient or T cell-deficient RAG1-/- mice, and adoptive transfer of wild-type (WT) T cells facilitated neutrophil engraftment. Gut decontamination with oral antibiotics suppressed T cell production of IL-17A and impaired neutrophil recovery. Transplantation of fecal microbiota collected from neutropenic, not naive, mice promoted neutrophil recovery in these mice, suggesting that neutropenia-associated microbiota had a potential to stimulate reactive granulopoiesis. Our study uncovered a cross talk between gut microbiota and neutropenia after SCT and chemotherapy.

Early bone marrow alterations in patients with adenosine deaminase 2 deficiency across disease phenotypes and severities.

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a complex monogenic disease caused by recessive mutations in the ADA2 gene. DADA2 exhibits a broad clinical spectrum encompassing vasculitis, immunodeficiency, and hematological abnormalities. Yet, the impact of DADA2 on the bone marrow (BM) microenvironment is largely unexplored. OBJECTIVE: This study comprehensively examined the BM and peripheral blood of pediatric and adult patients with DADA2 presenting rheumatologic/immunologic symptoms or severe hematological manifestations. METHODS: Immunophenotyping of hematopoietic stem cells (HSCs), progenitor cells, and mature cell populations was performed for 18 patients with DADA2. We also conducted a characterization of the mesenchymal stromal cells (MSCs). RESULTS: Our study revealed a significant decrease in primitive HSCs and progenitor cells, alongside their reduced clonogenic capacity and multilineage differentiation potential. These BM defects were evident in patients with both severe and non-severe hematological manifestations, including pediatric patients, demonstrating that BM disruption can emerge silently and early on, even in patients who do not show obvious hematological symptoms. Beyond stem cells, there was a reduction in mature cell populations in the BM and peripheral blood, affecting myeloid, erythroid, and lymphoid populations. Furthermore, BM MSCs in DADA2 patients exhibited reduced clonogenic and proliferation capabilities and were more prone to undergo cellular senescence marked by elevated DNA damage. CONCLUSION: Our exploration into the BM landscape of DADA2 patients sheds light on the critical hematological dimension of the disease and emphasizes the importance of vigilant monitoring, even in the case of subclinical presentation.

SARS-CoV-2 Infection in the Pediatric Oncology Population: The Definitive Comprehensive Report of the Infectious Diseases Working Group of AIEOP.

OBJECTIVE: The objective of this study was to assess the clinical impact and outcome of the SARS-CoV-2 infection on children with cancer or those who received a hematopoietic stem cell transplantation. METHODS: AIEOP (Italian Association of Pediatric Hematology and Oncology) performed a nationwide multicenter observational cohort study, including consecutive patients between April 2020 and November 2022. RESULTS: Twenty-five Italian centers participated and 455 patients were enrolled. We reported a significant increasing trend of symptomatic cases over the years, while the number of nonmild infections remained stable. Early infection after oncologic diagnosis (<60 days) and severe neutropenia were identified as independent risk factors for developing moderate, severe, or critical infections. The percentage of patients who were asymptomatic and mildly symptomatic and who stopped chemotherapy reduced over the years of the pandemic. Nine patients died, but no death was attributed to SARS-CoV-2 infection. CONCLUSIONS: SARS-CoV-2 infection presented a self-limiting benign course in the Italian pediatric oncohematology population during the pandemic, and its main consequence has been the discontinuation of cancer-directed therapies. The rate of patients who were asymptomatic and stopped chemotherapy reduced over the years, suggesting that the continuation of chemotherapy is a feasible option.

The Effect of Gastrointestinal Graft-Versus-Host Disease and Diarrhea on the Pharmacokinetic Profile of Sotrovimab in Hematopoietic Stem Cell Transplant Recipients.

BACKGROUND: Monoclonal antibodies (mAbs) are utilized broadly to treat cancer and infectious diseases, and mAb exposure (serum concentration over time) is one predictor of overall treatment efficacy. Herein, we present findings from a clinical trial evaluating the pharmacokinetics of the long-acting mAb sotrovimab targeting severe acute respiratory syndrome coronavirus 2 in hematopoietic cell transplant (HCT) recipients. METHODS: All participants received an intravenous infusion of sotrovimab within 1 week prior to initiating the pretransplant preparative regimen. The serum concentration of sotrovimab was measured longitudinally for up to 24 weeks posttransplant. RESULTS: Compared to non-HCT participants, we found that mAb clearance was 10% and 26% higher in autologous and allogeneic HCT recipients, respectively. Overall sotrovimab exposure was approximately 15% lower in HCT recipients compared to non-HCT recipients. Exposure was significantly reduced in HCT recipients who developed diarrhea and lower gastrointestinal graft-versus-host disease (GVHD) posttransplant. CONCLUSIONS: These data show that sotrovimab exposure may be reduced in HCT recipients, possibly related to increased gastrointestinal clearance in patients with GVHD. This phenomenon has implications for dose selection and duration of efficacy with sotrovimab and potentially other mAbs in this vulnerable patient population. Thus, mAb dose regimens developed in non-HCT populations may have to be optimized when applied to HCT populations.

Reconstitution of norovirus-specific T cell responses following hematopoietic stem cell transplantation in patients with inborn errors of immunity and chronic norovirus infection.

BACKGROUND: Chronic norovirus infection (CNI) causes significant morbidity in immunocompromised patients. No effective prevention or treatment currently exists. METHODS: Two patients with inborn errors of immunity, X- linked severe combined immunodeficiency (X-SCID) and DOCK8 deficiency, were followed longitudinally for clinical course, immune reconstitution, norovirus-specific T cell (NST) response, B cell reconstitution, and norovirus-specific antibody production. Samples were obtained in the peri-hematopoietic stem cell transplant setting (HSCT) before and after CNI clearance. The norovirus strain causing CNI was followed longitudinally for norovirus stool viral loads and sequencing. RESULTS: The noroviruses were identified as GII.4 Sydney[P4 New Orleans] in one patient and GII.17[P17] in the other. An exacerbation of diarrhea post-HSCT in the patient with X-SCID was consistent with norovirus infection but not with graft-vs-host-disease on pathologic samples. Both patients recovered polyfunctional NSTs in the CD4 and CD8 T cell compartments which recognized multiple norovirus structural and non-structural viral antigens. T cell responses were minimal during active CNI but detectable after resolution. Mapping of norovirus-specific T cell responses between the patient with DOCK8 and his matched sibling donor were nearly identical. B cell reconstitution or new endogenous antibody production for IgA or IgG were not observed. CONCLUSION: This report is the first to demonstrate reconstitution of norovirus-specific T cell immunity after HSCT closely temporally aligned with clearance of CNI suggesting that cellular immunity is sufficient for norovirus clearance.

Upper and/or Lower Respiratory Tract Infection Caused by Human Metapneumovirus After Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: Human metapneumovirus (hMPV) epidemiology, clinical characteristics and risk factors for poor outcome after allogeneic stem cell transplantation (allo-HCT) remain a poorly investigated area. METHODS: This retrospective multicenter cohort study examined the epidemiology, clinical characteristics, and risk factors for poor outcomes associated with human metapneumovirus (hMPV) infections in recipients of allo-HCT. RESULTS: We included 428 allo-HCT recipients who developed 438 hMPV infection episodes between January 2012 and January 2019. Most recipients were adults (93%). hMPV infections were diagnosed at a median of 373 days after allo-HCT. The infections were categorized as upper respiratory tract disease (URTD) or lower respiratory tract disease (LRTD), with 60% and 40% of cases, respectively. Patients with hMPV LRTD experienced the infection earlier in the transplant course and had higher rates of lymphopenia, neutropenia, corticosteroid use, and ribavirin therapy. Multivariate analysis identified lymphopenia and corticosteroid use (>30 mg/d) as independent risk factors for LRTD occurrence. The overall mortality at day 30 after hMPV detection was 2% for URTD, 12% for possible LRTD, and 21% for proven LRTD. Lymphopenia was the only independent risk factor associated with day 30 mortality in LRTD cases. CONCLUSIONS: These findings highlight the significance of lymphopenia and corticosteroid use in the development and severity of hMPV infections after allo-HCT, with lymphopenia being a predictor of higher mortality in LRTD cases.

Genetic Susceptibility in Endothelial Injury Syndromes after Hematopoietic Cell Transplantation and Other Cellular Therapies: Climbing a Steep Hill.

Hematopoietic stem cell transplantation (HSCT) remains a cornerstone in the management of patients with hematological malignancies. Endothelial injury syndromes, such as HSCT-associated thrombotic microangiopathy (HSCT-TMA), veno-occlusive disease/sinusoidal obstruction syndrome (SOS/VOD), and capillary leak syndrome (CLS), constitute complications after HSCT. Moreover, endothelial damage is prevalent after immunotherapy with chimeric antigen receptor-T (CAR-T) and can be manifested with cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Our literature review aims to investigate the genetic susceptibility in endothelial injury syndromes after HSCT and CAR-T cell therapy. Variations in complement pathway- and endothelial function-related genes have been associated with the development of HSCT-TMA. In these genes, CFHR5, CFHR1, CFHR3, CFI, ADAMTS13, CFB, C3, C4, C5, and MASP1 are included. Thus, patients with these variations might have a predisposition to complement activation, which is also exaggerated by other factors (such as acute graft-versus-host disease, infections, and calcineurin inhibitors). Few studies have examined the genetic susceptibility to SOS/VOD syndrome, and the implicated genes include CFH, methylenetetrahydrofolate reductase, and heparinase. Finally, specific mutations have been associated with the onset of CRS (PFKFB4, CX3CR1) and ICANS (PPM1D, DNMT3A, TE2, ASXL1). More research is essential in this field to achieve better outcomes for our patients.

Effect of allogeneic hematopoietic stem cell transplantation for chronic granulomatous disease in children: A multicentre, retrospective cohort study in China.

Chronic granulomatous disease (CGD) in children is a rare primary immunodeficiency disorder that can lead to life-threatening infections and inflammatory complications. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is increasingly being used to treat severe CGD in children. We conducted a multicenter retrospective analysis of children with CGD who were treated with allo-HSCT at four pediatric hematopoietic stem cell transplant centers in China from September 2005 to December 2019. The study included a total of 171 patients (169 males and 2 females). The median age at the time of transplantation was 6.1 (0-16.4) years. Among them, 154 patients had X-linked recessive inheritance caused by CYBB gene mutations, 12 patients were autosomal recessive, 1 patient had DNAH11 and HYDIN gene mutations, and 4 patients had no gene mutations. The median follow-up period was 36.3 (1.9-79) months. All participating patients were applied to myeloablative conditioning (MAC) regimens. The rates of OS, EFS, and GEFS within three years were 87.5%, 85.3%, and 75.2%, respectively. The total graft failure and the total mortality rate were 5.3% and 11.1%. The cumulative incidence of acute GVHD was 53.8% and the incidence of chronic GVHD was 12.9%, The incidence of chronic GVHD was higher for patients who received unrelated donor cord blood stem cell transplantation (UD-CB) (P = 0.001). Chronic GVHD and coinfections are the risk factors for OS and EFS in patients with CGD after receiving allo-HSCT. UD-CB is a risk factor for EFS and the presence of pneumonia before transplantation is a risk factor for OS. In conclusion, through this study, we have demonstrated that allo-HSCT has excellent efficacy in the treatment of CGD in children, especially, RD-haplo is associated with a lower rate of graft failure incidence and mortality than the treatment modalities of other donor type. Therefore, allo-HSCT is strongly recommended when a well-matched donor is available. If a well-matched donor is not available, the HLA-mismatched donor should be carefully evaluated, and the conditioning regimen modified accordingly.

Chemotherapy for a secondary malignancy nearly restores complete chimerism in an SCID-patient after HSCT.

For patients with inborn errors of immunity (IEI) and other inborn diseases, mixed donor chimerism is a well-accepted outcome of hematopoietic stem cell transplantation (HSCT). Cytoreductive chemotherapy for a secondary malignancy is a potential challenge for the stability of the graft function after HSCT. We report on a boy with X-SCID who developed Ewing sarcoma ten years after HSCT which was successfully treated with cytoreductive chemotherapy, surgery and local radiation. Surprisingly, this treatment had a positive impact on mixed chimerism with an increase of donor-cell proportions from 40% for neutrophils and 75% for non-T-mononuclear cells (MNCs) to >90% for both. T-cell counts remained stable with 100% of donor origin. This is -to our knowledge- the first report on the impact of cytoreductive chemotherapy on post-HSCT mixed chimerism and provides an important first impression for future patients.

Immune reconstitution and survival, following hematopoietic stem cell transplantation in Omani patients with inborn errors of immunity.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a curative treatment for certain inborn errors of immunity. METHODS: A 17-year retrospective cohort study was conducted on 40 immunodeficient patients who underwent HSCT. RESULTS: The median age at transplant was 11.0 months (4.6-61.0). Donors were primarily matched sibling donors (60%). 90% and 85% of patients received conditioning and graft-versus-host disease (GVHD) prophylaxis, respectively. The mean donor chimerism at the last follow-up was 88.6% ± 17.9% (40-100). Median serum immunoglobulin (Ig) G level, CD4+ T-cell count, and CD19+ B-cell count were 11.7 g/L (9.2-13.6), 0.9 × 109/L 0.6-1.2), and 0.5 × 109/L (0.2-0.7), respectively. 29 patients (72.5%) received intravenous immunoglobulins (IVIG) therapy, with a median duration of 10.0 months (4.0-14.0). The median post-transplant follow-up was 6.5 years (IQR:1.4-11.5). The 10-year overall probability of survival is 84.3%. CONCLUSION: Monitoring IRC is important in ensuring adequate disease-free survival.

Cytomegalovirus infection is associated with thymic dysfunction and chronic graft-versus-host disease after pediatric hematopoietic stem cell transplantation.

Pediatric hematopoietic stem cell transplantation (HSCT) is challenged by chronic graft-versus-host disease (cGvHD) significantly affecting survival and long-term morbidity, but underlying mechanisms including the impact of post-HSCT CMV infection are sparsely studied. We first investigated the impact of CMV infection for development of cGvHD in 322 children undergoing standard myeloablative HSCT between 2000 and 2018. Clinically significant CMV infection (n = 61) was an independent risk factor for chronic GvHD in a multivariable Cox regression analysis (HR = 2.17, 95% CI = 1.18-3.97, P = 0.013). We next explored the underlying mechanisms in a subcohort of 39 children. CMV infection was followed by reduced concentration of recent thymic emigrants (17.5 vs. 51.9 × 106/L, P = 0.048) and naïve CD4+ and CD8+ T cells at 6 months post-HSCT (all P < 0.05). Furthermore, CD25highFOXP3+ Tregs tended to be lower in patients with CMV infection (2.9 vs. 9.6 × 106/L, P = 0.055), including Tregs expressing the naivety markers CD45RA and Helios. CD8+ T-cell numbers rose after CMV infection and was dominated by exhausted PD1-expressing cells (66% vs. 39%, P = 0.023). These findings indicate that post-HSCT CMV infection is a main risk factor for development of chronic GvHD after pediatric HSCT and suggest that this effect is caused by reduced thymic function with a persistently impaired production of naïve and regulatory T cells in combination with increased peripheral T-cell exhaustion.

Successful Immune Reconstitution in a Patient with a TYK2 Deficiency after Allogeneic Stem Cell Transplantation from Unrelated Donors.

A boy with primary immunodeficiency, caused by a tyrosine kinase 2 (TYK2) mutation, presented with immune defects and a lifelong history of severe infections. Our aim was to determine whether allogeneic hematopoietic stem cell transplantation (HSCT) could restore the patient's immune defenses and reduce susceptibility to infection. In the absence of a suitable HLA-matched blood relative to act as a donor, the patient received an allogeneic HSCT from unrelated donors. The patient's clinical data were analyzed in the Children's Hospital of Chongqing Medical University (Chongqing, China) before transplantation and during the 4-year follow-up period using a combination of western blotting (e.g., TYK2 and STAT levels), qRT-PCR (e.g., T cell receptor rearrangement excision circles, kappa deletion element recombination circles, and TYK2 transcript levels), and flow cytometry (e.g., lymphocyte subpopulations and CD107α secretion). We found that HSCT significantly reduced the incidence of severe infections, restored normal TKY2 levels, and reversed defects such as impaired JAK/STAT signaling in response to interferon-α or interleukin-10 treatment. Although the patient did not develop acute graft-versus-host disease (GVHD) after transplantation, he did experience chronic GVHD symptoms in a number of organs, which were effectively managed. Our findings suggest that HSCT is a feasible strategy for reconstituting the immune system in TYK2-deficient patients; however, the factors associated with GVHD and autoimmune thyroiditis development in TYK2-deficient patients undergoing HSCT warrant further investigation.