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PubMed1979

Processing of peripheral blood stem cells for transplantation.

Canines were studied to determine the efficacy of peripheral blood collection by semicontinuous centrifugation to procure sufficient numbers of hematopoietic cells for marrow reconstitution. CFU-C assays on fresh and cryopreserved peripheral blood cells were compared to bone marrow aspirates. Attempts were made to partially separate hematopoietic cells from immunocompetent cells during buffy coat collection and by incubation with activated cyclophosphamide. Yields from 4 runs of semicontinuous centrifugation averaged 1.7 x 10(5) CFU-C compared to 1.9 x 10(5) CFU-C for standard marrow aspiration. Ratios of approximately 5/1 marrow to peripheral blood mononuclear cells (MNC) were found. Autologous transplantation with 1.6 x 10(4) CFU-C per kg resulted in evidence of marrow reconstitution within two weeks following otherwise lethal chemotherapy. Recovery of CFU-C following cryo-preservation was 82% for marrow and 78% for peripheral blood. Selective depression of MLC activity occurred when peripheral blood MNC were incubated for 30 minutes with activated cyclophosphamide. MLC was inhibited by greater than 90% while 70% of CFU-Cs were retained. It was concluded that peripheral blood may be a practical alternative to marrow for transplantation studies.

Animals↗
PubMed2026

Day + 30 detection of minimal residual FLT3-ITD by high-sensitivity PCR-NGS predicts relapse risk and guides post-transplant maintenance in AML.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has improved outcomes in patients with acute myeloid leukemia (AML) harboring FLT3-internal tandem duplication (FLT3-ITD) mutations. However, relapse still occurs in 15-35% of these patients after transplantation. Therefore, early and highly sensitive detection methods are required to identify patients at risk of relapse and enable timely post-transplant intervention. METHODS: In this NICHE cohort study, a total of 136 patients were included, then we evaluated whether high-sensitivity polymerase chain reaction (PCR)-next-generation sequencing (NGS) for FLT3-ITD (limit of detection: 5 × 10-6) on day + 30 post-HSCT could identify patients at a high risk of relapse and inform decisions regarding maintenance therapy. RESULTS: Among the 136 patients, 37 patients (27.2%) had detectable FLT3-ITD clones on day + 30. These patients exhibited a significantly higher cumulative incidence of post-HSCT multiparameter flow cytometry (MFC)-measurable residual disease (MRD) relapse (40.3% vs. 18.8%, p = 0.001). Notably, FLT3-ITD-positive patients who received FLT3 inhibitor maintenance therapy had no relapses, while 6 out of the 13 patients who did not receive maintenance therapy relapsed. Conversely, FLT3-ITD-negative patients without high-risk factors (2022 European LeukemiaNet adverse-risk group, relapsed/refractory AML, MFC-MRD positivity pre-HSCT) showed limited benefit from maintenance therapy (MFC-MRD-free survival: hazard ratio (HR) = 0.25 (0.03-2.11), p = 0.204; OS: HR = 0.20 (0.02-1.70), p = 0.142). CONCLUSIONS: This is the first study to demonstrate that detection of minimal FLT3-ITD clones at the fixed time point of day + 30 post-HSCT can reliably stratify relapse risk in AML patients and provide a rationale for individualized post-transplant maintenance therapy.

Humans↗
PubMed1978

Loss of proliferative capacity in immunohemopoietic stem cells caused by serial transplantation rather than aging.

Marrow stem cell lines from old donors and those from young controls gave equally rapid rates of colony growth on spleens of irradiated mice. Old and young stem cell lines competed equally well with chromosomally marked marrow stem cells from a young donor in producing cell types that are stimulated by bleeding; old cells competed 70% as well as young in producing cell types stimulated by phytohemagglutinin (PHA) in vitro. After a single serial transplantation, the rates of colony growth declined 1.5- to 2.5-fold, and the ability to compete declined 2- to 4-fold for bleeding-stimulated and 4- to 10-fold for PHA-stimulated cells. Thus, immediate stem cell proliferative capacities decline much more after one serial transplantation than after a lifetime of normal function.

Animals↗
PubMed1976

[Influence of the maternal effect on allogenic inhibition of hematopoietic stem cells].

Bone marrow cells (0,5-10(6)) of female mice of CBA or C57BL strains were injected intravenously to lethally irradiated CBA, C57BL/6, (femaleCBA X maleC57BL/6)F1 and (femaleC57BL/6 X maleCBA)F1 mice. Spleen of recipients as assayed for colony count on the 9th day after bone marrow transplantation by the method of Till and McCullouch. Stem cells of CBA mice demonstrated failure of allogenic inhibition in (CBA X C57BL/6)F1 hybrid mice and formed the same number of colonies as in the spleen of syngenic recipients. The level of allogenic inhibition of CBA stem cells transplanted to (C57BL/6 X X CBA)F1 hybrid mice was 50%. Bone marrow cells of C57BL/6 mice formed colonies in spleen of (CBA X C57BL/6)F1 mice at least in 20 times less than in syngenic combination. In the transplantation of bone marrow from C57BL/6 mice to (C57BL/6 X CBA)F1 hybrid mice the allogenic inhibition was less pronounced (77-85%) as compared with the transfer of cells to (CBA X C57BL/6)F1 hybrid mice (95%). The sex of a recipient did not influence the number of formed colonies. The different level of allogenic inhibition of parental stem cells can not be explained by the effect of linkage with sex as the female of reciprocal hybrid mice have identical structure of sex chromosomes (X(CBA)XC57BL/6). The data obtained indicate that the maternal effect affects allogenic inhibition of stem cells in parent--F1 system. It is possible that the maternal influence may be determined by cytoplasmic factors of inheritance which affect the expressivity of recessive genes Hh, controlling the inheritance of specific haematopoietic cell antigens.

Animals↗
PubMed1979

Mouse erythropoietic stem cell lines function normally 100 months: loss related to number of transplantations.

Marrow stem cell lines from old and young donors in parallel experiments were transplanted into genetically anemic W/WV recipients. These recipients were populated and their anemias were cured by stem cell lines from WCB6F1 or C57BL/6 dorons that had been repeatedly transplanted up to five times at annual intervals into successive W/WV recipients. Old marrow cell lines produced erythrocytes normally for as long as 2600 to 3000 days. However, after three to four serial transplantations many stem cell lines failed to cure at least two-thirds of the recipients, and all failed by transplantation six. This decline occurred in a similar pattern whether the original stem line donor was old or young. Two experiments suggested that the decline was caused by the transplantation procedure: (1) chromosomally marked donor cells from old and young donors permanently populated lymph nodes in lethally irradiated recipients after the first transplantation, but under the same conditions cell lines from the same donors transplanted a second time were substantially infiltrated by regenerating recipient cells; (2) the ability to compete with the same chromosomally marked cell line in populating irradiated recipients declined markedly in both old and young marrow stem cell lines that had been previoulsy transplanted.

Aging↗
PubMed2026

X-linked hyper-IgM syndrome presenting as severe Pneumocystis pneumonia in a 6-month-old infant: a case report.

BACKGROUND: X-linked hyper-immunoglobulin M (XHIGM) syndrome is a rare primary immunodeficiency caused by mutations in the CD40 ligand gene (CD40LG), characterized by defective T-cell-dependent B-cell class-switch recombination. Patients typically present with recurrent infections in early childhood, but diagnosis is often delayed due to heterogeneous clinical manifestations and the fact that serum IgM levels may remain within the normal range in a significant proportion of patients. Here we report a case of XHIGM in an infant whose diagnostic journey began with recurrent lymphadenitis and culminated in life-threatening Pneumocystis jirovecii pneumonia (PJP). CASE PRESENTATION: A 6-month-old male infant was admitted with severe respiratory distress and hypoxemia. He had recurrent axillary lymphadenitis at 1 and 2 months of age and significant failure to thrive. Chest CT showed bilateral consolidative and interstitial opacities. Immunological evaluation revealed markedly decreased IgA, normal IgM and IgG, and profound T-cell lymphopenia. Sputum metagenomic sequencing identified Pneumocystis jirovecii. Whole-genome sequencing identified a hemizygous likely pathogenic CD40LG mutation (NM_000074.3:c.520C>T, p.Q174*); his mother was a carrier. He was treated with mechanical ventilation, trimethoprim-sulfamethoxazole (TMP-SMX), micafungin, corticosteroids, and intravenous immunoglobulin (IVIG), and was discharged after 36 days. CONCLUSIONS: In infants with recurrent or opportunistic infections, persistently low IgA and declining T-cell counts-even when initial screening appears normal-should raise suspicion for underlying immunodeficiency and prompt genetic evaluation. Early aggressive management and evaluation for hematopoietic stem cell transplantation are essential to improve outcomes.Serial immunological evaluation is essential in infants with recurrent or opportunistic infections, as persistently low IgA and declining T-cell counts-even when initial screening appears normal-should prompt genetic evaluation for underlying immunodeficiency. Early aggressive management and evaluation for hematopoietic stem cell transplantation are essential to improve outcomes.

Humans↗
PubMed2025

Recipient-derived vs. donor-derived CAR-T-cell therapy in relapsed B-cell acute lymphoblastic leukemia patients after transplantation: A multi-center retrospective study.

BACKGROUND: Chimeric antigen receptor T (CAR-T) cells have been demonstrated to be an effective treatment for relapsed B-cell acute lymphoblastic leukemia (B-ALL) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). T cells for CAR-T therapy can be derived from the peripheral blood (recipient) of the patient or donor. Despite having identical genomes, the different maturation environments of these T cells can lead to functional differences. This study aimed to compare the clinical outcomes of CAR-T cells derived from these two sources. METHODS: This multicenter, retrospective cohort study collected clinical data from 36 patients who experienced B-ALL relapse after allo-HSCT and received CD19 CAR-T cell therapy between January 2016 and October 2023 across seven centers. The primary endpoint was complete remission (CR)/CR with an incomplete hematologic recovery (CRi) rate at 28 days post-CAR-T cell infusion. Secondary endpoints included the 2-year overall survival (OS) rate, 2-year event-free survival (EFS) rate, incidence of graft-versus-host disease (GVHD), cytokine release syndrome (CRS), and CAR-T cell-related encephalopathy syndrome (CRES). RESULTS: A retrospective analysis was performed on 36 patients: 12 in the recipient group and 24 in the donor group. The recipient and donor groups showed no statistically significant differences in CR/CRi rates (83.3% vs. 100.0%, P = 0.105), 2-year EFS rates (50.8% vs. 51.6%, P = 0.617), or 2-year OS rates (49.5% vs. 63.6%, P = 0.215). In addition, the incidences of GVHD, CRS, and CRES did not significantly differ between the two groups. Further analysis within the donor group revealed 12 matched sibling donors (MSDs) and 12 haploidentical donors (HIDs). The 2-year EFS rate was statistically significantly greater in the HID group than in the MSD group (75.0% vs. 30.7%, P = 0.043), whereas no significant differences were observed in the CR/CRi rates, 2-year OS, or the incidence of GVHD, CRS, and CRES between these subgroups. CONCLUSIONS: Both recipient-derived and donor-derived CD19 CAR-T cell therapies are effective treatment options for B-ALL relapsed post-allo-HSCT patients. HID-derived CAR-T cells offer a longer EFS and may be considered the optimal choice. TRIAL REGISTRATION: Chinese Clinical Trial Registry, No. ChiCTR2400085297.

Adolescent↗
PubMed2026

Biologic Therapies for Alleviating Neurodegeneration in Lysosomal Storage Diseases.

Lysosomal storage diseases (LSDs) are a group of rare inherited metabolic disorders characterized by lysosomal dysfunction and progressive accumulation of undegraded substrates, leading to multisystem involvement and, in many cases, severe neurodegeneration. Because the blood-brain barrier (BBB) restricts central nervous system (CNS) access for most therapeutic modalities, neurological manifestations remain the major unmet need across LSDs. In this review, we summarize current and emerging strategies aimed at correcting CNS pathology, including enzyme replacement therapy (ERT), adeno-associated virus (AAV)-mediated gene therapy, allogeneic hematopoietic stem cell transplantation (HSCT), and autologous HSCT with gene-modified hematopoietic stem cells. While ERT provides limited CNS benefits and allogeneic HSCT mitigates neurodegeneration only partially, their overall impact on CNS outcomes remains restricted. Newer approaches, such as BBB-shuttling ERTs, CNS-tropic AAV capsids, and genetically modified autologous hematopoietic stem and progenitor cells capable of sustained supraphysiological enzyme production, offer promising avenues for enhanced CNS delivery and cross-correction. Together, these advances underscore a shift toward integrated therapeutic strategies that combine systemic and CNS-directed interventions, with the potential to transform outcomes for patients with LSDs and other neurodegenerative disorders amenable to cross-correction.

Journal Article↗
PubMed2024

Bacteroides ovatus alleviates dysbiotic microbiota-induced graft-versus-host disease.

Acute lower gastrointestinal GVHD (aLGI-GVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation. Although the intestinal microbiota is associated with the incidence of aLGI-GVHD, how the intestinal microbiota impacts treatment responses in aLGI-GVHD has not been thoroughly studied. In a cohort of patients with aLGI-GVHD (n = 37), we found that non-response to standard therapy with corticosteroids was associated with prior treatment with carbapenem antibiotics and a disrupted fecal microbiome characterized by reduced abundances of Bacteroides ovatus. In a murine GVHD model aggravated by carbapenem antibiotics, introducing B. ovatus reduced GVHD severity and improved survival. These beneficial effects of Bacteroides ovatus were linked to its ability to metabolize dietary polysaccharides into monosaccharides, which suppressed the mucus-degrading capabilities of colonic mucus degraders such as Bacteroides thetaiotaomicron and Akkermansia muciniphila, thus reducing GVHD-related mortality. Collectively, these findings reveal the importance of microbiota in aLGI-GVHD and therapeutic potential of B. ovatus.

Graft vs Host Disease↗
PubMed1976

Transplantation of bursal stem cells into cyclophosphamide-treated chicks. Lymphoid repopulation of splenic structures.

After transplantation of bursal stem cells into cyclophoshamide-treated newly hatched chicks, the first lymphoid cells in the spleen of the recipients were observed on the first day after the cell transfer and the first plasma cells on day 3. The repopulation of the Schweigger-Seidel sheaths started from their periphery on day 6. The first germinal centers were detected 20 days after the cell transfer. In cyclophosphamide-treated birds without cell transplantation, only the periphery of the Schweigger-Seidel sheaths became repopulated, and no plasma cells or germinal centers were observed. The results indicate that already at the age of 3 days the bursa contains some cells of postbursal maturity, able to home to the spleen.

Animals↗
PubMed1979

Relative number and proliferation kinetics of hemopoietic stem cells in the mouse.

A model calculation of the hemopoiesis of the mouse based on known hematologic data leads to the conclusion that approximately 3% of all nucleated bone marrow cells are stem cells (pluripotent plus committed stem cells). By a new 125IUdR labeling technique on radiation chimeras, a relative number of 2%-7% stem cells was determined. In previous studies with test systems for stem cells using colony formation in vivo or in vitro, a relative number of stem cells of at least one order of magnitude lower has been estimated. In this study the stem cells are found to have a turnover time of about 4.3 days in the donor mice. This turnover time remained unchanged even after transfusion of marrow cells into lethally irradiated recipient mice. Radiosensitivity determinations yielded a D0 of 80 rad for stem cells in S-phase and D0 of 185 rad for stem cells distributed throughout the entire cell cycle. The respective extrapolation numbers were 1.23 and 1.14. Experiments using an 3H-TdR suicide technique revealed different cell cycle parameters for bone marrow stem cells seeding to the spleens and to the femurs of lethally irradiated recipients, primarily a shortening of S-phase in cells seeding to femurs. The method described here provides a new approach to hematologic stem cell research.

Animals↗
PubMed2026

A therapeutic atlas of monogenic inflammatory bowel disease.

BACKGROUND AND AIMS: Evidence-based, mechanism-guided therapies are urgently needed for treating monogenic inflammatory bowel disease (mIBD). For such rare diseases, mechanistic insight is essential to guide treatment when conventional clinical trials are often not feasible. We aimed to summarize literature-based evidence and to identify knowledge gaps. METHODS: We conducted a systematic review of published manuscripts evaluating the therapeutic efficacy in mIBD. We quantified and compared the global therapeutic response score across treatments and conditions. In a subset of conditions, biomarkers of longitudinal therapeutic response were evaluated in comparison to non-monogenic pediatric IBD cohorts. RESULTS: Responses to 35 therapeutics across the 102 known genetic causes of mIBD were evaluated in 241 articles and 669 patients, summarizing 302 gene-drug responses. The efficacy of at least one pharmacological intervention was identified in 61% (n = 62/102) of the mIBD conditions, highlighting a major unmet need for effective medications in many others. Gene- and pathway-specific responses were demonstrated for several therapies, including allogeneic hematopoietic stem cell transplantation, gene therapy, and advanced therapies such as anti-TNF agents, IL-1 inhibitors, mTOR inhibitors, as well as eculizumab in CD55 deficiency, abatacept in CTLA4 deficiency, and the immunometabolic agent empagliflozin in glycogen storage disease type 1b. CONCLUSIONS: This study highlights the potential of precision medicine approaches tailored to genetic and pathway-specific mechanisms, while underscoring the urgent need for effective therapies in many monogenic conditions that remain without established treatment options.

Humans↗
PubMed2025

Analysis of HLA Allelic and Haplotypic Frequencies in a Cohort of Bone Marrow Donors in Catalonia: Impact of Next-Generation Sequencing on Donor Registry Quality.

In haematopoietic stem cell transplantation (HSCT), the volunteer unrelated donor (VUD) has become the most common strategy in Europe, as improved outcomes are achieved through HLA compatibility at allelic-level resolution. In this context, the implementation of next-generation sequencing (NGS) in histocompatibility typing laboratories has significantly enhanced the quality of bone marrow registries, enabling a high level of resolution at a lower cost and improved performance. In this study, we analyse a large cohort of 21,787 bone marrow donors in Catalonia and present the observed HLA allelic and haplotypic frequencies, along with their linkage disequilibria. HLA-A, -B, -C, -E and -G were genotyped at full resolution, while -DRB1, -DQB1, -DQA1, -DPA1 and -DPB1 were genotyped at high resolution. We identified 236 new officially named HLA alleles, both coding and non-coding regions. This study highlights that the implementation of high-throughput HLA typing has led to an increase in the number of registered donors and an improvement in quality, which has been reflected in a rise in the number of effective donors.

Humans↗
PubMed2023

Bacteroides ovatus alleviates dysbiotic microbiota-induced intestinal graft-versus-host disease.

Acute gastrointestinal intestinal GVHD (aGI-GVHD) is a serious complication of allogeneic hematopoietic stem cell transplantation, and the intestinal microbiota is known to impact on its severity. However, an association between treatment response of aGI-GVHD and the intestinal microbiota has not been well-studied. In a cohort of patients with aGI-GVHD (n=37), we found that non-response to standard therapy with corticosteroids was associated with prior treatment with carbapenem antibiotics and loss of Bacteroides ovatus from the microbiome. In a mouse model of carbapenem-aggravated GVHD, introducing Bacteroides ovatus reduced severity of GVHD and improved survival. Bacteroides ovatus reduced degradation of colonic mucus by another intestinal commensal, Bacteroides thetaiotaomicron, via its ability to metabolize dietary polysaccharides into monosaccharides, which then inhibit mucus degradation by Bacteroides thetaiotaomicron and reduce GVHD-related mortality.

Bacteroides ovatus↗
PubMed1975

Hematopoietic differentiative properties of murine spleen implanted in the omenta of irradiated and nonirradiated hosts.

Whole body irradiation of the recipients of syngeneic splenic implants into the omentum greatly enchances hematopoiesis and permits survial of and repopulation by stem cells of donor origin. Donor hematopioetic stem cells do not survive in spleen implants of the nonirradiated host; irradiated hosts were therfore used in the bulk of the experiments. Differentiation in the implants of splenic fragments is predominantly erythrocytic at 10 days and shifts to predominantly granulocytic differentiation at 21 days. Suspensions of spleen cells injected into the ometntum are predominantly granulocytopioetic at 10 days. The differntiation in fragments of spleen depleted of stem cells by irradtion, seeded with bone marrow cells and implanted into the omentum results in mixed erythocytic and granulocytic hematopoiesis, with granulocytic predominance. Lymphocytic cells appeared late in the implants of irrdiated recipients even at a time of prolific lymphocytopoiesis in the host's own spleens. The cause of the delay in the implants is not clear. The data are consisent with the concept that differntiation of hematopioetic stem cells is influenced by the stromal cells of the parent organ. The erythrocytic inductive capacity of the stromal cells may be lost by mechanical disruption or modified by irraidation or a prolonged period of implantation.

Animals↗