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Cells and signals of the leukemic microenvironment that support progression of T-cell acute lymphoblastic leukemia (T-ALL).

Current intensified chemotherapy regimens have significantly increased survival rates for pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL), but these treatments can result in serious adverse effects; furthermore, patients who are resistant to chemotherapy or who relapse have inferior outcomes, together highlighting the need for improved therapeutic strategies. Despite recent advances in stratifying T-ALL into molecular subtypes with distinct driver mutations, efforts to target the tumor-intrinsic genomic alterations critical for T-ALL progression have yet to translate into m

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… IL-7R signaling is essential for survival and expansion of early T-cell precursors 52 , 53 and facilitates survival of thymocytes following β-selection, a checkpoint that tests developing thymocytes for productive TCRβ chain gene rearrangements 54 . … NOTCH signaling is required for immature thymocyte progenitors to commit to the T-cell lineage and for expression of transcription factors that regulate differentiation of CD4 - CD8 - DN thymocyte subsets from early progenitors through β-selection 53 . …

Haploidentical bone marrow transplantation in patients with relapsed or refractory severe aplastic anaemia in the USA (BMT CTN 1502): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Relapsed severe aplastic anaemia is a marrow failure disorder with high morbidity and mortality. It is often treated with bone marrow transplantation at relapse post-immunosuppressive therapy, but under-represented minorities often cannot find a suitably matched donor. This study aimed to understand the 1-year overall survival in patients with relapsed or refractory severe aplastic anaemia after haploidentical bone marrow transplantation. METHODS: We report the outcomes of BMT CTN 1502, a single-arm, phase 2 clinical trial done at academic bone marrow transplantation centres in th

Автономная трансплантация стволовых клеток с помощью гематопоиетической гематомии для множественных склерозов в Соединенном Королевстве: A 20-year Ретроспективный анализ деятельности и гематологических результатов Британского общества трансплантации крови и мозга и клеточной терапии (BSBMTCT).

Автологическая трансплантация стволовых клеток (AHSCT) была разработана в качестве средства лечения множественных склерозов (MS) с тех пор. 1995. Соединенное Королевство one :: из наиболее активных стран Европы, осуществляющих АХСХТ для НР. Мы сообщаем об опыте Соединенного Королевства в области AHSCT для MS 364 :: пациенты, имеющие MS, которые лечатся AHSCT между 2002 и 2023. Мы представляем данные о смертности, связанной с трансплантацией (ТМР), осложнениях и эффективности АХСПП, определяемых расширенной шкалой показателей инвалидности (ЭДСС) в условиях бесперебойного выживания (ПФС) 2 годы

Площадь метилирования ДНК клеток цереброспинальной жидкости в множестве склероза: исследование эпигеномной ассоциации.

Множественный склероз (MS) является хроническим воспалительным заболеванием центральной нервной системы, в которой метилация ДНК может увязывать генетические и экологические факторы риска. Methods: Мы профилировали содержание метилации ДНК по всему геному в клетках цереброспиновой жидкости (CSF) у людей с MS (pwMS) и совпадающими контрольными устройствами. Дифференцированные метилированные позиции (DMP) и регионы (DMR) были интегрированы с транскриптомными данными, аннотациями клеточного хроматина Т и анализом путей. Выражение гамма-протокадерина (ПХДГ) было оценено в первичных подмножествах C

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… : Double-positive thymocytes, CD4 thymocyte: CD4 + thymocytes, CD8 thymocyte: CD8 + thymocytes, Naive CD4: Naive CD4 + T cells, Naive CD8: Naive CD8 + T cells, Treg: Regulatory T cells, Th17: T helper 17 cells, CD4CM: CD4 + central memory T cells, CD4EM: CD4 + effector memory T cells, CD4TEMRA: CD4 + … : Double-positive thymocytes, CD4 thymocyte: CD4 + thymocytes, CD8 thymocyte: CD8 + thymocytes, Naive CD4: Naive CD4 + T cells, Naive CD8: Naive CD8 + T cells, Treg: Regulatory T cells, Th17: T helper 17 cells, CD4CM: CD4 + central memory T cells, CD4EM: CD4 + effector memory T cells, CD4TEMRA: CD4 + …

Множественный склероз: расстройство перестроенного T-Cell Homeostasis

Существует неопределенность в отношении того, способствуют ли аналогичные или различные механизмы патогенезу различных подтипов множественного склероза (МС). Детальный анализ наивного гомеостазиза клеток Т показывает, что пациенты с повторно излучающими MS (RRMS) и с первичным прогрессивным MS (PPMS) имеют раннее наступление тимической инструкции, что приводит к снижению тимической производительности. Снижение тимической производительности приводит к вторичным периферийным гомеостатическим изменениям в наивных CD4 Т-клеток, которые тесно имитируют изменения Т-клеток, наблюдаемые в эксперимента

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… Increased Naive T-Cell Proliferation and TCR Signalling in MS The magnitude of proliferation of early (CD3-CD4-CD8-) thymocytes is the main determinant of thymic output. … We concluded in our laboratory that calculations of sj/ β TREC ratios would not provide accurate, direct measures of thymocyte proliferation [ 23 ]. …

Impact of Anti-T-lymphocyte globulin dosing on GVHD and Immune reconstitution in matched unrelated myeloablative peripheral blood stem cell transplantation.

Data on the influence of different Anti-lymphocyte globulin (ATLG) doses on graft versus host disease (GVHD) incidence and immune reconstitution in matched unrelated (MUD) allogeneic Stem cell transplantation (allo-SCT) is limited. This retrospective study conducted at the University Medical-Center Hamburg compares GVHD and Immune reconstitution after myeloablative MUD (HLA 10/10) PBSC allogeneic stem cell transplant between 30 mg/Kg (n = 73) and 60 mg/Kg (n = 216) ATLG. Detailed phenotypes of T, B natural killer (NK), natural killer T (NKT) cells were analyzed by multicolor flow at day 30, 10

T-Cell Acute Lymphoblastic Leukemia-Current Concepts in Molecular Biology and Management.

T-cell acute lymphoblastic leukemia (T-ALL) is an uncommon, yet aggressive leukemia that accounts for approximately one-fourth of acute lymphoblastic leukemia (ALL) cases. CDKN2A/CDKN2B and NOTCH1 are the most common mutated genes in T-ALL. Children and young adults are treated with pediatric intensive regimens and have superior outcomes compared to older adults. In children and young adults, Nelarabine added to frontline chemotherapy improves outcomes and end of consolidation measurable residual disease has emerged as the most valuable prognostic marker. While outcomes for de-novo disease are

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… Thymocyte Development Thymocyte development in mice has been extensively studied using in vivo and in vitro models [ 13 ]. Uncommitted lymphoid cells from the bone marrow proliferate when stimulated by Interleukin-7 (IL-7) and stem cell factor (SCF) upon entering the thymus [ 14 , 15 ]. … The leukemic cells derive from immature thymocytes that retain stem cell and myeloid lineage characteristics. …

The risk of cytomegalovirus infection in non-myeloablative peripheral stem cell transplantation compared with conventional bone marrow transplantation.

Non-myeloablative allogeneic peripheral stem cell transplantation (NST) is a novel therapeutic strategy for patients with hematologic malignancies. Whether non-myeloablative transplants are associated with increased risk of cytomegalovirus (CMV) infections is unknown. To clarify this issue, we compared the outcome of CMV infection following 24 allogeneic non-myeloablative peripheral blood stem cell transplants and 40 conventional bone marrow transplants (CBT). The NST regimen consisted (mg/kg). Twelve patients (50%) in the NST group and 17 (43%) in the CBT group developed positive antigenemia

Impact of anti-T-lymphocyte globulin dosing on graft versus host disease in matched sibling peripheral blood stem cell transplantation.

Anti-T-lymphocyte globulin (ATLG) is commonly administered to reduce graft-versus-host disease (GVHD) in allogeneic stem cell transplantation (allo-SCT). However, the optimal ATLG dose in matched-sibling-donor (MSD) peripheral blood stem-cell transplantation (PBSCT) remains uncertain. We compared two ATLG doses (15 mg/kg vs. 30 mg/kg) in the MSD-PBSCT setting to assess allo-SCT outcomes. In this single-center retrospective study, we included 165 consecutive patients with hematologic malignancies who underwent MSD-PBSCT. Of these, 71 received 15 mg/kg ATLG (ATLG-15), and 94 received 30 mg/kg AT

Связанный с K27 ROR__t Уничтожение Nedd4 потенциалами Th17-посредованная автонепроницаемость.

СПРАВОЧНАЯ ИНФОРМАЦИЯ: Было продемонстрировано, что THCT E3 Ubriquitin ligase Nedd4 позитивно регулирует реакцию клеток Т, однако его роль в дифференциации клеток и автономном иммунитете Т неизвестна. Считается, что 17 клеток играют ключевую роль в развитии и патогенезе аутоиммунных заболеваний. Тем не менее, правила, регулирующие активацию РОРТ в ходе дифференциации клеток TH17 с помощью сигнала TCR, пока еще не уточнены. Эти неизведанные аспекты вдохновляют нас на изучение потенциальной роли Nedd4 в автоматическом иммунитете Th17.МЕТОДЫ: Мы провели оценку воздействия дефицита Nedd4 на развит

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… To avoid the confound effect of RORγt expression in DP thymocytes which impairs thymocyte development [ 39 ], we adoptively transferred CD4 + T cells from Rorc Cre and Rorc Cre - Nedd4 f/f mice to Tcrb –/– recipients [ 11 ], and immunized the recipients with MOG 35-55 in CFA. … Interestingly, Rorc Y479F mice phenocopied the mice deficient for RORγt which show defective thymocyte development and lack lymph nodes, but the expression of RORγt in thymocytes of Rorc Y479F mice was not affected (Supplementary Fig. 7). …

Interleukin-6 as Biomarker for Acute GvHD and Survival After Allogeneic Transplant With Post-transplant Cyclophosphamide.

Background: Although the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) has dramatically improved in the past decade, it is still compromised by transplant-related mortality (TRM), mainly caused by Graft-vs. -Host Disease (GvHD). Methods: We conducted a prospective observational study to ascertain the potential of serum interleukin-6 (IL6) levels, measured before conditioning and 7 days after allo-HSCT, in predicting acute GvHD, TRM and survival after allo-HSCT with Post-Transplant Cyclophosphamide (PT-Cy) based GvHD prophylaxis. Results: Between April 2014 and June

Role of allogeneic transplantation in multiple myeloma in the era of new drugs.

High-dose melphalan with autologous stem cell rescue has been regarded as the standard of care for patients with newly diagnosed myeloma up to the age of 65-70 years. The recent development of agents with potent anti-tumor activity such as thalidomide, lenalidomide and bortezomib has further improved overall survival and response rates. However, relapse is a continuous risk.Allografting is a potentially curative treatment for a subset of multiple myeloma patients for its well documented graft-vs-myeloma effects. However, its role has been hotly debated. Even though molecular remissions have be

Hematopoietic chimerism and transplantation tolerance: a role for regulatory T cells.

The immunosuppressive regimens currently used in transplantation to prevent allograft destruction by the host's immune system have deleterious side effects and fail to control chronic rejection processes. Induction of donor-specific non-responsiveness (i.e., immunological tolerance) to transplants would solve these problems and would substantially ameliorate patients' quality of life. It has been proposed that bone marrow or hematopoietic stem-cell transplantation, and resulting (mixed) hematopoietic chimerism, lead to immunological tolerance to organs of the same donor. However, a careful ana

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… Combined, the data discussed thus far showed that DC, and potentially other cells of hematopoietic origin, contribute to tolerance induction by elimination of developing thymocytes. … Thymocytes can tolerize thymocytes by clonal deletion in vitro . Int. Immunol. 4 , 1065 – 1069 10.1093/intimm/4.9.1065 1390437 Porcheray F. Wong W. Saidman S. L. De Vito J. Girouard T. C. Chittenden M. Shaffer J. Tolkoff-Rubin N. Dey B. R. Spitzer T. R. Colvin R. B. Cosimi A. B. Kawai T. Sachs D. …

Comparison of oral chronic graft-versus-host disease characteristics between patients with malignant and non-malignant hematopoietic disorders.

ObjectivesTo characterize and compare the clinical manifestations of oral chronic graft-versus-host disease (cGVHD) in patients with malignant hematopoietic disorders versus those with non-malignant hematopoietic disorders, and to analyze associated risk factors.Materials and methodsDetailed examinations of the oral cavity were conducted in patients with malignant hematopoietic disorders (n = 52) and non-malignant hematopoietic disorders (n = 56) who developed oral cGVHD following allogeneic hematopoietic stem cell transplantation (allo-HSCT). The severity of oral cGVHD was scored, and logisti

γδ T cells: origin and fate, subsets, diseases and immunotherapy.

The intricacy of diseases, shaped by intrinsic processes like immune system exhaustion and hyperactivation, highlights the potential of immune renormalization as a promising strategy in disease treatment. In recent years, our primary focus has centered on γδ T cell-based immunotherapy, particularly pioneering the use of allogeneic Vδ2+ γδ T cells for treating late-stage solid tumors and tuberculosis patients. However, we recognize untapped potential and optimization opportunities to fully harness γδ T cell effector functions in immunotherapy. This review aims to thoroughly examine γδ T cell im

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… In human, the incorporation of nucleotides during V(D)J recombination varies between embryonic, fetal, and postnatal γδ thymocytes. … In the absence of TdT, short homology repeats present in certain V/D/J segments can facilitate recombination, resulting in the formation of specific germline-encoded sequences in fetal γδ thymocytes. …

MicroRNAs and Glucocorticoid-Induced Apoptosis in Lymphoid Malignancies.

The initial response of lymphoid malignancies to glucocorticoids (GCs) is a critical parameter predicting successful treatment. Although being known as a strong inducer of apoptosis in lymphoid cells for almost a century, the signaling pathways regulating the susceptibility of the cells to GCs are only partly revealed. There is still a need to develop clinical tests that can predict the outcome of GC therapy. In this paper, I discuss important parameters modulating the pro-apoptotic effects of GCs, with a specific emphasis on the microRNA world comprised of small players with big impacts. The

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… MicroRNA during Thymocyte Development MicroRNA expression is dynamically regulated during thymocyte development, with different enriched microRNAs expressed at each developmental stage [ 539 ] ( Table 1 ). … It should be emphasized that the CD4 + CD8 + (double positive, DP) thymocytes are the most GC-sensitive thymocyte population [ 540 – 542 ]. Dicer-deficient DP thymocytes expressed higher levels of CD69 and TCR (T-cell receptor), but lower levels of Bcl-2 [ 539 ]. …

Cytokine Release Syndrome in the Immunotherapy of Hematological Malignancies: The Biology behind and Possible Clinical Consequences.

Cytokine release syndrome (CRS) is an acute systemic inflammatory syndrome characterized by fever and multiple organ dysfunction associated with (i) chimeric antigen receptor (CAR)-T cell therapy, (ii) therapeutic antibodies, and (iii) haploidentical allogeneic stem cell transplantation (haplo-allo-HSCT). Severe CRS can be life-threatening in some cases and requires prompt management of those toxicities and is still a great challenge for physicians. The pathophysiology of CRS is still not fully understood, which also applies to the identifications of predictive biomarkers that can forecast the

Bone marrow versus peripheral blood allogeneic haematopoietic stem cell transplantation for haematological malignancies in adults.

BACKGROUND: Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is an established treatment option for many malignant and non-malignant haematological disorders. Peripheral blood stem cells represent the main stem cell source in malignant diseases due to faster engraftment and practicability issues compared with bone marrow stem cells. Since the early 2000s, there have been many developments in the clinical field. Allo-HSCT using haploidentical family donors (haplo-HSCT) has emerged as an alternative for people who do not have human leukocyte antigen (HLA)-matched siblings or unrel

Early bilirubinemia after allogeneic stem cell transplantation-an endothelial complication.

Hyperbilirubinemia occurs frequently after allogeneic stem cell transplantation. Causes include primary liver damage and endothelial complications as major contributors. Here, we have investigated the impact of early bilirubinemia (EB) on posttransplant outcomes. Maximum total bilirubin levels (days 0-28) were categorized using maximally selected log rank statistics to identify a cut off for the endpoint non-relapse mortality (NRM) in a training cohort of 873 patients. EB above this cut off was correlated with NRM and overall survival (OS) and with pre- and posttransplant Angiopoietin-2, inter

Immunosenescence and the Geriatric Giants: Molecular Insights into Aging and Healthspan.

Aging is associated with complex immune dysfunction that contributes to the onset and progression of the "geriatric giants", including frailty, sarcopenia, cognitive decline, falls, and incontinence. Central to these conditions is immunosenescence, marked by thymic involution, the loss of naïve T cells, T-cell exhaustion, impaired B-cell class switch recombination, and increased autoreactivity. Concurrently, innate immunity deteriorates due to macrophage, neutrophil, and NK cell dysfunction, while chronic low-grade inflammation-or "inflammaging"-amplifies systemic decline. Key molecular pathwa