The role of germline mutation profiling in the selection of related donors for haematopoietic stem cell transplantation.
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ABSTRACT:
SUBMITTER: Zebisch A
PROVIDER: S-EPMC7334040 | biostudies-literature | 2020 Jul
REPOSITORIES: biostudies-literature
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The role of germline mutation profiling in the selection of related donors for haematopoietic stem cell transplantation.
Zebisch Armin A Winter Gerlinde G Kashofer Karl K Hatzl Stefan S Uhl Barbara B Wurm Sonja S Wölfler Albert A Greinix Hildegard T HT Hoefler Gerald G Sill Heinz H
Bone marrow transplantation 20190925 7
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Project description: Not available
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Project description:ObjectivesPaediatric and adolescent patients in need of allogeneic haematopoietic stem cell transplantation (HSCT) generally receive stem cells from older, unrelated or parental donors when a sibling donor is not available. Despite encouraging clinical outcomes, it has been suggested that immune reconstitution accompanied by increased replicative stress and a large difference between donor and recipient age may worsen immunosenescence in paediatric recipients.MethodsIn this study, paired samples were collected at the same time from donors and recipients of haploidentical haematopoietic stem cell transplantation (HaploSCT). We then conducted flow cytometry-based phenotypic and functional analyses and telomere length (TL) measurements of 21 paired T-cell sets from parental donors and children who received T-cell-replete HaploSCT with post-transplant cyclophosphamide (PTCy).ResultsSenescent T cells, CD28- or CD57+ cells, were significantly expanded in patients. Further, not only CD4+CD28- T cells, but also CD4+CD28+ T cells showed reduced cytokine production capacity and impaired polyfunctionality compared with parental donors, whereas their TCR-mediated proliferation capacity was comparable. Of note, the TL in patient T cells was preserved, or even slightly longer, in senescent T cells compared with donor cells. Regression analysis showed that senescent features of CD4+ and CD8+ T cells in patients were influenced by donor age and the frequency of CD28- cells, respectively.ConclusionOur data suggest that in paediatric HaploSCT, premature immunosenescent changes occur in T cells from parental donors, and therefore, long-term immune monitoring should be conducted.
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Project description:Three randomised controlled trials of haematopoietic stem cell transplantation (HSCT) in systemic sclerosis (SSc) demonstrated long-term survival benefits, induction of clinically meaningful, sustained improvement of forced vital capacity with improvements in skin thickening, vasculopathy and health-related quality of life, in contrast to a clinical decline in standard of care control groups. These benefits, however, must be weighed against the increased risk of transplant-related mortality. Further, with disease progression, severe extensive internal organ involvement and damage ensues, constituting an exclusion criterion for safety reasons, leaving a limited window whereby patients with SSc are eligible for HSCT. Although autologous HSCT offers the possibility of drug-free remission, relapse can occur, requiring re-initiation of disease modifying antirheumatic drugs. HSCT is also associated with secondary autoimmune diseases and gonadal failure. HSCT should be proposed for carefully selected patients with early rapidly progressive diffuse SSc whose clinical picture portends a poor prognosis for survival, but yet lacks advanced organ involvement.
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Project description:Haematopoietic stem cell transplantation (HSCT) is an established treatment for a variety of malignant and nonmalignant conditions. Pulmonary complications, both infectious and noninfectious, are a major cause of morbidity and mortality in patients who undergo HSCT. Recent advances in prophylaxis and treatment of infectious complications has increased the significance of noninfectious pulmonary conditions. Acute lung injury associated with idiopathic pneumonia syndrome remains a major acute complication with high morbidity and mortality. On the other hand, bronchiolitis obliterans syndrome is the most challenging chronic pulmonary complication facing clinicians who are taking care of allogeneic HSCT recipients. Other noninfectious pulmonary complications following HSCT are less frequent. This review provides a clinical update of the incidence, risk factors, pathogenesis, clinical characteristics and management of the main noninfectious pulmonary complications following HSCT.
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Project description:Haematopoietic stem cell transplantation currently remains the only curative treatment of primary forms of haemophagocytic lymphohistiocytosis (HLH). Rapid diagnosis, efficient primary treatment of hyperinflammation, and conditioning regimens tailored to this demanding condition have substantially improved prognosis in the past 40 years. However, refractory hyperinflammation, central nervous system (CNS) involvement, unavailability of matched donors, susceptibility to conditioning-related toxicities, and a high frequency of mixed chimaerism remain a challenge in a substantial proportion of patients. Gene therapeutic approaches for several genetic defects of primary HLH are being developed at pre-clinical and translational levels.
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Project description:Chronic granulomatous disease (CGD) is an inborn error of immunity due to defects in the transport or function of subunits of nicotinamide adenine dinucleotide phosphate oxidase, the enzyme that generates the phagocyte respiratory burst responsible for intracellular killing of engulfed micro-organisms. Patients present with infectious or inflammatory complications. Common bacterial pathogens include Staphylococcus aureus and Burkholderia cepacia complex. Fungal pathogens include Aspergillus species, particularly Aspergillus fumigatus. Inflammatory complications most commonly manifest as inflammatory bowel disease or lung disease. Granulomata are the distinguishing histological feature. Haematopoietic stem cell transplantation (HSCT) was first considered for CGD in the early 1970's. Since then, refinements in transplant technique, donor selection, conditioning regimens, and graft engineering have widened the option of HSCT to most patients with CGD. This review charts the progress made in HSCT for CGD.
| S-EPMC10532348 | biostudies-literature
Project description:HLA matching, transplantation technique, or underlying disease greatly influences the probability of long-term transplantation success. It has been hypothesised that genetic variation affecting antigen presentation also contributes to the outcomes of both solid organ transplantation and allogeneic haematopoietic stem cell transplantation (AHSCT). Those genes, along with those responsible for innate and adaptive immunity, have become targets of investigation. In this review, we focus on the role of CTLA4 in the process of acute graft rejection and summarise the progress in our understanding of its role in predicting the outcome. We present the results of the latest studies investigating the link between CTLA4 gene variability and AHSCT, as well as organ transplantation outcomes. While some studies found a link between +49 A/G and -318 C/T and transplantation outcomes, comprehensive meta-analyses have failed to present any association. The most recent field reviews suggest that the -1772 T/C (rs733618) CC genotype is weakly associated with a lower risk of acute graft rejection, while +49 A/G might be clinically meaningful when investigated in the context of combinations with other polymorphisms. Studies verifying associations between 12 CTLA4 gene SNPs and AHSCT outcomes present inexplicit results. Some of the most commonly studied polymorphisms in this context include +49 A/G (rs231775) and CT60 A/G (rs3087243). The results signify that, in order to understand the role of CTLA4 and its gene polymorphisms in transplantology, further studies must be conducted.
| S-EPMC8002677 | biostudies-literature
Project description:AimOral mucositis is a common and debilitating side effect of haematopoietic stem cell transplantation. Our study investigated parents' and children's experiences of oral mucositis treatment and whether the parents' perceptions accurately reflected the children's views.MethodsWe analysed 71 questionnaires completed by the parents of children who had undergone haematopoietic stem cell transplantation, together with 38 questionnaires completed by children who were 7 years of age or over.ResultsThe parent proxy and child self-reports showed good to excellent agreement. For example, 86% of the parents and 83% of the children reported oral pain and 44% of the parents and 47% of the children reported difficulty swallowing often or very often. The majority of the parents (61%) were satisfied with the pain treatment that had been given to their child. However, the treatment provided for oral mucositis was not altogether consistent.ConclusionOral mucositis affected the majority of the children undergoing haematopoietic stem cell transplantation, causing considerable pain and discomfort. The parent proxy reports proved to be reliable and are an important supplement to child self-reports on symptoms related to oral mucositis. But there is a clear need to establish more evidence-based care for children suffering from oral mucositis.
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Project description:Viral respiratory infections (VRIs) contribute to the morbidity and transplant-related mortality (TRM) after allogeneic haematopoietic stem cell transplantation (HSCT) and strategies to prevent and treat VRIs are warranted. We monitored VRIs before and after transplant in children undergoing allogeneic HSCT with nasopharyngeal aspirates (NPA) and assessed the impact on clinical outcome. Between 2007 and 2017, 585 children underwent 620 allogeneic HSCT procedures. Out of 75 patients with a positive NPA screen (12%), transplant was delayed in 25 cases (33%), while 53 children started conditioning with a VRI. Patients undergoing HSCT with a positive NPA screen had a significantly lower overall survival (54% vs. 79%) and increased TRM (26% vs. 7%) compared to patients with a negative NPA. Patients with a positive NPA who delayed transplant and cleared the virus before conditioning had improved overall survival (90%) and lower TRM (5%). Pre-HSCT positive NPA was the only significant risk factor for progression to a lower respiratory tract infection and was a major risk factor for TRM. Transplant delay, whenever feasible, in case of a positive NPA screen for VRIs can positively impact on survival of children undergoing HSCT.
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Project description:Haematopoietic stem cell transplantation (HSCT) is now an established practice with over 70,000 transplants performed annually, and over 1.5 million around the world so far. The practice of HSCT has improved over the years due to advances in conditioning regiments, preparatory practices for patients leading up to the transplant, graft versus host disease (GVHD) and infection prophylaxis, as well as a better selection of patients. However, in many instances, the stem cells supplied to the patient may not be adequate for optimal transplantation outcomes. This may be seen in a few areas including umbilical cord blood transplantation, inadequate bone marrow, peripheral blood stem cell harvest, or gene therapy. Growing and expanding HSCs in culture would provide an increase in cell numbers prior to stem cell infusion and accelerate haematopoietic recovery, resulting in improved outcomes. Several new technologies have emerged in recent years, which have facilitated the expansion of haematopoietic stem and progenitor cells (HSPCs) in culture with good outcomes in vitro, in vivo, and in clinical trials. In this review, we will outline some of the reasons for the expansion of HSPCs as well as the new technologies facilitating the advances in HSCT.
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