Osteonecrosis after allogeneic bone marrow transplantation.
Ontology highlight
ABSTRACT:
SUBMITTER: Zadegan F
PROVIDER: S-EPMC2505148 | biostudies-other | 2008 Feb
REPOSITORIES: biostudies-other
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Project description:Hematopoietic stem cell transplantation (HCT) is a curative treatment for patients with myelofibrosis (MF); however, many HCT-eligible patients decline this potentially life-saving procedure. The reasons behind this decision are not clear. We sought to survey patients with MF to understand their perspective on HCT. A 63-question survey was posted on myeloproliferative neoplasm patient advocacy websites. A total of 129 patients with MF responded to the survey. Among these patients, 49 (41%) were referred for HCT, and 41(32%) attended the transplantation consult. Of the patients who attended the transplantation consult, 24 (59%) did not plan on going on to HCT, and 16 (41%) intended to proceed with HCT. Reasons for the decision to not undergo transplantation included the desire to not be ill, desire to not spend time in the hospital, and concerns about overall quality of life. Specifically, concerns related to financial impact and the risk of graft-versus-host disease (GVHD) were expressed. Patients who decided to proceed with HCT felt that this would extend their survival and allow them to be around family for longer. This is the first survey to investigate patient perceptions regarding HCT for MF. Less than one-half of the patients were referred for HCT, and of those, less than one-half planned on proceeding with the transplantation, suggesting that many patients do not receive this life-saving procedure. Further exploration of the basis of patients' reluctance to proceed with HCT is warranted.
| S-EPMC8207329 | biostudies-literature
Project description:The PH-BEACH-WD40 (PBW) protein family members play a role in coordinating receptor signaling and intracellular vesicle trafficking. LPS-Responsive-Beige-like Anchor (LRBA) is a PBW protein whose immune function remains elusive. Here we show that LRBA-null mice are viable, but exhibit compromised rejection of allogeneic, xenogeneic and missing self bone-marrow grafts. Further, we demonstrate that LRBA-null Natural Killer (NK) cells exhibit impaired signaling by the key NK activating receptors, NKp46 and NKG2D. However, induction of IFN-? by cytokines remains intact, indicating LRBA selectively facilitates signals by receptors for ligands expressed on the surface of NK targets. Surprisingly, LRBA limits immunoregulatory cell numbers in tissues where GvHD is primed or initiated, and consistent with this LRBA-null mice also demonstrate resistance to lethal GvHD. These findings demonstrate that LRBA is redundant for host longevity while being essential for both host and donor-mediated immune responses and thus represents a unique and novel molecular target in transplant immunology.
| S-EPMC5099895 | biostudies-other
Project description:Despite a growing understanding of the link between intestinal inflammation and resident gut microbes, longitudinal studies of human flora before initial onset of intestinal inflammation have not been reported. Here, we demonstrate in murine and human recipients of allogeneic bone marrow transplantation (BMT) that intestinal inflammation secondary to graft-versus-host disease (GVHD) is associated with major shifts in the composition of the intestinal microbiota. The microbiota, in turn, can modulate the severity of intestinal inflammation. In mouse models of GVHD, we observed loss of overall diversity and expansion of Lactobacillales and loss of Clostridiales. Eliminating Lactobacillales from the flora of mice before BMT aggravated GVHD, whereas reintroducing the predominant species of Lactobacillus mediated significant protection against GVHD. We then characterized gut flora of patients during onset of intestinal inflammation caused by GVHD and found patterns mirroring those in mice. We also identified increased microbial chaos early after allogeneic BMT as a potential risk factor for subsequent GVHD. Together, these data demonstrate regulation of flora by intestinal inflammation and suggest that flora manipulation may reduce intestinal inflammation and improve outcomes for allogeneic BMT recipients.
| S-EPMC3348096 | biostudies-literature
Project description:Identifying the targets of immune response after allogeneic hematopoietic cell transplantation (HCT) promises to provide relevant immune therapy candidate proteins. We used protein microarrays to serologically identify nucleolar and spindle-associated protein 1 (NuSAP1) and chromatin assembly factor 1, subunit B (p60; CHAF1b) as targets of new antibody responses that developed after allogeneic HCT. Western blots and enzyme-linked immunosorbent assays (ELISA) validated their post-HCT recognition and enabled ELISA testing of 120 other patients with various malignancies who underwent allo-HCT. CHAF1b-specific antibodies were predominantly detected in patients with acute myeloid leukemia (AML), whereas NuSAP1-specific antibodies were exclusively detected in patients with AML 1 year after transplantation (P < .001). Complete genomic exon sequencing failed to identify a nonsynonymous single nucleotide polymorphism (SNP) for NuSAP1 and CHAF1b between the donor and recipient cells. Expression profiles and reverse transcriptase-polymerase chain reaction (RT-PCR) showed NuSAP1 was predominately expressed in the bone marrow CD34(+)CD90(+) hematopoietic stem cells, leukemic cell lines, and B lymphoblasts compared with other tissues or cells. Thus, NuSAP1 is recognized as an immunogenic antigen in 65% of patients with AML following allogeneic HCT and suggests a tumor antigen role.
| S-EPMC2837325 | biostudies-literature
Project description:Treatment of severe aplastic anemia has improved significantly over the past 4 decades. This review will summarize the key areas of progress in the use of allogeneic hematopoietic cell transplantation and nontransplant immunosuppressive therapy (IST) for the treatment of aplastic anemia and then summarize the recommendations for first-line treatment. Based on recent data, we argue that guidelines for the initial treatment of patients with newly diagnosed severe aplastic anemia require revision. At the time of diagnosis, before beginning treatment, HLA typing should be done to identify a marrow donor among family members or in the unrelated donor registries, and a marrow transplant should be considered first-line therapy. The priority order of donor source for bone marrow transplantation is: (1) HLA-identical sibling, (2) HLA-matched unrelated donor, and (3) HLA-haploidentical donor if an HLA-matched unrelated donor is not rapidly available. Each of these donor marrow sources may be preferable to nontransplant IST. We make this recommendation because of the long-term persistent risk for disease relapse and secondary myelodysplastic syndrome or acute myeloid leukemia with the use of nontransplant IST for patients with aplastic anemia. In contrast, marrow transplantation is associated with high cure rates of aplastic anemia and a relatively low risk for graft-versus-host disease, with many patients now living for decades without the risk for disease recurrence or the development of clonal disorders. Implementation of this first-line treatment strategy will provide patients with severe aplastic anemia the best chance of long-term disease-free survival.
| S-EPMC6093726 | biostudies-literature
Project description:Background & aimsDurable remissions of Crohn's Disease (CD) have followed myeloablative conditioning therapy and allogeneic marrow transplantation. For patients with treatment-refractory disease, we used reduced-intensity conditioning to minimize toxicity, marrow from donors with low Polygenic Risk Scores for CD as cell sources, and protracted immune suppression to lower the risk of graft-versus-host disease (GVHD). Our aim was to achieve durable CD remissions while minimizing transplant-related complications.MethodsDNA from patients and their HLA-matched unrelated donors was genotyped and Polygenic Risk Scores calculated. Donor marrow was infused following non-myeloablative conditioning. Patient symptoms and endoscopic findings were documented at intervals after transplant.ResultsWe screened 807 patients, 143 of whom met eligibility criteria; 2 patients received allografts. Patient 1 had multiple complications and died at day 332 from respiratory failure. Patient 2 had resolution of CD symptoms until day 178 when CD recurred, associated with persistent host chimerism in both peripheral blood and intestinal mucosa. Withdrawal of immune suppression was followed by dominant donor immune chimerism in peripheral blood and resolution of CD findings. Over time, mucosal T-cells became donor-dominant. At 5 years after allografting, Patient 2 remained off all medications but had mild symptoms related to a jejunal stricture that required stricturoplasty at 6 years. At 8 years, she remains stable off medications.ConclusionsThe kinetics of immunologic chimerism after allogeneic marrow transplantation for CD patients depends on the intensity of the conditioning regimen and the magnitude of immune suppression. One patient achieved durable improvement of her previously refractory CD only after establishing donor immunologic chimerism in intestinal mucosa. Her course provides proof-of-principal for allografting as a potential treatment for refractory CD, but an immunoablative conditioning regimen should be considered for future studies.(ClinicalTrials.gov, NCT01570348).
| S-EPMC10818189 | biostudies-literature
Project description:High-throughput sequencing (HTS) of human T cell receptors has revealed a high level of complexity in the T cell repertoire, which makes it difficult to correlate T cell reconstitution with clinical outcomes. The associations identified thus far are of a broadly statistical nature, precluding precise modeling of outcomes based on T cell repertoire development following bone marrow transplantation (BMT). Previous work has demonstrated an inherent, mathematically definable order observed in the T cells from a diverse group of donors, which is perturbed in recipients following BMT. In this study, T cell receptor (TCR)-β sequences from HLA-matched related donor and recipient pairs are analyzed to further develop this methodology. TCR-β sequencing from unsorted and sorted T cell subsets isolated from the peripheral blood samples of BMT donors and recipients show conservation and symmetry of VJ segment usage in the clonal frequencies, linked to the organization of the gene segments along the TCR locus. This TCR-β VJ segment translational symmetry is preserved post-transplantation and even in cases of acute graft-versus-host disease (aGVHD), suggesting that GVHD occurrence represents a polyclonal donor T cell response to recipient antigens. The complexity of the repertoire is significantly diminished after BMT, and the T cell clonal hierarchy is altered post-transplantation. Low-frequency donor clones tended to take on a higher rank in the recipients following BMT, especially in patients with aGVHD. Over time, the repertoire evolves to a more donor-like state in the recipients who did not develop GVHD as opposed to those who did. The results presented here support new methods of quantifying and characterizing post-transplantation T cell repertoire reconstitution.
| S-EPMC6645918 | biostudies-literature
Project description:BackgroundAllogeneic hematopoietic stem cell transplantation (AHSCT) is a curative therapeutic approach for different hematological malignancies (HMs), and epigenetic modifications, including DNA methylation, play a role in the reconstitution of the hematopoietic system after AHSCT. This study aimed to explore global DNA methylation dynamic of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs) from donors and their respective recipients affected by acute myeloid leukemia (AML), acute lymphoid leukemia (ALL) and Hodgkin lymphoma (HL) during the first year after transplant.MethodsWe measured DNA methylation profile by Illumina HumanMethylationEPIC in BM HSPC of 10 donors (t0) and their matched recipients at different time points after AHSCT, at day + 30 (t1), + 60 (t2), + 120 (t3), + 180 (t4), and + 365 (t5). Differential methylation analysis was performed by using R software and CRAN/Bioconductor packages. Gene set enrichment analysis was carried out on promoter area of significantly differentially methylated genes by clusterProfiler package and the mSigDB genes sets.ResultsResults show significant differences in the global methylation profile between HL and acute leukemias, and between patients with mixed and complete chimerism, with a strong methylation change, with prevailing hyper-methylation, occurring 30 days after AHSCT. Functional analysis of promoter methylation changes identified genes involved in hematopoietic cell activation, differentiation, shaping, and movement. This could be a consequence of donor cell "adaptation" in recipient BM niche. Interestingly, this epigenetic remodeling was reversible, since methylation returns similar to that of donor HSPCs after 1 year. Only for a pool of genes, mainly involved in dynamic shaping and trafficking, the DNA methylation changes acquired after 30 days were maintained for up to 1 year post-transplant. Finally, preliminary data suggest that the methylation profile could be used as predictor of relapse in ALL.ConclusionsOverall, these data provide insights into the DNA methylation changes of HSPCs after transplantation and a new framework to investigate epigenetics of AHSCT and its outcomes.
| S-EPMC6528331 | biostudies-literature
Project description:Tumor protein 53 mutations adversely affect the prognosis of myelodysplastic syndromes (MDS); however, few studies have reported on the prognostic significance of the expression of p53 protein in MDS. The current study investigated p53 immunoreactivity (p53-IR) in bone marrow biopsies (BMBs) obtained at diagnosis from 18 patients (6 females and 12 males; mean age, 50.5 years) with MDS that underwent bone marrow transplantation (BMT) to determine the associations between clinical and histopathological data and outcome. There were 5 refractory cytopenia with multilineage dysplasia (RCMD) and 13 refractory anemia with excess blasts, type 2 (RAEB-2) cases. p53-IR was assessed as the percentage of hematopoietic cells exhibiting intense nuclear staining. The cut off for positivity was 5% of stained cells. A positive p53-IR was detected in 7 patients (38.9%) and was associated with age (P=0.005) and pattern of BM fibrosis (P=0.03). A positive p53-IR was more frequent in females, in highly cellular BMBs and in RAEB-2 cases. Overall survival (OS) was associated with patients' age (P=0.01), hemoglobin level (P=0.04), type of MDS (P=0.05), degree of BM fibrosis (P=0.006) and number of BM blasts (P=0.05). The OS of patients with negative p53-IR tended to be longer compared with that of patients with positive p53-IR, although this difference was not statistically significant (P=0.1). Despite the limitation of the low number of cases, the present results indicate that a positive p53-IR at diagnosis is associated with clinically more aggressive MDS subtypes and adverse histological prognostic factors, such as BM fibrosis. Therefore, the evaluation of p53 expression of BMBs of patients with MDS may be introduced in the histopathological work-up of the disease.
| S-EPMC5451870 | biostudies-other
Project description:Identifying the targets of immune response after allogeneic hematopoietic cell transplantation (HCT) promises to provide relevant immune therapy candidate proteins. We used protein microarrays to serologically identify Nucleolar and Spindle Associated Protein 1 (NuSAP1) and Chromatin Assembly Factor 1, subunit B (p60) [CHAF1b] as targets of new antibody responses that developed after allogeneic HCT. Western blots and ELISA validated their post-HCT recognition and enabled ELISA testing of 120 other allo-HCT patients. CHAF1b specific antibodies were predominantly detected in AML patients whereas NuSAP1 specific antibodies were exclusively detected in AML patients one year post-transplant (p<0.0001). Complete genomic exon sequencing failed to identify a nonsynonymous SNP for NuSAP1 and CHAF1b between the donor and recipient cells. Expression profiles and RT-PCR showed NuSAP1 was predominately expressed in the bone marrow CD34+CD90+ hematopoietic stem cells (HSC), leukemic cell lines and B lymphoblasts as compared to other tissues or cells. Thus, NuSAP1 is recognized as an immunogenic antigen in 65% AML patients and suggests a tumor antigen role. In conclusion, clinically important tumor antigens can be identified as new antibody targets after allogeneic HCT using high density protein microarrays Plasma Profiling using ProtoArrays: Protein microarrays were obtained (ProtoArrays⢠V3, Invitrogen Corporation, Carlsbad, CA) displaying 5,056 full-length human proteins, derived from the Ultimate ORF collection (Invitrogen Corp., Carlsbad, CA) printed in duplicate with N-terminal GST epitopes expressed in Baculovirus and affinity purified under native conditions maintaining their cellular enzymatic activities/native conformations. The arrays also contained control spots consisting of buffer, empty spots, and human IgG printed in four different concentrations (IgG[1] to IgG[4]). The arrays were incubated with blocking buffer for one hr followed by application of the plasma sample diluted 1:150 for 90 min. After washing the array four times for 10 min each with PBST buffer, secondary antibody was added (goat anti-human Alexa 647, Molecular Probes, Eugene, OR) for 90 min. After washing the slides with PBST buffer, the arrays were dried and fluorescent intensity was detected using a microarray scanner (GenePix 4000B, Molecular Devices, CA). All incubations were carried out on a rotating platform at 4 ºC. ProtoArray data acquisition and measurement: The slides were scanned at a PMT gain of 60% with a laser power of 90% and a focus point of 0 μm. Fluorescence intensity data were acquired using GenePix Pro 6.0 software (Molecular devices, Sunnyvale, CA) with the appropriate â.galâ file downloaded from the ProtoArray central portal on the Invitrogen website (http://www.invitrogen.com/protoarray) by submitting the barcode of each ProtoArray slide
2010-06-21 | E-GEOD-15255 | biostudies-arrayexpress