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Hematopoietic stem cell transplantation (HSCT) is an important therapeutic option for some hematological diseases. However, patients who undergo HSCT acquire a state of immunodeficiency that causes significant mortality. Reconstitution of thymic function is needed to support the immune system. One way to measure thymic function is through T-cell receptor excision circle (TREC) quantification. TRECs are generated by T-cell receptor gene rearrangements during T-cell maturation in the thymus and represent a reliable marker for thymic output. In this study, we aimed to assess aging and malignant hematological diseases as two important factors that may influence thymic output before HSCT. We observed that patients before HSCT presented signal joint TREC (sjTREC) numbers lower than 606.55 copies/μg DNA (low values) compared with healthy individuals, with an odds ratio (OR) of 12.88 [95% confidence interval (CI): 5.26-31.53; p < 0.001]. Our results showed that a group of older individuals (≥50 years old), comprising both healthy individuals and patients, had an OR of 10.07 (95% CI: 2.80-36.20) for low sjTREC values compared with younger individuals (≤24 years old; p < 0.001). Multiple logistic regression analysis confirmed that both older age (≥50 years old) and malignant hematological diseases and their treatments were important and independent risk factors related to thymic function impairment (p < 0.001). The median sjTREC value for patients of all ages was significantly lower than the sjTREC median for the subgroup of older healthy individuals (≥50 years old; p < 0.001). These data suggested that patients before HSCT and healthy individuals exhibited age-dependent thymic impairment, and that prior treatment for hematological diseases may exacerbate aging-related deterioration of natural thymic function. Furthermore, we analyzed these patients 9 months post-HSCT and compared patients who underwent autologous HSCT with those who underwent allogeneic HSCT. Both groups of patients achieved sjTREC copy numbers similar to those of healthy individuals. We did not find a close relationship between impaired thymic function prior to HSCT and worse thymic recovery after HSCT.
Delayed immune reconstitution and the consequently high rates of leukemia relapse and infectious complications are the main limitations of haploidentical hematopoietic stem cell transplantation. Donor T cell addback can accelerate immune reconstitution but the therapeutic window between graft-vs.-host disease and protective immunity is very narrow in the haploidentical transplant setting. Hence, strategies to improve the safety and efficacy of adoptive T cell transfer are particularly relevant in this setting. Adoptive T cell transfer strategies in haploidentical transplantation include the use of antigen-specific T cells, allodepletion and alloanergy induction, immune modulation by the co-infusion of regulatory cell populations, and the use of safety switch gene-modified T cells. Whilst common principles apply, there are features that are unique to haploidentical transplantation, where HLA-mismatching directly impacts on immune reconstitution, and shared vs. non-shared HLA-allele can be an important consideration in antigen-specific T cell therapy. This review will also present an update on safety switch gene-modified T cells, which can be conditionally deleted in the event of severe graft- vs.-host disease or other adverse events. Herpes Virus Simplex Thymidine Kinase (HSVtk) and inducible caspase-9 (iCasp9) are safety switches that have undergone multicenter studies in haploidentical transplantation with encouraging results. These gene-modified cells, which are trackable long-term, have also provided important insights on the fate of adoptively transferred T cells. In this review, we will discuss the biology of post-transplant T cell immune reconstitution and the impact of HLA-mismatching, and the different cellular therapy strategies that can help accelerate T cell immune reconstitution after haploidentical transplantation.
Stroke is a major cause of mortality and morbidity in the United States. The ideal therapeutic approach would minimize cell death and regenerate brain tissue. In order to investigate some questions that are related to such an approach, we have generated a mouse model in which we induce a stroke using the middle cerebral artery occlusion method. After 2h occlusion followed by reperfusion, 99% of mice died within 8 days of stroke. Total bone marrow cell transplantation by intravenous injection revealed an optimal timing of cell transfer in two doses on days 1 (same day of surgery) and 2 after surgery. Moreover, intravenous injection of Sca1+ bone marrow cells (enriched in hematopoietic stem cells) showed a dose-response effect on survival. Surviving mice also had no signs of apparent paralysis or weakness. Tracking analysis using donor stem cells expressing LacZ revealed only few donor cells in the brain. We conclude that hematopoietic stem cell-rich Sca1+ bone marrow cell transplantation after stroke protects the brain of a sizeable portion of mice subjected to stroke and alleviate remarkably the resulting neurological morbidity in surviving mice.
The interaction of hematopoietic cells and the bone microenvironment to maintain bone homeostasis is increasingly appreciated. We hypothesized that the transfer of allogeneic T lymphocytes has extensive effects on bone biology and investigated trabecular and cortical bone structures, the osteoblast reconstitution, and the bone vasculature in experimental hematopoietic stem cell transplantations (HSCT). Allogeneic or syngeneic hematopoietic stem cells (HSC) and allogeneic T lymphocytes were isolated and transferred in a murine model. After 20, 40, and 60 days, bone structures were visualized using microCT and histology. Immune cells were monitored using flow cytometry and bone vessels, bone cells and immune cells were fluorescently stained and visualized. Remodeling of the bone substance, the bone vasculature and bone cell subsets were found to occur as early as day +20 after allogeneic HSCT (including allogeneic T lymphocytes) but not after syngeneic HSCT. We discovered that allogeneic HSCT (including allogeneic T lymphocytes) results in a transient increase of trabecular bone number and bone vessel density. This was paralleled by a cortical thinning as well as disruptive osteoblast lining and loss of B lymphocytes. In summary, our data demonstrate that the adoptive transfer of allogeneic HSCs and allogeneic T lymphocytes can induce profound structural and spatial changes of bone tissue homeostasis as well as bone marrow cell composition, underlining the importance of the adaptive immune system for maintaining a balanced bone biology.
During hematopoietic stem cell transplantation, a substantial number of donor cells are lost because of apoptotic cell death. Transplantation-associated apoptosis is mediated mainly by the proapoptotic BCL-2 family proteins BIM and BMF, and their proapoptotic function is conserved between mouse and human stem and progenitor cells. Permanent inhibition of apoptosis in donor cells caused by the loss of these BH3-only proteins improves transplantation outcome, but recipients might be exposed to increased risk of lymphomagenesis or autoimmunity. Here, we address whether transient inhibition of apoptosis can serve as a safe but efficient alternative to improve the outcome of stem cell transplantation. We show that transient apoptosis inhibition by short-term overexpression of prosurvival BCL-XL, known to block BIM and BMF, is not only sufficient to increase the viability of hematopoietic stem and progenitor cells during engraftment but also improves transplantation outcome without signs of adverse pathologies. Hence, this strategy represents a promising and novel therapeutic approach, particularly under conditions of limited donor stem cell availability.
The Hematopoietic Cell Transplantation (HCT)-Specific Comorbidity Index (HCT-CI) has been extensively studied in myeloablative and reduced-intensity conditioning regimens, with less data available regarding the validity of HCT-CI in nonmyeloablative (NMA) allogeneic transplantation. We conducted a retrospective analysis to evaluate the association between HCT-CI and nonrelapse mortality (NRM) and all-cause mortality (ACM) in patients receiving the total lymphoid irradiation and antithymocyte globulin (TLI/ATG) NMA transplantation preparative regimen. We abstracted demographic and clinical data from consecutive patients, who received allogeneic HCT with the TLI/ATG regimen between January 2008 and September 2014, from the Stanford blood and marrow transplantation database. We conducted univariable and multivariable Cox proportional hazards regression models to evaluate the association between HCT-CI and NRM and ACM. In all, 287 patients were included for analysis. The median age of the patients was 61 (range, 22 to 77) years. The median overall survival was 844 (range, 374 to 1484) days. Most patients had Karnofsky performance score of 90 or above (85%). Fifty-two (18%) patients relapsed within 3 months and 108 (38%) patients relapsed within 1 year, with a median time to relapse of 163 (range, 83 to 366) days. Among the comorbidities in the HCT-CI identified at the time of HCT, reduced pulmonary function was the most common (n = 89), followed by prior history of malignancy (n = 39), psychiatric condition (n = 38), and diabetes (n = 31). Patients with higher HCT-CI scores had higher mortality risks for ACM (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.22 to 3.14 for HCT-CI score 1 or 2 and HR, 1.85; 95% CI, 1.11 to 3.08 for HCT-CI score ≥ 3, compared with 0, respectively). Among individual HCT-CI variables, diabetes (HR, 2.31; 95% CI, 1.79 to 2.89; P = .003) and prior solid tumors (HR, 1.75; 95% CI, 1.02 to 3.00; P = .043) were associated with a higher risk of ACM. Higher HCT-CI scores were significantly associated with higher risk of death. HCT-CI is a valid tool for predicting ACM in NMA TLI/ATG allogeneic HCT.
The disruption of gut microbiota eubiosis has been linked to major complications in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Various strategies have been developed to reduce dysbiosis and related complications. Fecal microbiota transplantation (FMT) consists of the infusion of fecal matter from a healthy donor to restore impaired intestinal homeostasis, and could be applied in the allo-HSCT setting. We conducted a systematic review of studies addressing the use of FMT in allo-HSCT patients. In the 23 papers included in the qualitative synthesis, FMT was used for the treatment of recurrent Clostridioides difficile infections or as a therapeutic strategy for steroid-resistant gut aGvHD. FMT was also performed with a preventive aim (e.g., to decolonize from antibiotic-resistant bacteria). Additional knowledge on the biological mechanisms underlying clinical findings is needed in order to employ FMT in clinical practice. There is also concern regarding the administration of microbial consortia in immune-compromised patients with altered gut permeability. Therefore, the safety profile and efficacy of the procedure must be determined to better assess the role of FMT in allo-HSCT recipients.
Hematopoietic stem cells (HSCs) reside in hypoxic niches within bone marrow and cord blood. Yet, essentially all HSC studies have been performed with cells isolated and processed in non-physiologic ambient air. By collecting and manipulating bone marrow and cord blood in native conditions of hypoxia, we demonstrate that brief exposure to ambient oxygen decreases recovery of long-term repopulating HSCs and increases progenitor cells, a phenomenon we term extraphysiologic oxygen shock/stress (EPHOSS). Thus, true numbers of HSCs in the bone marrow and cord blood are routinely underestimated. We linked ROS production and induction of the mitochondrial permeability transition pore (MPTP) via cyclophilin D and p53 as mechanisms of EPHOSS. The MPTP inhibitor cyclosporin A protects mouse bone marrow and human cord blood HSCs from EPHOSS during collection in air, resulting in increased recovery of transplantable HSCs. Mitigating EPHOSS during cell collection and processing by pharmacological means may be clinically advantageous for transplantation.
The binding of CXCR4 with its ligand (stromal-derived factor-1) maintains hematopoietic stem/progenitor cells (HSPCs) in a quiescent state. We hypothesized that blocking CXCR4/SDF-1 interaction after hematopoietic stem cell transplantation (HSCT) promotes hematopoiesis by inducing HSC proliferation.
Clostridium difficile infection (CDI) is frequently diagnosed in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We characterized early-transplant CDI and its associations, and analyzed serially-collected feces to determine intestinal carriage of toxigenic C. difficile. Fecal specimens were collected longitudinally from 94 patients during allo-HSCT hospitalization, from the start of pre-transplant conditioning until up to 35 days after stem cell infusion. Presence of C. difficile 16S rRNA and tcdB genes was determined. Clinical variables and specimen data were analyzed for association with development of CDI. Historical data from an additional 1144 allo-HSCT patients was also used. Fecal specimens from 37 patients (39%) were found to harbor C. difficile. Early-transplant CDI was diagnosed in 16 of 94 (17%) patients undergoing allo-HSCT; cases were generally mild and resembled non-CDI diarrhea associated with transplant conditioning. CDI was associated with preceding colonization with tcdB-positive C. difficile and conditioning regimen intensity. We found no associations between early-transplant CDI and graft-versus-host disease or CDI later in transplant. CDI occurs with high frequency during the early phase of allo-HSCT, where recipients are pre-colonized with toxigenic C. difficile. During this time, CDI incidence peaks during pre-transplant conditioning, and is correlated to intensity of the treatment. In this unique setting, high rates of CDI may be explained by prior colonization and chemotherapy; however, cases were generally mild and resembled non-infectious diarrhea due to conditioning, raising concerns of misdiagnosis. Further study of this unique population with more discriminating CDI diagnostic tests are warranted.
Metachromatic leukodystrophy is a lysosomal storage disease caused by deficient arylsulfatase A. It is characterized by progressive demyelination and thus mainly affects the white matter. Hematopoietic stem cell transplantation may stabilize and improve white matter damage, yet some patients deteriorate despite successfully treated leukodystrophy. We hypothesized that post-treatment decline in metachromatic leukodystrophy might be caused by gray matter pathology.
Impaired T cell reconstitution remains a major deterrent in the field of bone marrow (BM) transplantation (BMT) due to pre-conditioning-induced damages inflicted to the thymi of recipient hosts. Given the previously reported thymo-stimulatory property of interleukin (IL)-21, we reasoned that its use post-BMT could have a profound effect on de novo T cell development.
In 1963 George Mathé announced to the world that he had cured a patient of leukaemia by means of a bone-marrow transplant. Since than much progress has been made and nowadays Hematopoietic Stem Cell Transplantation (HSCT) is considered the most effective treatment of numerous severe haematological diseases. Gynaecological complications in HSCT women represent a serious concern for these patients, but often underestimated by clinicians in the view of Overall Survival. The main gynaecological complications of HSCT are represented by: premature ovarian failure (POF), thrombocytopenia-associated menorrhagia, genital symptoms or sexual problems in course of chronic GVHD (cGVHD), osteoporosis, secondary solid tumours due to immunosuppressive drugs to treat cGVHD and severity of cGVHD, and fertility and pregnancy issues. In particular fertility-related issues are always more relevant for patients, whose life expectation is constantly growing up after HSCT.Thus, taking care of a patient undergoing HSCT should primarily include gynaecological evaluation, even before conditioning regimen or chemotherapy for the underlying malignancy, as, in our opinion, it is of great importance to ensure a complete diagnostic work-up and intervention options to guarantee maximum reproductive health and a better quality of life in HSCT women.The present review aims at describing principal features of the aforementioned gynaecological complications of HSCT, and to define, on the basis of current international literature, a specific protocol for the prevention, diagnosis, management and follow-up of gynaecological complications of both autologous and heterologous transplantation, before and after the procedure.
Hematopoietic cell transplant (HCT) is an increasingly common and curative treatment strategy to improve survival among individuals with malignant and nonmalignant diseases, with over one million HCTs having been performed worldwide. Neurocognitive dysfunction is a common and untoward consequence of HCT for many recipients, although few studies have examined the profile of neurocognitive impairments in HCT or their association with clinical features, such as frailty, or the incidence of pre-HCT neurocognitive impairments across all ages, which may influence post-HCT neurocognitive impairments. We examined the pattern and correlates of pre-transplant neurocognitive dysfunction in a prospective sample of adults undergoing HCT. Neurocognition was assessed using the Montreal Cognitive Assessment Battery. Frailty was assessed using the Short Physical Performance Battery. Linear regression analysis was used to examine the associations between neurocognitive performance and frailty. Neurocognitive screening profiles were also examined by partitioning MoCA into domain scores, including Executive Function and Memory. We also examined the associations between neurocognition, frailty, and clinical outcomes, including length of transplant hospitalization and survival. One hundred and ten adults were evaluated across a wide age range (range: 19-75; mean age = 54.7 [SD = 14.1]). Neurocognitive performance tended to fall below published normative levels (mean MoCA = 25.5 [SD = 4.1]), with 17% of participants demonstrating impaired performance compared with medical normative data (MoCA ≤ 22) and 34% exhibiting impaired performance relative to healthy samples (MoCA ≤ 25). Mild impairments (MoCA ≤ 25) were common across age ranges, including middle-aged patients (23% for age < 50; 35% for age 50-60, 41% for age ≥ 60), particularly for items assessing Executive Function. Greater levels of frailty associated with lower neurocognitive screening scores (r = -0.29, P < 0.01) and Executive Functioning (r = -0.24, P < 0.01), whereas greater age was associated with poorer Memory performance only (r = -0.33, P < 0.01). Greater levels of frailty prior to transplant associated with longer length of stay (β = 0.10, P = 0.046), but were not associated with survival. Neurocognitive impairments are common among adults undergoing HCT and the pattern of performance varies by age. Pre-transplant frailty is associated with neurocognitive functioning and may portend worse post-transplant early clinical outcomes.
WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is a rare disease, caused by CXCR4 gene mutations, which incorporates features of combined immunodeficiency, congenital neutropenia, and a predisposition to human papillomavirus infection. Established conventional treatment for WHIM syndrome does not fully prevent infectious complications in these patients. Only single case reports of hematopoietic stem cell transplantation (HSCT) efficacy in WHIM have been published.
Allogeneic hematopoietic stem cell transplantation (HSCT) is associated with several potentially lethal complications. Higher levels of CD3+ T-cells in the graft have been associated with increased risk of graft-versus-host disease (GVHD), but also beneficial graft-versus-leukemia effect and reduced infections. To tackle post-transplant complications, donor lymphocyte infusions have been used but with an increased risk of GVHD. To reduce this risk, we performed depletion of αβ T-cells and treated 12 patients post-HSCT suffering from infections and/or poor immune reconstitution. The αβ T-cell depleted cell products were characterized by flow cytometry. The median log depletion of αβ T-cells was -4.3 and the median yield of γδ T-cells was 73.5%. The median CD34+ cell dose was 4.4 × 106/kg. All 12 patients were alive 3 months after infusion and after 1 year, two patients had died. No infusion-related side effects were reported and no severe acute GVHD (grade III-IV) developed in any patient post-infusion. Overall, 3 months after infusion 11 out of 12 patients had increased levels of platelets and/or granulocytes. In conclusion, we describe the use of αβ T-cell depleted products as stem cell boosters with encouraging results.
Extrinsic factors and genetic predisposition contribute to the etiology of sarcoidosis, converging in a phenotype of altered immune response associated with multisystemic inflammatory granulomatous tissue infiltration. Immunological reconstitution after hematopoietic stem cell transplantation (HSCT) may represent a unique window for the pathogenesis of the disease. We describe the incidence, clinicopathological features, and HLA associations of sarcoidosis after HSCT in a single-center cohort of patients, together with data from previously published cases.
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