Transplantation Of Umbilical Cord Blood Cells Research Articles

Epidemiology, Risk Factors and Outcome of Bacterial, Fungal, and Viral Infections in Pediatric Allogeneic and Autologous Hematopoietic Stem Cell Transplantation Recipients

Objectives Infection remains a major cause of morbidity and mortality after hematopoietic stem cell transplant (HSCT). With recent changes in transplant practices, such as the increasing use of alternative donors and T-cell depletion, how various risk factors interplay and affect the timeline of infections have not been well elucidated in children. While the epidemiology and risk factors for viral infections post-HSCT were well described for cytomegalovirus (CMV) and Epstein-Barr virus (EBV), the corresponding information on human herpes virus 6 (HHV-6), adenovirus (ADV) and BK virus (BKV) infection in children is limited. This study aims to review comprehensively the epidemiology, risk factors and outcome of bacterial, viral and fungal infections after contemporary HSCT to inform future infection prophylaxis strategies. Method We retrospectively reviewed the first 100 consecutive HSCT for malignant and non-malignant diseases from April 2019 to October 2021 in the only pediatric HSCT center in Hong Kong. The incidences were recorded and risk factors were analyzed for bacterial, viral and fungal infections and infection-related mortality. Results The vast majority of the allogeneic transplant recipients (69/74, 93.2%) had infections after HSCT, amongst which bacterial, viral and fungal infection rate was 35.1%, 90.5% and 9.5% respectively. In contrast, only 30.8% (8/26) of autologous transplant recipients had infections, and their respective rate of bacterial, viral and fungal infection was 19.2%, 15.4% and 3.8%. HHV-6 and BKV typically occurred early after HSCT, ADV and varicella zoster virus (VZV) thereafter, and CMV and EBV throughout the entire 2.5-year observation period. The cumulative incidences of HHV-6 and BKV were significantly higher in patients receiving umbilical cord blood (UCB) or haploidentical stem cell transplant (p = 0.0001; p <0.0001, respectively) when compared with matched sibling (MSD) or matched unrelated donor (MUD) transplant (Figure 1 and 2). Ex vivo T-cell depletion was a general risk factor for viral infection with HHV-6 (HR = 3.03), BKV (HR = 3.36), CMV (HR = 4.45) and EBV (HR = 7.15); all p < 0.02. Cancer in second- compared with first-complete remission was a risk factor for bacterial infection in multivariate analyses (OR = 6.0, 95% CI = 1.12-32.2, p = 0.037). Patients with gut graft-versus-host disease were at risk for fungal infections (OR = 12.3, 95% CI = 1.33-114.4, p = 0.027). The infection-related mortality (IRM) rate was 10%, which occurred only in allogeneic HSCT patients with hematological malignancies receiving cord blood (n = 4) or haploidentical HSCT (n = 6). History of bacterial infection after HSCT was associated with an increased risk of IRM (HR = 4.13, 95% CI = 1.05-16.3, p = 0.042). Conclusion Not all HSCT recipients are of equal risk to infections and IRM. Our findings in pediatric patients after contemporary HSCT support both time-dependent and risk-adapted measures against infective complications to improve transplant outcome. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hal E. Broxmeyer PhD: Experimental hematologist and umbilical cord blood cell transplant pioneer (27 November, 1944–8 December, 2021)

Hal E. Broxmeyer PhD: Experimental hematologist and umbilical cord blood cell transplant pioneer (27 November, 1944–8 December, 2021)

Hal E. Broxmeyer PhD: Experimental haematologist and umbilical cord blood cell transplant pioneer (27 November, 1944–8 December, 2021)

Hal E. Broxmeyer PhD: Experimental haematologist and umbilical cord blood cell transplant pioneer (27 November, 1944–8 December, 2021)

Umbilical Cord Blood Cell Transplant Into Injured Spinal Cord With Lithium Carbonate or Placebo Followed by Locomotor Training

Umbilical Cord Blood Cell Transplant Into Injured Spinal Cord With Lithium Carbonate or Placebo Followed by Locomotor Training

Neonatal umbilical cord blood transplantation halts skeletal disease progression in the murine model of MPS-I

Umbilical cord blood (UCB) is a promising source of stem cells to use in early haematopoietic stem cell transplantation (HSCT) approaches for several genetic diseases that can be diagnosed at birth. Mucopolysaccharidosis type I (MPS-I) is a progressive multi-system disorder caused by deficiency of lysosomal enzyme α-L-iduronidase, and patients treated with allogeneic HSCT at the onset have improved outcome, suggesting to administer such therapy as early as possible. Given that the best characterized MPS-I murine model is an immunocompetent mouse, we here developed a transplantation system based on murine UCB. With the final aim of testing the therapeutic efficacy of UCB in MPS-I mice transplanted at birth, we first defined the features of murine UCB cells and demonstrated that they are capable of multi-lineage haematopoietic repopulation of myeloablated adult mice similarly to bone marrow cells. We then assessed the effectiveness of murine UCB cells transplantation in busulfan-conditioned newborn MPS-I mice. Twenty weeks after treatment, iduronidase activity was increased in visceral organs of MPS-I animals, glycosaminoglycans storage was reduced, and skeletal phenotype was ameliorated. This study explores a potential therapy for MPS-I at a very early stage in life and represents a novel model to test UCB-based transplantation approaches for various diseases.

Granulocyte-colony stimulating factor and umbilical cord blood cell transplantation: Synergistic therapies for the treatment of traumatic brain injury.

Traumatic brain injury (TBI) is now characterized as a progressive, degenerative disease and continues to stand as a prevalent cause of death and disability. The pathophysiology of TBI is complex, with a variety of secondary cell death pathways occurring which may persist chronically following the initial cerebral insult. Current therapeutic options for TBI are minimal, with surgical intervention or rehabilitation therapy existing as the only viable treatments. Considering the success of stem-cell therapies in various other neurological diseases, their use has been proposed as a potential potent therapy for patients suffering TBI. Moreover, stem cells are highly amenable to adjunctive use with other therapies, providing an opportunity to overcome the inherent limitations of using a single therapeutic agent. Our research has verified this additive potential by demonstrating the efficacy of co-delivering human umbilical cord blood (hUCB) cells with granulocyte-colony stimulating factor (G-CSF) in a murine model of TBI, providing encouraging results which support the potential of this approach to treat patients suffering from TBI. These findings justify ongoing research toward uncovering the mechanisms which underlie the functional improvements exhibited by hUCB + G-CSF combination therapy, thereby facilitating its safe and effect transition into the clinic. This paper is a review article. Referred literature in this paper has been listed in the reference section. The datasets supporting the conclusions of this article are available online by searching various databases, including PubMed. Some original points in this article come from the laboratory practice in our research center and the authors’ experiences.

Characterization of IFNγ-producing natural killer cells induced by cytomegalovirus reactivation after haploidentical hematopoietic stem cell transplantation.

During human cytomegalovirus (CMV) infection after umbilical cord blood or HLA-matched hematopoietic stem cell transplantation (HSCT), a population of NKG2C-expressing natural killer (NK) cells expand and persist. The expanded NK cells express high levels of inhibitory killer immunoglobulin-like receptors (KIR) specific for self-HLA and potently produce IFNγ. However, it remains unknown whether similar events would occur after haploidentical HSCT (haplo-HSCT). Here, we demonstrated that IFNγ-producing NK cells were expanded in haplo-HSCT patients with CMV reactivation. We then identified these expanded cells as a subset of CD56dim NK cells that expressed higher levels of both NKG2C and KIR, but lower level of NKG2A. Functionally, the subset of NK cells expressing NKG2C and self-KIR in patients with CMV reactivation accounted for IFNγ production in response to K562 cells. However, these phenomena were not observed in patients without CMV reactivation. We therefore characterized a subset of NK cells with the CD56dim, NKG2C+, and self-KIR+ phenotype that expanded and were responsible for IFNγ production during CMV infection after haplo-HSCT. Together, these findings support a notion that CMV reactivation induces expansion of more mature NK cells with memory-like features, which contributes to long-term control of both CMV infection and leukemia relapse after haplo-HSCT.

Translating G-CSF as an Adjunct Therapy to Stem Cell Transplantation for Stroke.

Among recently investigated stroke therapies, stem cell treatment holds great promise by virtue of their putative ability to replace lost cells, promote endogenous neurogenesis,and produce behavioral and functional improvement through their "bystander effects." Translating stem cell in the clinic, however, presents a number of technical difficulties. A strategy suggested to enhance therapeutic utility of stem cells is combination therapy, i.e., co-transplantation of stem cells or adjunct treatment with pharmacological agents and substrates,which is assumed to produce more profound therapeutic benefits by circumventing limitations of individual treatments and facilitating complementary brain repair processes. We previously demonstrated enhanced functional effects of cotreatment with granulocyte-colony stimulating factor (GCSF)and human umbilical cord blood cell (hUCB) transplantation in animal models of traumatic brain injury (TBI). Here,we suggest that the aforementioned combination therapy may also produce synergistic effects in stroke. Accordingly, G-CSF treatment may reduce expression of pro-inflammatory cytokines and enhance neurogenesis rendering a receptive microenvironment for hUCB engraftment. Adjunct treatment of GCSF with hUCB may facilitate stemness maintenance and guide neural lineage commitment of hUCB cells. Moreover, regenerative mechanisms afforded by G-CSF-mobilized endogenous stem cells, secretion of growth factors by hUCB grafts and G-CSF-recruited endothelial progenitor cells(EPCs), as well as the potential graft–host integration that may promote synaptic circuitry re-establishment could altogether produce more pronounced functional improvement in stroked rats subjected to a combination G-CSF treatment and hUCB transplantation. Nevertheless, differences in pathology and repair processes underlying TBI and stroke deserve consideration when testing the effects of combinatorial G-CSF and hUCB cell transplantation for stroke treatment. Further studies are also required to determine the safety and efficacy of this intervention in both preclinical and clinical stroke studies.

Human umbilical cord blood-derived mononuclear cells improve murine ventricular function upon intramyocardial delivery in right ventricular chronic pressure overload

IntroductionStem cell therapy has emerged as potential therapeutic strategy for damaged heart muscles. Umbilical cord blood (UCB) cells are the most prevalent stem cell source available, yet have not been fully tested in cardiac regeneration. Herein, studies were performed to evaluate the cardiovascular safety and beneficial effect of mononuclear cells (MNCs) isolated from human umbilical cord blood upon intramyocardial delivery in a murine model of right ventricle (RV) heart failure due to pressure overload.MethodsUCB-derived MNCs were delivered into the myocardium of a diseased RV cardiac model. Pulmonary artery banding (PAB) was used to produce pressure overload in athymic nude mice that were then injected intramyocardially with UCB-MNCs (0.4 × 10^6 cells/heart). Cardiac functions were then monitored by telemetry, echocardiography, magnetic resonance imaging (MRI) and pathologic analysis of heart samples to determine the ability for cell-based repair.ResultsThe cardio-toxicity studies provided evidence that UCB cell transplantation has a safe therapeutic window between 0.4 to 0.8 million cells/heart without altering QT or ST-segments or the morphology of electrocardiograph waves. The PAB cohort demonstrated significant changes in RV chamber dilation and functional defects consistent with severe pressure overload. Using cardiac MRI analysis, UCB-MNC transplantation in the setting of PAB demonstrated an improvement in RV structure and function in this surgical mouse model. The RV volume load in PAB-only mice was 24.09 ± 3.9 compared to 11.05 ± 2.09 in the cell group (mm3, P-value <0.005). The analysis of pathogenic gene expression (BNP, ANP, Acta1, Myh7) in the cell-transplanted group showed a significant reversal with respect to the diseased PAB mice with a robust increase in cardiac progenitor gene expression such as GATA4, Kdr, Mef2c and Nkx2.5. Histological analysis indicated significant fibrosis in the RV in response to PAB that was reduced following UCB-MNC’s transplantation along with concomitant increased Ki-67 expression and CD31 positive vessels as a marker of angiogenesis within the myocardium.ConclusionsThese findings indicate that human UCB-derived MNCs promote an adaptive regenerative response in the right ventricle upon intramyocardial transplantation in the setting of chronic pressure overload heart failure.

G-CSF as an adjunctive therapy with umbilical cord blood cell transplantation for traumatic brain injury.

Traumatic brain injury (TBI), a major contributor to deaths and permanent disability worldwide, has been recently described as a progressive cell death process rather than an acute event. TBI pathophysiology is complicated and can be distinguished by the initial primary injury and the subsequent secondary injury that ensues days after the trauma. Therapeutic opportunities for TBI remain very limited with patients subjected to surgery or rehabilitation therapy. The efficacy of stem cell-based interventions, as well as neuroprotective agents in other neurological disorders of which pathologies overlap with TBI, indicates their potential as alternative TBI treatments. Furthermore, their therapeutic limitations may be augmented when combination therapy is pursued instead of using a single agent. Indeed, we demonstrated remarkable combined efficacy of human umbilical cord blood (hUCB) cell therapy and granulocyte-colony-stimulating factor (G-CSF) treatment in TBI models, providing essential evidence for the translation of this approach to treat TBI. Further studies are warranted to determine the mechanisms underlying therapeutic benefits exerted by hUCB + G-CSF in order to enhance its safety and efficacy in the clinic.

BK polyomavirus reactivation after reduced-intensity double umbilical cord blood cell transplantation

Serial serum samples from 27 patients who underwent double umbilical cord blood transplantation (dUCBT) were analyzed for BK polyomavirus (BKPyV) DNA by real-time PCR and BKPyV-specific immune globulin by ELISA. Clinical data were collected on all patients. All pre-transplant sera had detectable anti-BKPyV IgG. Fifteen patients (56%) had detectable serum BKPyV DNA (median 8.9×104copies/ml; range 4.1×103–7.9×106copies/ml) a median of 40days (range, 27–733days) after dUCBT, with highest viral loads on Day 100 assessment. The cumulative probability of developing BKPyV viremia by Day 100 was 0.52 (95% CI, 0.33–0.71). Six of 15 patients with BKPyV viremia experienced hemorrhagic cystitis by Day 100. By Day 100, there was a trend towards higher BKPyV viral loads in sera of patients with hemorrhagic cystitis than in those BKPyV viremic patients without hemorrhagic cystitis (p=0.06). BKPyV viremia was associated with significantly higher anti-BKPyV IgM values at 6months post-dUCBT (P=0.003). BKPyV viremia occurs early after dUBCT and is associated with a detectable humoral immune response by 6months post-dUBCT.

Autologous umbilical cord blood cells for newborn infants with hypoxic-ischemic encephalopathy

Many of the recent clinical trials have shown high therapeutic potential of cord blood stem cells to treat various diseases in children. In this report we present the results of pilot study of autologous umbilical cord blood cells transplantation for newborn infants with hypoxic-ischemic brain injury. At one year old, case 1 was normal developmentally. Case 2 has gross motor delay with relative sparing of cognition. A multicentre randomised-controlled trial is needed to evaluate clinical effectiveness of this treatment.

Hyperbaric oxygen improves engraftment of ex-vivo expanded and gene transduced human CD34+ cells in a murine model of umbilical cord blood transplantation

Delayed engraftment and graft failure represent major obstacles to successful umbilical cord blood (UCB) transplantation. Herein, we evaluated the use of hyperbaric oxygen (HBO) therapy as an intervention to improve human UCB stem/progenitor cell engraftment in an immune deficient mouse model. Six- to eight-week old NSG mice were sublethally irradiated 24 hours prior to CD34⁺ UCB cell transplant. Irradiated mice were separated into a non-HBO group (where mice remained under normoxic conditions) and the HBO group (where mice received 2 hours of HBO therapy; 100% oxygen at 2.5 atmospheres absolute). Four hours after completing HBO therapy, both groups intravenously received CD34⁺ UCB cells that were transduced with a lentivirus carrying luciferase gene and expanded for in vivo imaging. Mice were imaged and then sacrificed at one of 10 times up to 4.5 months post-transplant. HBO treated mice demonstrated significantly improved bone marrow, peripheral blood, and spleen retention and subsequent engraftment. In addition, HBO significantly improved peripheral, spleen and bone marrow engraftment of human myeloid and B-cell subsets. In vivo imaging demonstrated that HBO mice had significantly higher ventral and dorsal bioluminescence values. These studies suggest that HBO treatment of NSG mice prior to UCB CD34⁺ cell infusion significantly improves engraftment.

Functional Adaptive Immune Responses in Hematopoietic Chimeric Mice After Umbilical Cord Blood Cell Transplantation.

Abstract 2995 Introduction:An increasing number of clinical trials have demonstrated the usefulness of cord blood as a source of hematopoietic stem cells for reconstitution of the hematopoietic system. Nevertheless, due to a lack of convenient animal models, information about the immunological competence of umbilical cord blood cell (UCBC)-derived lymphocytes has been relatively limited. Recently, we have established a murine model of UCBC transplantation, which reconstitutes the hematopoietic system of immunodeficient mice, and studied the correct immunological functions of UCBC-derived lymphocytes generated in an allogeneic environment. Materials and Methods:UCBC prepared from C57BL/6 (H-2b) mice were transferred into lethally irradiated BALB/c (H-2d) mice lacking T- and B-lymphocytes (RAG2 knockout). In order to evaluate the adaptive immune response in the recipient mice, rejection of skin grafts from third-party C3H/He (H-2k) mice and antibody responses to immunization with a T-dependent antigen, 2,4,6-trinitrophenyl-keyhole limpet hemocyanin (TNP-KLH), were assessed. Additionally, the responsiveness of generated T cells was verified by mixed lymphocyte reaction (MLR) assay, cytotoxic T-lymphocyte (CTL) assay and phytohemagglutinin (PHA) blast formation assay. Results:In this UCBC transplantation model, the overall survival of the recipient mice was dose-dependent, and all surviving recipient mice were hematopoietic chimeras possessing all lineages. These allogeneic chimeras specifically rejected skin grafts from third-party C3H/He mice (rejection time; 9–16 days) while showing tolerance to skin grafts from both donor-type and recipient type, although with a significant delay in comparison to normal BALB/c mice (8–12 days) and C57BL/6 mice (9–11 days). Although accurate antibody responses of the allogeneic chimeras against TNP-KLH immunization were not anticipated, substantial amounts of TNP-specific IgG were detected in their sera. Interestingly, the level of TNP-specific IgM was significantly higher than that of normal BALB/c mice after TNP-KLH immunization, indicating retarded immunoglobulin class-switching in the allogeneic chimeras. The mechanism responsible for the antibody production by allogeneic chimeras still remains unclear. CTL and MLR assay revealed cell-mediated third-party-specific activity of killer and helper T cells, consistent with the tendency for the skin graft rejection and antibody production capability of the allogeneic chimeras to be inferior to those of normal mice. T cells of the allogeneic chimeras also proliferated non-specifically in response to PHA stimulation. The T-cell proliferation indices of the allogeneic chimeras when those of normal mice were taken as 100 were 21 in the MLR assay and 48 in the PHA blast formation assay, suggesting relative inferiority of the recognition and response system of T cells generated in an allogeneic environment. In any event, it may be important to note that T-dependent antigen-specific antibody production and alloantigen-specific rejection were substantial in the allogeneic chimeras. Conclusions:Overall, the present findings suggest that UCBC-derived lymphocytes generated in HLA-mismatched recipients are immunologically functional and competent. Regarding the relative inferiority of immune responses in the allogeneic chimeras, we predict the causes originate from narrowing of the T- and B-cell receptor repertoire by the allogeneic environment, and this possibility is now being examined. Disclosures:No relevant conflicts of interest to declare.

Double-Unit Umbilical Cord Blood Transplantation Induces MHC-Matched Single-Unit Dominance with Development of Immunocompetent Lymphocytes in Recipient Mice

Abstract 4097 Background:Double-unit umbilical cord blood cell (dUCBC) transplantation has emerged as an effective strategy for improving the engraftment of umbilical cord blood stem cells in the bone marrow of recipients. Due to a lack convenient animal models, analyses of the differentiation capacity of dUCBC in recipients have been limited to in vivo xenogeneic experiments and clinical observations. In the present study, we evaluated the characteristics of immune reconstitution induced by dUCBC transplantation in mice. Materials and Methods:Natural killer cells were depleted from female C57BL/6 (B6) [H-2b] recipient mice by intraperitoneal administration of rabbit anti-asialo GM1 polyclonal antibody 1 day before transplantation. On the following day, the lethal X-ray-irradiated B6 recipients were given transplants of three different combinations of dUCBC {group (1) GFP-Tg B6 [H-2b] and BALB/c [H-2d]; group (2) GFP-Tg B6 [H-2b] and C3H [H-2k]; group (3) BALB/c [H-2d] and C3H [H-2k]}, each combination containing an equal number of cells. At 16 weeks after transplantation, reconstitution of immune cells was evaluated by flow cytometric analysis utilizing specific antibodies against lineage markers such as CD3 (T cells), CD45R/B220 (B cells), CD11b (macrophages), or Ly-6G (granulocytes). The donor origin of each lineage population was determined by anti-H-2Kk (for C3H) and/or H-2Kd (for BALB/c) antibody staining. GFP+ lineage cells were identified as being of B6 donor origin. Skin grafting was then performed in all recipients to assess the functional maturity of the newly developed T and B cells induced by dUCBC transplantation. Results:The survival rate at 16 weeks after transplantation was 73% (8/11) for case (1), 92% (12/13) for case (2), and 50% (3/6) for case (3). In the great majority of cases (1) and (2), in which dUCBC were administered as a stem cell source, the MHC-matched single unit from GFP-Tg B6 acts as the sole source of long-term hematopoiesis (75% (6/8) for case (1); 100% (12/12) for case (2)). CD3+ T cell peripheral blood chimerism from BALB/c was observed in two of the eight B6 survival recipient mice in case (1) at an early stage of hematopoiesis, predicting the long-term engrafting unit. On the other hand, hematopoiesis in case (3) with fully allogenenic dUCBC transplantation was reconstituted by the B6 recipients' own X-ray-resistant hematopoietic stem cells (HSC). Our results indicate that MHC-matched UCBC-HSC predominantly engraft in the recipient's bone marrow after dUCBC transplantation. However, the nature of this selective mechanism remains largely unknown. In all cases, alloreactive cytotoxic cells in recipient may participate in such selection. In dUCBC transplantation, the included allogeneic cells probably act as stimulators for promoting the differentiation and maturation of MHC-matched HSC through activation of certain types of signal transduction (for example, through cytokine secretion). Currently, we are investigating the possible presence of alloreactive cytotoxic cells in bone marrow. Functionally, these recipients were tolerant of skin grafted from B6, whereas they rejected skin from BALB/c and C3H within 20 days, indicating that both CD4+ helper and CD8+ killer T cells were functionally mature in the recipient mice. Correspondingly, only the alloantibody to BALB/c and C3H was produced in the recipients. One of two chimeric recipient mice in case (1) reacted to only C3H skin with T and B cells. Conclusions:dUCBC transplantation clearly rescued mice that had been subjected to lethal X-ray irradiation. Furthermore, our observations indicate that T and B cells derived from dUCBCs transplants are immunologically fully competent with the ability to distinguish self from non-self MHC antigens. However, a clear understanding of the mechanisms underlying the predominant engraftment of MHC-matched HSCs in the recipient's bone marrow will be necessary. Disclosures:No relevant conflicts of interest to declare.

Hyperbaric Oxygen Therapy Improves Post-Transplant Umbilical Cord Blood Engraftment

AbstractAbstract 4663 Background:Delayed engraftment following umbilical cord blood (UCB) transplantation is associated with increased transplant-related mortality. Earlier, we have reported that hyperbaric oxygen therapy (HBO) might have altered early UCB engraftment kinetics in a transplant animal model. Herein, we report use of HBO to improve long-term UCB engraftment. Methods:Six-to eight-week old NSG mice were sublethally irradiated 24 hours prior to CD34 selected UCB cell transplant. The irradiated mice were separated into a control group (where mice remained under normoxic conditions) and the HBO group (where mice received two hours of HBO therapy; 100% oxygen at 2.5 atmospheres absolute). Six hours after starting HBO therapy, both groups received 1×105 CD34 selected UCB cells via tail vein injection. The infused CD34 selected cells were transduced with a lentivirus carrying luciferase gene for in vivo imaging. Mice (n=4) from each treatment group were sacrificed after 3 and 4 months to assess long-term engraftment. Engraftment was measured as assessed by flow cytometry. Myeloid, B-cell, and T-cell subset engraftment was determined by flow cytometry. Results:At 3 and 4 months post-transplant, the mean percentage of human CD45 expressing cells in peripheral blood of HBO mice was significantly higher than controls (p=0.03 and p=.008 respectively). The mean percentage of human CD45 expression was higher in bone marrow of HBO mice at 3 months and 4 months, but only reached statistical significance at 4-month time point (p=0.04). At 3 months, the mean percentage of human CD19 expressing cells was significantly higher in peripheral blood of HBO mice (p=0.03) while no differences were noted between the two groups in terms of CD33 or CD3 expression. At 4 months, the mean percentage of human CD19 expressing cells and human CD3 expressing cells was significantly higher in peripheral blood of HBO mice (p=0.009 and p=0.0009, respectively) while no differences were noted between the two groups in terms of CD33 expression. Conclusions:HBO therapy given prior to UCB cell infusion significantly improved UCB's long-term engraftment. At 3 months, engraftment was skewed toward B-cell engraftment, while more balanced engraftment was noted at 4 months. Future studies are planned to confirm these findings and to determine the underlying mechanisms by which HBO improved UCB CD34 cell engraftment. Disclosures:No relevant conflicts of interest to declare.

The Levels of Pro-Inflammatory Factors Are Significantly Decreased in Cerebral Palsy Patients Following an Allogeneic Umbilical Cord Blood Cell Transplant

The transplantation of human umbilical cord blood cells (hUCBCs) has been shown to attenuate the unregulated activation of microglia in a rat model of cerebral palsy (CP). To investigate whether hUCBCs transplantation is also anti-inflammatory in humans, we performed a clinical trial in patients with CP. Allogeneic or autologous hUCBCs and erythropoietin (EPO) were intravenously injected into human patients with CP (mean age of approximately 38 weeks), and patients were analyzed for their motor function and social behavior. Blood samples were tested for cytokine levels. The most surprising finding in the study was that the cytokine levels were dependent on the donor cell source (allogeneic or autologous). Interestingly, the allogeneic treatment group demonstrated significantly decreased levels of pro-inflammatory factors, such as IL-1α, IL-6, TNF-β, and RANTES, and showed a statistically significant improvement in motor and social behavior compared to the autologous treatment group. Given that inflammation plays a pivotal role in CP, our results suggest that allogeneic hUCBCs therapy may be an appropriate strategy for CP treatment. In addition, prior to transplantation, a detailed analysis of the amount of proinflammatory cytokines in cord blood may be needed to avoid exacerbating inflammatory responses.

Umbilical cord blood mononuclear cell transplantation for neonatal hypoxic–ischemic encephalopathy

Despite recent advances in the treatment of neonatal hypoxic-ischemic encephalopathy (HIE) using therapeutic hypothermia, at least 30% of the cooled infants will die or have moderate/severe neurological disability. Umbilical cord blood cells (UCBCs), which are readily available at birth, have been shown to reduce sensorimotor and/or cognitive impairments in several models of brain damage, representing a promising option for the treatment of neurological diseases. In this review, we discuss recent preclinical studies that assessed the effects of UCBC transplantation in the Rice-Vannucci animal model of HIE. We also review the possible cell types and mechanisms involved in the therapeutic effect of UCBC transplantation, including neuroprotection, immunomodulation, and stimulation of neural plasticity and regeneration. In addition, we discuss how neuroimaging methods, such as bioluminescence imaging, nuclear-medicine imaging, or magnetic resonance imaging, could be used to evaluate the biodistribution of UCBCs in both preclinical and clinical studies.

Actions of keratinocyte growth factor in leukemic mice allogeneic umbilical cord blood cell transplantation

To explore the actions of keratinocyte growth factor (KGF) in leukemic mice allogeneic umbilical cord blood cell transplantation (UCBT) and elucidate its mechanism. Peripheral blood drawn from the litters of C57BL/6 females was used as umbilical cord blood (UCB) graft. BALB/c mice were randomly divided into 7 groups (n = 12 each). The grouping was as follows. Control group 1, inoculated with leukemia. Control group 2, inoculated with leukemia at -4 d and total body irradiation (TBI) treatment. Control group 3, TBI treatment and reconstituted with 2 × 10(6) UCB-TNCs. Control group 4, injected with PBS subcutaneously, TBI treatment and reconstituted with UCB-TNCs with platelet transfusion. Control group 5, inoculated with leukemia, injected with PBS subcutaneously, TBI treatment and reconstituted with UCB-TNCs with platelet transfusion. Experiment group 1, injected with KGF subcutaneously, TBI treatment and reconstituted with UCB-TNCs with platelet transfusion. Experiment group 2, inoculated with leukemia, injected with KGF subcutaneously, TBI treatment and reconstituted with UCB-TNCs with platelet transfusion. The survival status, pathohistological changes, splenic lymphoid cell subsets and thymic output post-UCBT were compared between groups. The survival time of control group 1 was (11.1 ± 1.5) days and all died of leukemia. The survival time of control group 2 was (11.5 ± 2.5) days and all died of aplasia. Five of 12 mice of control group 3 survived for 100 days and 7 mice died of visceral hemorrhage. Four of 12 mice of control group 5 survived for 100 days and 8 mice died of leukemia with a survival rate of 33.3%. Nine of 12 mice of experiment group 2 survived for 100 days and 3 mice died of leukemia with a survival rate of 75.0%. The survival was prolonged in experiment group 2 mice as compared with that of control group 5 mice (χ² = 4.996, P = 0.0254). The splenic T, NK and B cell counts in control group 4 mice at +35 d were (9.32 ± 0.48) × 10⁶, (1.59 ± 0.11) × 10⁶ and (18.74 ± 2.01) × 10⁶ respectively. While in group 6 mice at +35 d were (13.20 ± 1.14) × 10⁶, (1.75 ± 0.12) × 10⁶ and (20.36 ± 0.86) × 10⁶ respectively. The counts of T cell and NK cell of group 6 were higher than those of group 4 (both P < 0.05). The level of signal joint T-Cell receptor excision circles (sjTRECs) in control group 4 mice was (167 ± 17) copies per 10⁵ cells while that of experiment group 1 mice (228 ± 24) copies per 10⁵ cells. They were higher than that of control mice (P = 0.002). Hematopoietic stem/precursor cells are abundant in full-term murine fetal peripheral blood. The infusion of KGF reduces the post-UCBT relapse of leukemia through the enhancement of thymic output.

Successful unrelated umbilical cord blood cell transplantation without conditioning for a neonate with severe combined immunodeficiency

A neonate was diagnosed as having SCID from his umbilical cord blood cells immediately after birth because his older brother had died of SCID eight months earlier. One locus-mismatched unrelated umbilical cord blood cell transplantation without conditioning was performed at the age of 30 days. The CD3-positive cells were detected on day 14 post-transplantation. There were no peri-transplantation complications. Four yr after transplantation, the boy is in excellent condition and T and NK cell engraftments are complete. His peripheral B cells with a common gamma chain were not detected by flow cytometry, and he still needs IgG replacement; however, his IgM and IgA levels have gradually increased, and the dosage of IVIG per body weight has gradually decreased. We speculate that the very few B cells that proliferate from transplanted cord blood cells produce gamma globulin. Unrelated cord blood cell transplantation, even though mismatched, without conditioning would be a treatment option for neonates with severe combined immunodeficiency.