Use Of Bone Marrow Transplantation Research Articles

History and legal aspects of bone marrow donor banks in Brazil

Introduction: Bone marrow transplants primarily depend on people who previously registered to be donors. From then on, the search for compatibility between donor and recipient begins. Objective: To describe the historical landmarks and the legal apparatus of bone marrow donor banks in Brazil based on an integrative review. Methods: LILACS database and PubMed and SciELO journals were used. The term bone marrow transplantation was the descriptor. Eligibility criteria were: articles with the theme of Bone Marrow Transplantation (BMT) and studies carried out on the national territory. Results: A total of 88,855 articles were identified, among which 185 met the eligibility criteria. After they were thoroughly read, 14 articles were selected. The studies pointed out fragments that dealt with important historical landmarks for the establishment of bone marrow transplantation as a conventional treatment for oncohematological diseases. Conclusion: The use of BMT has a history of more than thirty years in Brazil. However, none of the articles identified specifically addresses the historical content of bone marrow transplantation.

State-of-the-art review on management of end-stage heart failure in amyloidosis: transplant and beyond.

Cardiac involvement occurs in light-chain (AL), transthyretin wild-type (wtATTR), and hereditary (hATTR) amyloidosis; other types of amyloidosis account for < 5% of all cardiac amyloidosis (CA). CA can present subclinically on screening, insidiously with symptoms such as exertional dyspnea, or abruptly as cardiogenic shock. Initially, CA patients were thought to be poor candidates for transplant due to short long-term survival; however, there is a marked improvement in heart and multi-organ transplant outcomes over the past 10years with newer treatments and improvements in support with temporary and durable mechanical circulatory support while awaiting transplant. Patients with AL CA were reported to have worse post-OHT outcomes than patients with ATTR CA, but this gap is quickly closing with improved patient selection, novel chemotherapeutics, and perhaps with selected use of bone marrow transplantation. Waitlist mortality and transplantation rates have markedly improved for CA after the United Network for Organ Sharing (UNOS) policy change in October 2018. In this review, we will evaluate contemporary data from the last 5years on advances in the field of transplantation and mechanical circulatory support in this patient population.

Risk of developing second malignant neoplasms in patients with neuroblastoma: a population study of the US SEER database

BackgroundNeuroblastoma is a common extracranial malignant tumor in children. Its main treatment modality is a combination of chemotherapy, radiotherapy, and surgery. Given the advances in chemotherapy regimens and the widespread use of bone marrow transplantation over the decades, there has been improvement in treatment efficacy, which has led to prolonged patient survival. Accordingly, long-term complications have become a growing concern among physicians and patients. This study aimed to analyze the survival rate of patients with neuroblastoma and the risk factors for developing second malignant neoplasms (SMNs).MethodsThe SEER 18 Regs (1973–2015) and SEER 9 Regs (1973–2015) data of the surveillance, epidemiology, and end results (SEER) database of the US National Cancer Institute were adopted for survival and SMN analysis.ResultsThe 5-, 10-, and 20-year overall survival rates of patients with neuroblastoma were 67%, 65%, and 62%, respectively. Among 38 patients with neuroblastoma who presented with SMNs, those with abdomen as the primary site accounted for the majority (63.2%), followed by those with thorax (26.3%) and other sites (10.5%). SMNs occurred more commonly in non-specific neuroblastoma (incidence: 0.87%) than ganglioneuroblastoma (incidence: 0.3%). Compared with the general population, the risk of SMN is significantly higher (SIR = 4.36). The risk of developing SMNs was significantly higher in the digestive system (SIR = 7.29), bones and joints (SIR = 12.91), urinary system (SIR = 23.48), brain and other nervous systems (SIR = 5.70), and endocrine system (SIR = 5.84). Multivariate analysis revealed that the year of diagnosis (OR = 2.138, 95% CI = 1.634–2.797, p < 0.001) was the only independent risk factor for developing SMNs.ConclusionThis study identifies the risk factor for developing SMNs in patients with neuroblastoma, which could facilitate individualized screening for high-risk patients, to allow early diagnosis and treatment of SMNs.

Non-Genotoxic Conditioning Using Amanitin Antibody-Drug Conjugates Targeting CD45 Effectively Deplete Human and Non-Human Primate Hematopoietic Stem Cells and Immune Cells

Introduction Bone Marrow Transplant (BMT) is a potentially curative treatment for malignant and non-malignant blood disorders. Current regimens for patient preparation, or conditioning, prior to BMT limit the use of this curative procedure due to regimen-related mortality and morbidities, including risks of organ toxicity, infertility and secondary malignancies. To safely condition patients for BMT, we are developing antibody drug conjugates (ADCs) targeting CD45, a target expressed throughout the hematopoietic system to specifically deplete both hematopoietic stem cell (HSCs) and immune cells prior to transplant. Results We created anti-CD45 ADCs by conjugating antibodies to alpha-amanitin payload (an RNA polymerase II inhibitor). A resulting anti-CD45 amanitin ADC (CD45-AM) exhibited potent in vitro killing of primary human bone marrow CD34+CD90+ HSCs (IC50 67 pM, Figure 1A) and PBMC immune cells (IC50 55 pM, Figure 1B). Next, we explored the CD45-AM ADC in vivo in humanized NSG mice. A single dose of 3 mg/kg CD45-AM enabled >95% depletion of human CD34+ cells in the bone marrow (Figure 1C) and >95% depletion of human B-, T- and myeloid cells in the periphery and bone marrow. Control non-targeting isotype matched-ADCs and anti-CD45 antibody not bearing a toxin had minimal effect on either HSC or immune cells. As CD45 is highly expressed on many leukemia and lymphomas, we also assessed the leukemia-depleting activity of CD45-AM in an ALL model and 3 PDX-AML models. A single dose of 1 mg/kg CD45-AM more than doubled the median survival in all 4 models (p values As BMT will require fast clearing ADCs to avoid depleting the incoming graft, we engineered a fast half-life CD45-AM variant with a half-life of 8-15 hours in mice, and 9 hours in cynomolgus monkeys. Dose escalation of the cross-reactive fast half-life CD45-AM in cynomolgus monkeys showed dose-dependent peripheral lymphocyte depletion. A single dose of 1 mg/kg was well tolerated and enabled >95% depletion of HSCs (CD34+CD90+CD45RA- cells) and >80% lymphocyte depletion in the marrow 14 days post-administration (Figure 1D). Conclusion Targeting CD45 with an amanitin ADC resulted in potent in vitro and in vivo human HSC and immune cell depletion. The anti-CD45 amanitin ADC significantly reduced disease burden in multiple leukemia models. Preliminary assessment of a fast half-life ADC in cynomolgus monkeys showed efficient HSC and immune cell depletion in the marrow. An alpha-amanitin ADC targeted to CD45 may i) be non-genotoxic; ii) avoid bystander toxicity, due to amanitin's poor cell permeability as a free toxin; and iii) kill cycling and non-cycling cells, the latter being necessary for effective HSC and immune cell depletion. Together, these properties may enable safer targeted conditioning and expand the use of BMT in malignant and non-malignant conditions.

In Vitro Activity and Target Modulation of PV-10 Against Relapsed and Refractory Pediatric Leukemia

Introduction: Leukemias are the most common childhood cancers, accounting for 30% of all pediatric cancer diagnoses. Although the survival rate for pediatric leukemia has greatly improved, relapse is a major cause of treatment failure. Approximately 15-20% of pediatric acute lymphoblastic leukemia (ALL) patients and 30-40% of acute myeloid leukemia (AML) patients relapse, with relapsed ALL identified as the fourth most common malignancy in children. Treatment of relapsed pediatric leukemia includes intensification of chemotherapeutic regimens and use of bone marrow transplantation (BMT). However, increasing the intensity of combination chemotherapies and introduction of second-line drugs is often accompanied by cumulative toxicity with marginal incremental benefits. Therefore, research to identify and develop novel tolerable and effective agents is urgently needed. PV-10 (4,5,6,7-tetrachloro-2',4',5',7'-tetraiodofluorescein) is a novel therapeutic that induces direct cytotoxicity in adult and pediatric solid tumors and stimulates tumor specific immune activation through immunogenic cell death. Our studies aim to identify the potential of PV-10 in future clinical trials for relapsed and refractory pediatric leukemias.Methods: A panel of eleven cell lines derived from patients with either primary or relapsed pediatric leukemia (CEM-C1, CCRF-SB, Kasumi-1, KOPN8, Molm-13, Molt-3, Molt-4, MV4-11, SEM, SUP-B15 and TIB-202) and cells from three primary leukemia patient specimens (T-ALL, AML, Infant AML) were treated with increasing concentrations of PV-10 and cell viability was measured by alamar blue assay, 96 h post-treatment. Target modulation and induction of cell death pathways were investigated by western blot, phase-contrast microscopy and time-lapse video microscopy. Analysis of cell cycle alterations and induction of apoptosis were measured by flow cytometry. Combination studies will be performed to identify anti-cancer agents that are synergistic with PV-10 and animal models of pediatric leukemia used to identify the activity of PV-10 against pediatric leukemia in vivo.Results: PV-10 decreased cell viability in a concentration and time dependent manner in the eleven pediatric leukemia cell lines (mean IC50 93 µM), and three primary leukemia samples (mean IC50 122 µM) tested. Observation of four different leukemia cell lines (Molm-13, MV4-11, SEM, TIB-202) by phase-contrast and time-lapse video microscopy indicated that PV-10 was cytotoxic and not cytostatic to cells. Quantification of dead cells from time-lapse video microscopy experiments showed that PV-10 was cytotoxic in a cell line and concentration dependent manner. At 24 h post-treatment with 100 µM PV-10, 88% of MV4-11 cells, 69% of Molm-13 cells, 27% of TIB-202 cells and 25% of SEM cells had undergone cell death. When the concentration of PV-10 was increased to 200 µM, 100% of MV4-11 and Molm13 cells, 94% of SEM cells and 60% of TIB-202 cells had undergone cell death, 24 h after treatment. Additionally, observation by time-lapse video microscopy suggested that cells were dying by apoptosis, as treatment with PV-10 led to cell shrinkage. Induction of apoptosis by PV-10 was confirmed by dose and time dependent PARP cleavage, detected by western blot.Conclusions: Our studies provide first proof-of-concept pre-clinical data for the activity and mechanisms of action of PV-10 in pediatric leukemia. These data provide the rationale for additional studies and the formulation of an early-phase clinical trial for patients with relapsed and refractory pediatric leukemia. DisclosuresNo relevant conflicts of interest to declare.

Safety and Toxicity of Oral Melphalan Use in Bone Marrow Transplantation in Patients with Multiple Myeloma, in a Setting Without Venous Medication Supply

Safety and Toxicity of Oral Melphalan Use in Bone Marrow Transplantation in Patients with Multiple Myeloma, in a Setting Without Venous Medication Supply

Inaugural Message from the Founding Editor-in-Chief.

Given the remarkable advances made over the last several decades in science and medicine, there could be no better and opportune time to launch the Journal of Translational Science (JTS). We have been fortunate to witness the integration of multiple areas of discovery in science and medicine to push the envelope for the diagnosis and treatment of disorders that can affect any region of the body. In developed countries such as the United States, life expectancy continues to increase and is accompanied by a one percent decrease in the age-adjusted death rate from the years 2000 through 2011. Yet, with the increasing growth and lifespan of the world's population, it is expected that the incidence of a number of disorders, such as metabolic disease, and neurodegenerative disorders, also will continue to grow. For example, the World Health Organization reports that diabetes mellitus will be ranked as the seventh leading cause of death by the year 2030. As a result, multiple novel therapeutic strategies are currently being advanced to treat disorders that currently have limited remedies. In particular, stem cell applications have quickly advanced and are being considered for numerous disorders that include cardiovascular disease, diabetes mellitus, cancer, inflammatory bowel disease, peripheral ischemia, graft versus host disease, and nervous system disorders. More than 40 years prior, the use of bone marrow transplantation set the stage for the treatment of hematological disorders and cancer with the use of stem cells. Presently, more than 50,000 bone marrow transplants are performed every year using autologous and allogeneic hematopoietic stem cells. In addition, unique cellular channels, such as the vanilloid (capsaicin) receptor TRPV1 (transient receptor potential, vanilloid subfamily member 1) and a member of the TRP superfamily of cation channels, are being pursued for a diverse spectrum of disorders that range from pain management to neuronal protection of the brain following stroke. Increasing consideration also is being directed to the field of microRNAs (miRNAs). MiRNAs consist of 19-25 nucleotides, are small non-coding ribonucleic acids (RNAs), and can control gene expression by silencing targeted messenger RNAs (mRNAs) translated by specific genes. With the explosion of new studies, miRNAs are reported to play critical roles in stem cell renewal, tissue repair, and potential disease progression in areas such as those of the cardiac, gastrointestinal, and nervous systems. Although these therapeutic strategies appear initially to be diverse, upon closer inspection each depends upon a “common signaling platform” that is intimately connected through cellular pathways that can significantly affect clinical outcome in patients. It is clear that cellular and genetic targets can easily impact multiple disease entities. The translation of these pathways into relevant clinical treatments can yield fruit for many disorders. JTS was conceived with this knowledge in mind. JTS is a novel open access journal that will focus upon the translation of cellular, molecular, and genetic pathways into clinical strategies for multiple medical disciplines that can impact a broad spectrum of disorders. These disorders can involve all aspects of translational research and medicine to include stem cells, degenerative diseases, aging, immune function, tumorigenesis, epigenetics, musculoskeletal function, cognition, behavior, metabolic function, and targets of the neuronal, cardiac, pulmonary, gastrointestinal, and vascular systems. JTS will provide a platform in today's scientific and medical literature to serve as an international forum for the healthcare and scientific communities worldwide to translate basic and clinical research studies into clinical therapies as well as report upon prognostics, novel therapeutic strategies, and biomarker development. JTS will offer multiple venues to present authors' thoughts and investigations as original research papers, review papers, clinical studies, editorials, expert opinion and perspective papers, commentaries, book reviews, and letters to the editor. Ultimately, JTS will promote a rigorous, fair, and constructive evaluation of all submitted articles. Papers will be processed in an extremely timely fashion so that all authors can follow the progress of the papers during the evaluation, copyediting, and publication phases. We are extremely excited with the launch of JTS and believe that the journal will fill a great void in the reporting of today's scientific and medical discoveries. JTS will serve as an international forum for the greatest degree of scholarship in the research and clinical communities worldwide to translate pioneering “bench to bedside” breakthroughs into successful clinical strategies. On behalf of the Editorial Team and the Editorial Board, welcome to JTS!

Comparison of haematopoietic stem cell engraftment through the retro-orbital venous sinus and the lateral vein: alternative routes for bone marrow transplantation in mice

Bone marrow transplantation in mice is performed by intravenous administration of haematopoietic repopulating cells, usually via the lateral tail vein. This technique can be technically challenging to carry out and may cause distress to the mice. The retro-orbital sinus is a large area where there is a confluence of several vessels that provides an alternative route for intravenous access. Retro-orbital injection, although aesthetically unpleasant, can be performed rapidly without requiring mechanical restriction or heat-induced vasodilation. In addition, this technique can be easily learned by novice manipulators. This route of administration has been reported for use in bone marrow transplantation but there is no comparison of retro-orbital and tail vein injections reported for this specific purpose, although both routes have been compared for many other applications. Here, we provide for the first time a comprehensive comparison between tail vein and retro-orbital injections for two different bone marrow transplant scenarios in P3B and B6D2F1 mice. In both cases, no significant differences regarding donor engraftment were observed between mice transplanted using each of the techniques. Haematological counts and leukocyte subpopulation distribution were practically identical between both animal groups. Moreover, donor engraftment levels were less homogenous when cells were transplanted by tail vein injection, probably due to a higher risk of failure associated with this technique. All these data suggest that retro-orbital injection is a compelling alternative to conventional tail vein injection for bone marrow transplant in mice, providing similar and more homogenous haematopoietic reconstitution.

Abstract 19808: Short Term Outcomes After Use of Bone Marrow Transplantation for Management of Heart Failure: A Meta-analysis

The role of bone marrow cell transplant in ischemic heart failure is being increasingly recognized. Multiple studies have been published evaluating their use with varying results. We aimed to perform a meta-analysis of the published literature. We searched Pubmed, EBSCO and Cochrane databases for terms “bone marrow transplant”, “stem cell transplant”, “heart failure”, “cardiac failure” and their combinations. Only studies comparing bone marrow cell transplantation via intracoronary route to placebo, and those with 6 month follow up data were included. Studies in language other than English were excluded. Results: Ejection fraction was significantly increased with the use of bone marrow cell transplant compared to placebo (mean difference 6.16% 95%CI 4.16 to 8.16, p &lt; 0.00001). No significant differences were observed in left ventricular (LV) end-systolic volume (mean difference -1.58 ml 95%CI -4.98 to 1.82, p = 0.36), LV end-diastolic volume (mean difference -0.77 ml 95%CI -3.75 to 2.22, p = 0.61) and mortality (odds ratio 1.08 95%CI 0.26 to 4.56, p = 0.92). Results of heterogeneity analysis showed significant heterogeneity only for ejection fraction endpoint (p = 0.01). Conclusion: As compared to placebo, intracoronary bone marrow cell transplant is associated with improved LV ejection fraction by 6% in ischemic heart failure patients at 6 month follow up.

Historical Perspectives in the Diagnosis and Treatment of Primary Immune Deficiencies

The field of Primary Immune Deficiency Disorders (PIDD) has advanced rapidly over the past several years with over 200 different gene mutations defined. With the recent institution of newborn screening for T cell deficiencies in many states and earlier recognition of the signs and symptoms of patients with immune deficiency, it is now apparent that PIDD is not as "rare" as was originally thought several decades ago. With the earlier recognition of patients with recurrent infections and various immune perturbations, advancements in the treatment of these immune deficiency disorders have led to enhanced survival and quality of life. In this issue, the diagnosis of PIDD through laboratory testing and skin manifestations is reviewed. The more recently described cellular immune deficiencies, selective immune deficiencies, and advances in the use of bone marrow transplantation in the correction of some of these immune deficiencies are discussed.

Induction of Graft-versus-host Disease and &lt;em&gt;In Vivo&lt;/em&gt; T Cell Monitoring Using an MHC-matched Murine Model

Graft-versus-host disease (GVHD) is the limiting barrier to the broad use of bone marrow transplant as a curative therapy for a variety of hematological deficiencies. GVHD is caused by mature alloreactive T cells present in the bone marrow graft that are infused into the recipient and cause damage to host organs. However, in mice, T cells must be added to the bone marrow inoculum to cause GVHD. Although extensive work has been done to characterize T cell responses post transplant, bioluminescent imaging technology is a non-invasive method to monitor T cell trafficking patterns in vivo. Following lethal irradiation, recipient mice are transplanted with bone marrow cells and splenocytes from donor mice. T cell subsets from L2G85.B6 (transgenic mice that constitutively express luciferase) are included in the transplant. By only transplanting certain T cell subsets, one is able to track specific T cell subsets in vivo, and based on their location, develop hypotheses regarding the role of specific T cell subsets in promoting GVHD at various time points. At predetermined intervals post transplant, recipient mice are imaged using a Xenogen IVIS CCD camera. Light intensity can be quantified using Living Image software to generate a pseudo-color image based on photon intensity (red = high intensity, violet = low intensity). Between 4-7 days post transplant, recipient mice begin to show clinical signs of GVHD. Cooke et al. developed a scoring system to quantitate disease progression based on the recipient mice fur texture, skin integrity, activity, weight loss, and posture. Mice are scored daily, and euthanized when they become moribund. Recipient mice generally become moribund 20-30 days post transplant. Murine models are valuable tools for studying the immunology of GVHD. Selectively transplanting particular T cell subsets allows for careful identification of the roles each subset plays. Non-invasively tracking T cell responses in vivo adds another layer of value to murine GVHD models.

Induction of Graft-versus-host Disease and &lt;em&gt;In Vivo&lt;/em&gt; T Cell Monitoring Using an MHC-matched Murine Model

Graft-versus-host disease (GVHD) is the limiting barrier to the broad use of bone marrow transplant as a curative therapy for a variety of hematological deficiencies. GVHD is caused by mature alloreactive T cells present in the bone marrow graft that are infused into the recipient and cause damage to host organs. However, in mice, T cells must be added to the bone marrow inoculum to cause GVHD. Although extensive work has been done to characterize T cell responses post transplant, bioluminescent imaging technology is a non-invasive method to monitor T cell trafficking patterns in vivo. Following lethal irradiation, recipient mice are transplanted with bone marrow cells and splenocytes from donor mice. T cell subsets from L2G85.B6 (transgenic mice that constitutively express luciferase) are included in the transplant. By only transplanting certain T cell subsets, one is able to track specific T cell subsets in vivo, and based on their location, develop hypotheses regarding the role of specific T cell subsets in promoting GVHD at various time points. At predetermined intervals post transplant, recipient mice are imaged using a Xenogen IVIS CCD camera. Light intensity can be quantified using Living Image software to generate a pseudo-color image based on photon intensity (red = high intensity, violet = low intensity). Between 4-7 days post transplant, recipient mice begin to show clinical signs of GVHD. Cooke et al.1 developed a scoring system to quantitate disease progression based on the recipient mice fur texture, skin integrity, activity, weight loss, and posture. Mice are scored daily, and euthanized when they become moribund. Recipient mice generally become moribund 20-30 days post transplant. Murine models are valuable tools for studying the immunology of GVHD. Selectively transplanting particular T cell subsets allows for careful identification of the roles each subset plays. Non-invasively tracking T cell responses in vivo adds another layer of value to murine GVHD models.

Hematopoietic stem cell transplantation in Europe. Differences between Eastern and Western countries

Hemopoietic stem cell transplantation (HSCT) is increasingly used worldwide. The geographical distribution of this procedure is not homogenous within a particular continent. We have previously reviewed these differences in the use of bone marrow transplant in Europe, and in two reports we emphasized the economical reasons explaining these differences. The increasing demand for this high cost procedure represents a challenge for health care institutions. While patients need an optimal therapy, public health is confronted with limited resources. Information on changes in HSCT technology and on factors associated with its utilization might be of help. Insights into mechanisms of HSCT use are essential for rational decision making.

Bone marrow transplantation as an established approach for understanding the role of macrophages in atherosclerosis and the metabolic syndrome

Bone marrow transplantation (BMT) technology is a firmly established tool for studying atherosclerosis. Only recently it is helping us to understand the inflammatory mechanisms leading to the development of obesity, insulin resistance and type 2 diabetes. Here we review the use of BMT as a tool for studying the metabolic syndrome. Bone marrow-derived cells, and particularly monocytes and macrophages, have been a major subject in the study of atherogenesis, and they are highly amenable for research purposes because of their application in bone marrow transplantations. For example, the many pathways studied using BMT have helped unmask ABC transporters as the genes controlling reverse cholesterol transport and foam cell formation, as well as other genes like CCR2 and IκBα controlling leukocyte development, migration and activation. The invasion of leukocytes, not only in the vessel wall, but also in adipose tissue and liver, shares many common mechanisms relevant to atherosclerosis and metabolic diseases. BMT is an efficient and versatile tool for assessing the roles of specific genes that are restricted to hematopoietic cells, and especially the monocytes and macrophages in metabolic syndrome and its related pathologies.

Outcomes of lymphoma in South Australia, 1977–2007

To determine survival rates of patients with lymphoma in South Australia. De-identified data from the SA Cancer Registry on all patients with lymphoma were analysed, as well as the subgroup treated at the Royal Adelaide Hospital (RAH). For non-Hodgkin lymphoma (NHL), we used the International Working Formulation (IWF) grading. SA and RAH data on survival rates were compared with those for the whole of Australia and the United States. All patients diagnosed with lymphoma and treated in SA in 1977-2007. 5-year survival rates for patients with lymphoma, by type of lymphoma and age. Of the total of 8651patients with lymphoma, 939were classified as having Hodgkin lymphoma (HL) and 7712as having NHL. Of those with NHL, 1805had low-grade, 3576intermediate-grade, and 510high-grade NHL. In another 1821patients, the data were insufficient to make an IWF grading. There was a substantial increase in 5-year survival rates for patients with lymphoma between 1977and 2007in SA. While the increase in 5-year survival rates for HL was 7.6percentage points, survival rates peaked at 88%. For NHL, there was an 18.7percentage points increase in 5-year survival rates. The first significant increase of 7percentage points was associated with the introduction of bone marrow transplantation; this was maintained with the increase in 5-year survival rates reaching 14percentage points by 1995-1999. Since 1999, there has been a further increase of 5percentage points in 5-year survival rates with the introduction of rituximab. Outcomes in patients with NHL have improved significantly, most likely because of the use of bone marrow transplantation and rituximab. Hospital- and state-based cancer registry data reflect the reality of population outcomes and the impact of new technologies.

Simulation of ex vivo bone marrow culture: Application to chronic myeloid leukaemia growth model

The three-dimensional (3-D) architecture of the bone marrow (BM) supports the renewal, maintenance, proliferation and differentiation of haematopoietic stem cells (HSCs). Efforts have been made towards the reconstruction of an ex vivo HSC culture system, which could have several potential applications, such as the detailed understanding of normal and leukaemic haematopoiesis and expansion of haematopoietic stem cells for use in bone marrow transplantation (BMT). In this paper, a numerical model has been developed to investigate the advanced aspects of haematopoiesis, the regulatory effects of growth factor granulocyte colony-stimulating factor (G-CSF), thrombopoietin (TPO) and erythropoietin (EPO) on the production of chronic myeloid leukaemia (CML) cells within a purpose-designed scaffold placed inside a perfused bioreactor. A multi-lineage cellular growth model of haematopoietic cells was incorporated in order to mimic the complexity of the diseased BM. The simulation results demonstrate that different combinations and concentrations of cytokines can alter the self-renewal, differentiation, and proliferation of CML cells and this effect is also dependent upon operation conditions and scaffold properties. The numerical model presented here enables the optimisation of scaffold design parameters and mass transfer environment necessary for developing a suitable ex vivo haematopoietic system.

Grand Challenges in Alloimmunity and Transplantation

The pioneering Times Although the concept of Transplantation could be traced back as early as Saint Cosmas and Damian most famous miracle, grafting of a leg to replace a patient’s ulcered leg, it is not before the 50’s that it entered reality. Important steps were made before, from sewing vessels to understanding the basis of the major histocompatibility complex (MHC) in mice (Snell, 1986). This medical field was pioneered in renal transplantation with nearly concomitant attempts in Paris, London, Edinburgh, Boston. The first successful attempt was carried out in Boston by Joseph Murray in 1954. The donor and recipient were identical twins, showing indeed the importance of Genetic compatibility. Organ transplantation (OT) then became one of the most exciting “success story” of modern Medicine, admixing advances in Surgery and intensive care Medicine, Immunology, Genetics, and Pharmacology. The crucial point was first to avoid acute graft rejection which quickly appeared to be immune-mediated. The development of potent immunosuppressive (IS) drugs (corticosteroids, calcineurin inhibitors) opened the way to clinical transplantation. Most critical landmarks were in 1957 the first hepatic transplantation followed by transplantation of other organs, in 1967 the first successful heart transplantation, lung (1968), trachea (1979), pancreas, and more recently hands (2000) and facial tissue (2005). In hematopoietic stem-cell transplantation (HSCT), the initial report of the use of bone marrow transplantation in cancer treatment was made by Thomas in 1957. Several Nobel prizes were awarded to some of the transplantation “founding fathers”: Medawar and Burnet (1960), Benacerraf, Dausset and Snell (1980), Murray and Thomas (1990).

Transplantation immunology: Solid organ and bone marrow

Development of the field of organ and tissue transplantation has accelerated remarkably since the human MHC was discovered in 1967. Matching of donor and recipient for MHC antigens has been shown to have a significant positive effect on graft acceptance. The roles of the different components of the immune system involved in the tolerance or rejection of grafts and in graft-versus-host disease have been clarified. These components include antibodies, antigen-presenting cells, helper and cytotoxic T-cell subsets, immune cell-surface molecules, signaling mechanisms, and cytokines. The development of pharmacologic and biological agents that interfere with the alloimmune response has had a crucial role in the success of organ transplantation. Combinations of these agents work synergistically, leading to lower doses of immunosuppressive drugs and reduced toxicity. Reports of significant numbers of successful solid-organ transplantations include those of the kidneys, liver, heart, and lung. The use of bone marrow transplantation for hematologic diseases, particularly hematologic malignancies and primary immunodeficiencies, has become the treatment of choice in many of these conditions. Other sources of hematopoietic stem cells are also being used, and diverse immunosuppressive drug regimens of reduced intensity are being proposed to circumvent the mortality associated with the toxicity of these drugs. Gene therapy to correct inherited diseases by means of infusion of gene-modified autologous hematopoietic stem cells has shown efficacy in 2 forms of severe combined immunodeficiency, providing an alternative to allogeneic tissue transplantation.

Manhattan Transfer: Lethal Radiation, Bone Marrow Transplantation, and the Birth of Stem Cell Biology, ca. 1942–1961

This study investigates how, in the late 1940s and 1950s, fears of nuclear accidents and nuclear warfare shaped postwar radiobiology. The new and intense forms of radiation generated by nuclear reactor technology, and which would be released in the event of a nuclear war, created concerns about a public-health hazard unprecedented in form and scale. Fears of inadvertent exposure to acute and potentially lethal radiation launched a search for anti-radiation therapies, out of which emerged the new technique of bone marrow transplantation (BMT). This study analyzes the use of BMT first as a research tool to explore the biological effects of ionizing radiation, and then as an adjunct to radiotherapy for the treatment of cancer. In highlighting how BMT became the province of different research and clinical constituencies, this study develops an understanding of the forces and contingencies that shaped its development. Exploring the emergence of BMT and the uses to which it was put, it reveals that BMT remained a technique in the making -- unstable and far from standardized, even as it became both a widely used research tool and rapidly made its way into the clinic. More broadly, it casts new light on one route through which the Manhattan Project influenced postwar radiobiology; it also affords new insights into one means by which radiobiology came to serve the interests of the Cold War state. In its focus on BMT this paper provides a new perspective on the evolving relationship between radiobiology and biomedicine in the postwar period.

Allogeneic intra-bone marrow transplantation prevents rheumatoidarthritis in SKG/Jcl mice

The treatment of autoimmune diseases by allogeneic bone marrow transplantation remains a promising therapeutic avenue. However, more intensive studies on murine models are essential before application to a large number of human patients. In particular, the use of bone marrow transplantation to treat rheumatoid arthritis has been problematic. We have taken advantage of the SKG/Jcl mouse that develops a chronic T cell-mediated autoimmune disease that mimics rheumatoid arthritis which attempted to prevent the development of immunopathology in these mice by allogeneic bone marrow transplantation (BMT). In particular, we utilized our unique technology in which bone marrow cells (BMCs) of control C57BL/6J mice are directly injected into the bone marrow cavity in the tibia of SKG mice (intra-bone marrow [IBM]-BMT). As controls, SKG/Jcl mice were transplanted with whole BMCs from syngeneic SKG mice. Importantly, 12 months after IBM-BMT [B6→SKG] demonstrated no evidence of arthritis, whereas the control [SKG→SKG] mice demonstrated, the expected immunopathology of a rheumatoid arthritis-like condition. Further, hematolymphoid cells in [B6→SKG] mice were reconstituted by donor-derived cells and the percentages of Treg (Foxp3+/CD4+) cells, the percentages of receptor activator of nuclear factor-κB ligand (RANKL)+ cells on the CD4+T cells and the serum levels of tumor necrosis factor-α, interleukin-1 and interleukin-6 were normalized in the [B6→SKG] mice. These data suggest that IBM-BMT is a viable method of immunological manipulation that suppresses the severe joint destruction and bone absorption in SKG/Jcl mice and lends further credence to the use of this methodology in humans with intractable rheumatoid arthritis.