scholarly journals Evolutionary Origin of the Mammalian Hematopoietic System Found in a Colonial Chordate

2017 ◽  
Author(s):  
Benyamin Rosental ◽  
Mark Kowarsky ◽  
Jun Seita ◽  
Daniel M. Corey ◽  
Katherine J. Ishizuka ◽  
...  

SummaryHematopoiesis is an essential process that evolved in multicellular animals. At the heart of this process are hematopoietic stem cells (HSCs), which are multipotent, self-renewing and generate the entire repertoire of blood and immune cells throughout life. Here we studied the hematopoietic system of Botryllus schlosseri, a colonial tunicate that has vasculature, circulating blood cells, and interesting characteristics of stem cell biology and immunity. Self-recognition between genetically compatible B. schlosseri colonies leads to the formation of natural parabionts with shared circulation, whereas incompatible colonies reject each other. Using flow-cytometry, whole-transcriptome sequencing of defined cell populations, and diverse functional assays, we identified HSCs, progenitors, immune-effector cells, the HSC niche, and demonstrated that self-recognition inhibits cytotoxic reaction. Our study implies that the HSC and myeloid lineages emerged in a common ancestor of tunicates and vertebrates and suggests that hematopoietic bone marrow and the B. schlosseri endostyle niche evolved from the same origin.

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 19-20
Author(s):  
Joel Livingston ◽  
Maria Di-Mola ◽  
Jane Lowry ◽  
Nigel Ruse ◽  
Christoph Licht ◽  
...  

Introduction: Collection of hematopoietic stem cells (HSC) for HSC transplantation (HSCT) and immune effector cells (IEC) for cellular manufacturing (e.g. CAR T-cells) in children and young adults has unique challenges. In order to maintain adequate flow rates, central venous catheters (CVCs) are often utilized at pediatric institutions. However, CVCs are associated with additional procedural risks (anesthetic complications, thrombotic events) and resource utilization (anesthesia, interventional radiology). In adults collection through peripheral venous catheter (PVC) access has become increasingly standard practice, but has not yet been routinely used in pediatrics. The aim of this study was to determine if it is feasible and safe to utilize PVC access in a select population of older children and young adults to reduce the need for CVC insertions. Methods: All individuals undergoing HSC and IEC collections at our institution (patients and sibling donors) between February 2019 and July 2020 were considered for PVC collection if in the treating physicians assessment the patient would be able to tolerate the procedure (arms outstretched for up to 6 hours) and venous vessels were deemed suitable for an 18 gauge PVC. For blood return patients received either a second PVC (minimum 20 gauge) or if present their port/central line was used. For patients screened after April 2020, assessment by ultrasound was performed prior to the procedure to determine venous vessel size. All patients had topical analgesia applied prior to PVC insertion. All collections were carried out using the Continuous mononuclear cell collection (CMNC) protocol on an Optia apheresis device. Collection-related parameters such as demographics, collection efficiency (CE2), collection time, flow rate and product quality were collected. Results: A total of 27 patients were screened for PVC collection from February 2019 until July 2020. The median age was 16.1 years (range 9.7-27.3) and median weight 67.7 kg (range 29.4-115.4). Ten out of 27 patients had ultrasound screening prior to collection on which one patient was deemed not suitable for PVC collection due to a venous anomaly. Cells were collected successfully by PVC in 24/26 (92%) of patients, 2/26 (8%) patients required CVC insertion after an unsuccessful PVC attempt due to inability to maintain an adequate flow rate. Average PVC collection flow rate was 50.3 ml/min (range 34-91) with median collection time of 244.5 min (range 87-397 min). Median collection efficiency (CE2) for CD3 cells was 59% (range 21-88), for CD34 cells 55% (range 28-69), product cell viability was 100%. Collection and product parameters were comparable to institutional collections performed utilizing CVCs. PVC collections were well tolerated, no patient had to stop the procedure due to discomfort or patient safety concerns. Conclusion: PVC collection of IEC and HSC is feasible and safe in older children and young adults. Ultrasound screening prior to PVC insertion and collection attempt can reduce failure rate and streamline the collection process. Disclosures Krueger: Novartis: Consultancy, Other: Travel support; no honoraria, Speakers Bureau; Kite, a Gilead Company: Other: Travel support; Atara: Other: Travel support.


Blood ◽  
2020 ◽  
Author(s):  
Siddhartha Jaiswal

Clonal expansions of mutated hematopoietic cells, termed clonal hematopoiesis, are common in aging humans. One expected consequence of mutation-associated clonal hematopoiesis is an increased risk of hematologic cancers, which has now been shown in several studies. However, the hematopoietic stem cells that acquire these somatic mutations also give rise to mutated immune effector cells, such as monocytes, granulocytes, and lymphocytes. These effector cells can potentially influence many disease states, especially those with a chronic inflammatory component. Indeed, several studies have now shown that clonal hematopoiesis associates with increased risk of atherosclerotic cardiovascular disease. Emerging data also associate clonal hematopoiesis to other non-hematologic diseases. Here, we will review recent studies linking clonal hematopoiesis to altered immune function, inflammation, and non-malignant diseases of aging.


2021 ◽  
Vol 79 (3) ◽  
pp. 961-968
Author(s):  
Wolfgang J. Streit ◽  
Habibeh Khoshbouei ◽  
Ingo Bechmann

Microglia constitute the brain’s immune system and their involvement in Alzheimer’s disease has been discussed. Commonly, and in line with the amyloid/neuroinflammation cascade hypothesis, microglia have been portrayed as potentially dangerous immune effector cells thought to be overactivated by amyloid and producing neurotoxic inflammatory mediators that lead to neurofibrillary degeneration. We disagree with this theory and offer as an alternative the microglial dysfunction theory stating that microglia become impaired in their normally neuroprotective roles because of aging, i.e., they become senescent and aging neurons degenerate because they lack the needed microglial support for their survival. Thus, while the amyloid cascade theory relies primarily on genetic data, the dysfunction theory incorporates aging as a critical etiological factor. Aging is the greatest risk factor for the sporadic (late-onset) and most common form of Alzheimer’s disease, where fully penetrant genetic mutations are absent. In this review, we lay out and discuss the human evidence that supports senescent microglial dysfunction and conflicts with the amyloid/neuroinflammation idea.


Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 570-578
Author(s):  
Rafet Basar ◽  
May Daher ◽  
Katayoun Rezvani

Abstract T cells engineered with chimeric antigen receptors (CARs) have revolutionized the field of cell therapy and changed the paradigm of treatment for many patients with relapsed or refractory B-cell malignancies. Despite this progress, there are limitations to CAR-T cell therapy in both the autologous and allogeneic settings, including practical, logistical, and toxicity issues. Given these concerns, there is a rapidly growing interest in natural killer cells as alternative vehicles for CAR engineering, given their unique biological features and their established safety profile in the allogeneic setting. Other immune effector cells, such as invariant natural killer T cells, γδ T cells, and macrophages, are attracting interest as well and eventually may be added to the repertoire of engineered cell therapies against cancer. The pace of these developments will undoubtedly benefit from multiple innovative technologies, such as the CRISPR-Cas gene editing system, which offers great potential to enhance the natural ability of immune effector cells to eliminate refractory cancers.


2010 ◽  
Vol 113 (2) ◽  
pp. 280-285 ◽  
Author(s):  
James Miller ◽  
Guenter Eisele ◽  
Ghazaleh Tabatabai ◽  
Steffen Aulwurm ◽  
Gabriele von Kürthy ◽  
...  

Object Given the overall poor outcome with current treatment strategies in malignant gliomas, immunotherapy has been considered a promising experimental approach to glioblastoma for more than 2 decades. A cell surface molecule, CD70, may induce potent antitumor immune responses via activation of the costimulatory receptor CD27 expressed on immune effector cells. There is evidence that a soluble form of CD70 (sCD70) may exhibit biological activity, too. A soluble costimulatory ligand is attractive because it may facilitate immune activation and may achieve a superior tissue distribution. Methods To test the antiglioma effect of sCD70, the authors genetically modified SMA-560 mouse glioma cells to secrete the extracellular domain of CD70. They assessed the immunogenicity of the transfected cells in cocultures with immune effector cells by the determination of immune cell proliferation and the release of interferon-γ. Syngeneic VM/Dk mice were implanted orthotopically with control or sCD70-releasing glioma cells to determine a survival benefit mediated by sCD70. Depletion studies were performed to identify the cellular mediators of prolonged survival of sCD70-releasing glioma-bearing mice. Results The authors found that ectopic expression of sCD70 enhanced the proliferation and interferon-γ release of syngeneic splenocytes in vitro. More importantly, sCD70 prolonged the survival of syngeneic VM/Dk mice bearing intracranial SMA-560 gliomas. The survival rate at 60 days increased from 5 to 45%. Antibody-mediated depletion of CD8-positive T cells abrogates the survival advantage conferred by sCD70. Conclusions These data suggest that sCD70 is a potent stimulator of antiglioma immune responses that depend critically on CD8-positive T cells. Soluble CD70 could be a powerful adjuvant for future immunotherapy trials for glioblastoma.


Author(s):  
John C. Morris ◽  
Thomas A. Waldmann

Over the past decade, monoclonal antibodies have dramatically impacted the treatment of haematological malignancies, as evidenced by the effect of rituximab on the response rate and survival of patients with follicular and diffuse large B cell non-Hodgkin's lymphoma. Currently, only two monoclonal antibodies – the anti-CD33 immunotoxin gemtuzumab ozogamicin and the CD52-directed antibody alemtuzumab – are approved for treatment of relapsed acute myeloid leukaemia in older patients and B cell chronic lymphocytic leukaemia, respectively. Although not approved for such treatment, alemtuzumab is also active against T cell prolymphocytic leukaemia, cutaneous T cell lymphoma and Sézary syndrome, and adult T cell leukaemia and lymphoma. In addition, rituximab has demonstrated activity against B cell chronic lymphocytic and hairy cell leukaemia. Monoclonal antibodies targeting CD4, CD19, CD20, CD22, CD23, CD25, CD45, CD66 and CD122 are now being studied in the clinic for the treatment of leukaemia. Here, we discuss how these new antibodies have been engineered to reduce immunogenicity and improve antibody targeting and binding. Improved interactions with Fc receptors on immune effector cells can enhance destruction of target cells through antibody-dependent cellular cytotoxicity and complement-mediated cell lysis. The antibodies can also be armed with cellular toxins or radionuclides to enhance the destruction of leukaemia cells.


2021 ◽  
Vol 101 ◽  
pp. 108220
Author(s):  
Markus Bo Schoenberg ◽  
Xiaokang Li ◽  
Xinyu Li ◽  
Yongsheng Han ◽  
Nikolaus Börner ◽  
...  

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