Publications by authors named "John D M Campbell"

Introduction: Acute liver failure (ALF) has no effective treatment other than liver transplantation and is commonly caused by paracetamol overdose. New treatments are needed to treat and prevent ALF. Alternatively-activated macrophages (AAMs) can promote resolution of liver necrosis and stimulate hepatocyte proliferation.

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Chemokines regulate leukocyte navigation to inflamed sites and specific tissue locales and may therefore be useful for ensuring accurate homing of cell therapeutic products. We, and others, have shown that atypical chemokine receptor 2 (ACKR2)-deficient mice (ACKR2-/-) are protected from metastasis development in cell line and spontaneous mouse models. We have shown that this relates to enhanced CCR2 expression on ACKR2-/- natural killer cells, allowing them to home more effectively to CCR2 ligand-expressing metastatic deposits.

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Adoptive immunotherapy with Epstein-Barr virus (EBV)-specific T cells is an effective treatment for relapsed or refractory EBV-induced post-transplant lymphoproliferative disorders (PTLD) with overall survival rates of up to 69%. EBV-specific T cells have been conventionally made by repeated stimulation with EBV-transformed lymphoblastoid cell lines (LCL), which act as antigen-presenting cells. However, this process is expensive, takes many months, and has practical risks associated with live virus.

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The manufacturing of clinical cellular therapies is a complex process frequently requiring manipulation of cells, exchange of buffers and volume reduction. Current manufacturing processes rely on either low throughput open centrifugation-based devices, or expensive closed-process alternatives. Inertial focusing (IF) microfluidic devices offer the potential for high-throughput, inexpensive equipment which can be integrated into a closed system, but to date no IF devices have been approved for use in cell therapy manufacturing, and there is limited evidence for the effects that IF processing has on human cells.

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Article Synopsis
  • Demyelination in the central nervous system can lead to serious conditions like paralysis, prompting research into cell therapies for recovery, especially using mesenchymal stromal cells (MSCs).
  • Human olfactory mucosa-derived MSCs (hOM-MSCs) show greater potential for promoting myelination compared to bone marrow-derived MSCs, but previous methods of development were not compliant with good manufacturing practices (GMP).
  • New methods for isolating and expanding hOM-MSCs without harmful techniques have been created, making them compliant with GMP; however, while they are promising in lab tests, they do not significantly improve outcomes in a model of demyelinating disease, indicating the need for more research before clinical application.
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Mesenchymal stromal cells (MSC) show promise as cellular therapeutics. Psoriasis is a chronic inflammatory disease affecting the skin and the joints. Injury, trauma, infection and medications can trigger psoriasis by disrupting epidermal keratinocyte proliferation and differentiation, which activates the innate immune system.

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Article Synopsis
  • * Researchers have isolated human biliary epithelial cells (hBECs) from livers not used for transplants to explore new treatment options.
  • * In mouse models, hBECs showed promise by improving biliary structure and function, suggesting they could be a viable alternative to liver transplants for treating biliary diseases.
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Introduction: Liver cirrhosis is a growing global healthcare challenge. Cirrhosis is characterised by severe liver fibrosis, organ dysfunction and complications related to portal hypertension. There are no licensed antifibrotic or proregenerative medicines and liver transplantation is a scarce resource.

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Adoptive immunotherapy using Epstein-Barr Virus (EBV)-specific T cells is a potentially curative treatment for patients with EBV-related malignancies where other clinical options have proved ineffective. We describe improved good manufacturing practice (GMP)-compliant culture and analysis processes for conventional lymphoblastoid cell line (LCL)-driven EBV-specific T cell manufacture, and describe an improved phenotyping approach for analysing T cell products. We optimized the current LCL-mediated clinical manufacture of EBV-specific T cells to establish an improved process using xenoprotein-free GMP-compliant reagents throughout, and compared resulting products with our previous banked T cell clinical therapy.

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Multipotent mesenchymal stromal cells (MSCs) are promising cellular therapeutics for the treatment of inflammatory and degenerative disorders due to their anti-inflammatory, immunomodulatory and regenerative potentials. MSCs can be sourced from a variety of tissues within the body, but bone marrow is the most frequently used starting material for clinical use. The chemokine family contains many regulators of inflammation, cellular function and cellular migration-all critical factors in understanding the potential potency of a novel cellular therapeutic.

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COVID-19 disease caused by the SARS-CoV-2 virus is characterized by dysregulation of effector T cells and accumulation of exhausted T cells. T cell responses to viruses can be corrected by adoptive cellular therapy using donor-derived virus-specific T cells. One approach is the establishment of banks of HLA-typed virus-specific T cells for rapid deployment to patients.

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More than seven months into the coronavirus disease -19 (COVID-19) pandemic, infection from the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to over 21.2 million cases and resulted in over 760,000 deaths worldwide so far. As a result, COVID-19 has changed all our lives as we battle to curtail the spread of the infection in the absence of specific therapies against coronaviruses and in anticipation of a proven safe and efficacious vaccine.

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Background Aims: Mesenchymal stromal cells (MSCs) isolated from various tissues are under investigation as cellular therapeutics in a wide range of diseases. It is appreciated that the basic biological functions of MSCs vary depending on tissue source. However, in-depth comparative analyses between MSCs isolated from different tissue sources under Good Manufacturing Practice (GMP) conditions are lacking.

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Islet transplantation is an efficacious therapy for type 1 diabetes; however, islets from multiple donor pancreata are required, and a gradual attrition in transplant function is seen. Here, we manufactured human umbilical cord perivascular mesenchymal stromal cells (HUCPVCs) to Good Manufacturing Practice (GMP) standards. HUCPVCs showed a stable phenotype while undergoing rapid ex vivo expansion at passage 2 (p2) to passage 4 (p4) and produced proregenerative factors, strongly suppressing T cell responses in the resting state and in response to inflammation.

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Therapies to reduce liver fibrosis and stimulate organ regeneration are urgently needed. We conducted a first-in-human, phase 1 dose-escalation trial of autologous macrophage therapy in nine adults with cirrhosis and a Model for End-Stage Liver Disease (MELD) score of 10-16 (ISRCTN 10368050). Groups of three participants received a single peripheral infusion of 10, 10 or up to 10 cells.

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Immunization of patients with autologous, matured dendritic cell (DC) preparations, in order to prime antitumor T-cell responses, is the focus of intense research. Despite progress and approval of clinical approaches, significant enhancement of these personalized immunotherapies is urgently needed to improve efficacy. We show that immunotherapeutic murine and human DC, generated in the presence of the antimicrobial host defense peptide LL-37, have dramatically enhanced expansion and differentiation of cells with key features of the critical CD103/CD141 DC subsets, including enhanced cross-presentation and co-stimulatory capacity, and upregulation of CCR7 with improved migratory capacity.

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Article Synopsis
  • Dendritic cells (DC) are key immune cells that connect innate and adaptive immune responses, and their development is influenced by vitamin D, which is linked to autoimmune diseases.
  • The study explored how vitamin D affects mouse-derived dendritic cells (CD11c BMDC) by analyzing gene expression, finding that vitamin D increases CD31 expression, which hampers DC's ability to activate T cells.
  • Higher CD31 levels in DC lead to shorter interaction times with CD4 T cells, reducing the effectiveness of T cell priming, a result confirmed in both mouse and human DC studies.
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Limbal stem cell deficiency (LSCD) is a disease resulting from the loss or dysfunction of epithelial stem cells, which seriously impairs sight. Autologous limbal stem cell transplantation is effective in unilateral or partial bilateral disease but not applicable in total bilateral disease. An allogeneic source of transplantable cells for use in total bilateral disease can be obtained from culture of donated cadaveric corneal tissue.

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Cellular therapeutics are a fast-growing, highly innovative area of medicine. This field encompasses well-established immune therapies for infection and cancer, as well as newer cell therapies aimed at regenerating diseased tissue. Flow cytometry is arguably the most important tool in the development of advanced cellular therapeutics and plays a role in many aspects of manufacturing.

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Blood transfusion is a mainstay of modern medical practice. In many parts of the world the use of this life-saving therapy is hampered by issues of supply and the potential for transfusion transmitted infections. Accordingly, there are many studies seeking to find an alternative to donated red blood cells (RBCs) for transfusion, including large-scale production from adult and pluripotent stem cells, or erythroid cell lines.

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Background Aims: Autologous macrophage therapy represents a potentially significant therapeutic advance for the treatment of severe progressive liver cirrhosis. Administration of macrophages has been shown to reduce inflammation and drive fibrotic scar breakdown and tissue repair in relevant models. This therapeutic approach is being assessed for safety and feasibility in a first-in-human trial (MAcrophages Therapy for liver CirrHosis [MATCH] trial).

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The promise of human pluripotent stem cells to serve as a scalable and renewable starting material for "off the shelf" therapeutic cell products to repair or replace cells and tissues damaged by disease or injury is unparalleled. Whether originating from embryos or the genetic manipulation of adult tissue-derived cells, this prospective impact dictates a comprehensive yet practicable standard of quality assured characterization, blending existing and bespoke standards and considerations. Here, we provide a guide to qualifying the suitability of this resource for human clinical application.

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Mesenchymal stromal cells (MSCs), multipotent cells present in tissues throughout the body, can reconstitute adipogenic, osteogenic and chondrogenic tissues, but are also of great interest as mediators of immune modulation and suppression. MSCs are able to improve transplant engraftment, treat graft versus host disease and suppress T cell responses and therefore have great potential as therapeutic agents. Their immune modulatory capacity is mediated through both cell-to-cell contact and cytokine secretion, but it is becoming clear that extracellular vesicles (EV) produced by MSC also possess immunomodulatory properties.

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