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Busulfan as a Myelosuppressive Agent for Generating Stable High-level Bone Marrow Chimerism in Mice

Bone marrow transplantation (BMT) is often used to replace the bone marrow (BM) compartment of recipient mice with BM cells expressing a distinct ...

Simon Fraser University

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation of the synovial membranes and progressive joint destruction. Increased understanding of the immunopathology of RA has resulted in the development of new therapies to manage the disease, including several infusion-based therapies. Abatacept, a selective costimulation modulator, has been shown to be effective in clinical trials. Abatacept has a mechanism of action that is different from any other biologic RA therapy, and it provides a valuable alternative for RA patients. This article provides practical guidance for nurses to ensure safe administration and to maximize patient outcomes with abatacept.

A nursing guide to infusion therapy with abatacept for the treatment of rheumatoid arthritis.

A process evaluation was conducted to evaluate a newly established active influenza surveillance program that utilized 6 sentinel hospitals to collect epidemiologic information for influenza-like illness admissions. Objectives were to determine whether the new system was implemented successfully and met surveillance objectives, including determination of the proportion of patients with 2009 H1N1 influenza, extent of disease severity, and identifying high-risk groups.

A process evaluation of an active surveillance system for hospitalized 2009-2010 H1N1 influenza cases.

To better understand the severity of 2009 H1N1 influenza disease, enhanced surveillance of patients hospitalized with influenza was conducted during the 2009-2010 influenza season in New York State through existing Emerging Infections Program surveillance and a newly established sentinel hospital surveillance program. The 2 surveillance systems were compared to determine consistency across surveillance modalities and reveal the strengths and weaknesses of each to accomplish comprehensive influenza surveillance.

Two distinct surveillance methods to track hospitalized influenza patients in New York State during the 2009-2010 influenza season.

Sharing knowledge to advance healthcare policies in Europe for people living with dementia and their carers: the ALCOVE project.

Myeloablative preconditioning using irradiation is the most commonly used technique to generate rodents having chimeric bone marrow, employed for the study of bone marrow-derived cell accumulation in the healthy and diseased central nervous system. However, irradiation has been shown to alter the blood-brain barrier, potentially creating confounding artefacts. To better study the potential of bone marrow-derived cells to function as treatment vehicles for neurodegenerative diseases alternative preconditioning regimens must be developed. We treated transgenic mice that over-express human mutant superoxide dismutase 1, a model of amyotrophic lateral sclerosis, with busulfan to determine whether this commonly used chemotherapeutic leads to stable chimerism and promotes the entry of bone marrow-derived cells into spinal cord. Intraperitoneal treatment with busulfan at 60 mg/kg or 80 mg/kg followed by intravenous injection of green fluorescent protein-expressing bone marrow resulted in sustained levels of chimerism (~80%). Bone marrow-derived cells accumulated in the lumbar spinal cord of diseased mice at advanced stages of pathology at both doses, with limited numbers of bone marrow derived cells observed in the spinal cords of similarly treated, age-matched controls; the majority of bone marrow-derived cells in spinal cord immunolabelled for macrophage antigens. Comparatively, significantly greater numbers of bone marrow-derived cells were observed in lumbar spinal cord following irradiative myeloablation. These results demonstrate bone marrow-derived cell accumulation in diseased spinal cord is possible without irradiative preconditioning.

Myelosuppressive conditioning using busulfan enables bone marrow cell accumulation in the spinal cord of a mouse model of amyotrophic lateral sclerosis.

The treat-to-target (T2T) approach to the care of patients with rheumatoid arthritis involves using validated metrics to measure disease activity, frequent follow-up visits for patients with moderate to high disease activity, and escalation of therapy when patients have inadequate therapeutic response as assessed by standard disease activity scores. The study described is a newly launched cluster-randomized behavioral intervention to assess the feasibility and effectiveness of the T2T approach in US rheumatology practices. It is designed to identify patient and provider barriers to implementing T2T management. This initial paper focuses on the novel study design and methods created to provide these insights.

The rheumatoid arthritis treat-to-target trial: a cluster randomized trial within the Corrona rheumatology network.

Previous work has suggested that bone marrow (BM)-derived cells (BMDCs) accumulate within the CNS and could potentially associate with β-amyloid plaques in Alzheimer's disease (AD). To explore the accumulation of BMDCs in murine AD, we transplanted green fluorescent protein (GFP)-labeled BM cells into triple transgenic (3×Tg) and wild-type (wt) mice using non-irradiative myelosuppresive conditioning with busulfan (BU). We find that BU (80mg/kg) is sufficient to obtain adequate chimerism (>85%) in wt mice. In order to obtain appreciable non-irradiative chimerism in the 3×Tg mice (>80%), anti-asialo ganglio-N-tetraosylceramide (α-ASGM-1) antibody was also used to reduce natural killer cell function and thereby abrogate the hybrid resistance of the 3×Tg mouse strain. Using BU conditioning and α-ASGM-1 together, we observed sustained BM chimerism and BMDC accumulation within the CNS of the 3×Tg and wt mice. In cortex and hippocampus, BMDC accumulation was perivascular in distribution and similar between 3×Tg and wt mice, with no clear association between BMDCs and AD plaques. We conclude that non-irradiative BM chimerism can be achieved with BU in 3×Tg mice, but requires α-ASGM-1 (or similar appropriate NK-cell depletion). Use of this chimerism protocol permits BMDCs accumulation in the CNS of mixed strain recipient mice although BMDCs appear to be largely perivascular within cortex and hippocampus.

Christine Barr

Department of Biomedical Physiology and Kinesiology

Simon Fraser University

Busulfan as a Myelosuppressive Agent for Generating Stable High-level Bone Marrow Chimerism in Mice