Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel

Mesenchymal stem cells (MSCs) are a heterogeneous subset of stromal stem cells that can be isolated from many adult tissues. They can differentiate into cells of the mesodermal lineage, such as adipocytes, osteocytes and chondrocytes, as well as cells of other embryonic lineages. MSCs can interact with cells of both the innate and adaptive immune systems, leading to the modulation of several effector functions. After in vivo administration, MSCs induce peripheral tolerance and migrate to injured tissues, where they can inhibit the release of pro-inflammatory cytokines and promote the survival of damaged cells. This Review discusses the targets and mechanisms of MSC-mediated immunomodulation and the possible translation of MSCs to new therapeutic approaches.

Mesenchymal stem cells in health and disease

Natural killer (NK) cells are effector lymphocytes of the innate immune system that control several types of tumors and microbial infections by limiting their spread and subsequent tissue damage. Recent research highlights the fact that NK cells are also regulatory cells engaged in reciprocal interactions with dendritic cells, macrophages, T cells and endothelial cells. NK cells can thus limit or exacerbate immune responses. Although NK cells might appear to be redundant in several conditions of immune challenge in humans, NK cell manipulation seems to hold promise in efforts to improve hematopoietic and solid organ transplantation, promote antitumor immunotherapy and control inflammatory and autoimmune disorders.

Functions of natural killer cells

BACKGROUND Preclinical studies suggest that Reed–Sternberg cells exploit the programmed death 1 (PD-1) pathway to evade immune detection. In classic Hodgkin’s lymphoma, alterations in chromosome 9p24.1 increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and promote their induction through Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling. We hypothesized that nivolumab, a PD-1–blocking antibody, could inhibit tumor immune evasion in patients with relapsed or refractory Hodgkin’s lymphoma. METHODS In this ongoing study, 23 patients with relapsed or refractory Hodgkin’s lymphoma that had already been heavily treated received nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks until they had a complete response, tumor progression, or excessive toxic effects. Study objectives were measurement of safety and efficacy and assessment of the PDL1 and PDL2 (also called CD274 and PDCD1LG2, respectively) loci and PD-L1 and PD-L2 protein expression. RESULTS Of the 23 study patients, 78% were enrolled in the study after a relapse following autologous stem-cell transplantation and 78% after a relapse following the receipt of brentuximab vedotin. Drug-related adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively. An objective response was reported in 20 patients (87%), including 17% with a complete response and 70% with a partial response; the remaining 3 patients (13%) had stable disease. The rate of progression-free survival at 24 weeks was 86%; 11 patients were continuing to participate in the study. Reasons for discontinuation included stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 patients). Analyses of pretreatment tumor specimens from 10 patients revealed copy-number gains in PDL1 and PDL2 and increased expression of these ligands. Reed–Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicative of active JAK-STAT signaling. CONCLUSIONS Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin’s lymphoma. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT01592370.)

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PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin's Lymphoma

Bone marrow stromal cells exhibit multiple traits of a stem cell population. They can be greatly expanded in vitro and induced to differentiate into multiple mesenchymal cell types. However, differentiation to non-mesenchymal fates has not been demonstrated. Here, adult rat stromal cells were expanded as undifferentiated cells in culture for more than 20 passages, indicating their proliferative capacity. A simple treatment protocol induced the stromal cells to exhibit a neuronal phenotype, expressing neuron-specific enolase, NeuN, neurofilament-M, and tau. With an optimal differentiation protocol, almost 80% of the cells expressed NSE and NF-M. The refractile cell bodies extended long processes terminating in typical growth cones and filopodia. The differentiating cells expressed nestin, characteristic of neuronal precursor stem cells, at 5 hr, but the trait was undetectable at 6 days. In contrast, expression of trkA, the nerve growth factor receptor, persisted from 5 hr through 6 days. Clonal cell lines, established from single cells, proliferated, yielding both undifferentiated and neuronal cells. Human marrow stromal cells subjected to this protocol also differentiated into neurons. Consequently, adult marrow stromal cells can be induced to overcome their mesenchymal commitment and may constitute an abundant and accessible cellular reservoir for the treatment of a variety of neurologic diseases.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/1097-4547%2820000815%2961%3A4%3C364%3A%3AAID-JNR2%3E3.0.CO%3B2-C

Adult rat and human bone marrow stromal cells differentiate into neurons

Primary immune deficiencies (PID) are rare diseases, but cause significant morbidity and typically lead to early mortality. The first patient successfully treated by hematopoietic stem cell transplantation (HSCT) was an infant with severe combined immune deficiency (SCID) who received bone marrow from his human leukocyte antigen (HLA)-identical sister in 1968 (Gatti, 1968(. Since then, HSCT has become the standard of care for treatment of children with severe PID. Transplantation has the capacity to cure the majority of patients with PID, and although a stem cell graft from an unaffected matched related donor (MRD) is preferred, that option exists for only a minority of patients, leaving alternative donor stem cell sources as the choice for the majority of patients. Mismatched related donor, matched unrelated donor, and umbilical cord blood (UCB) have all been used, and outcomes vary by disease and stem cell source. The optimal stem cell source for PID patients with no available MRD is not clear (Dvorak, 2008). UCB is an attractive source for many reasons including rapid access to the donor unit allowing for (1) expedient transplant in patients at very high risk for life-threatening infection, (2) a lower risk of latent viral transmission in immunologically naive recipients, (3) a lower risk of Graft-versus-Host Disease (GvHD) despite HLA mismatch, (4) a higher likelihood of finding an acceptable HLA-matched unit in patients who are often of ethnic minorities and/or the product of consanguinity, and (5) at least hypothetically the potential that UCB stem cells may have greater self-renewing capacity than those obtained from an adult donor (Gennery, 2007). Published studies examining the use of UCB in PID are scarce, but its use is becoming more common. PID encompasses a variety of diseases all of which are extremely rare. In this chapter, we focus on the more common disorders in this group treated with HSCT, specifically SCID and Wiskott–Aldrich syndrome.

Immunodeficiencies and Metabolic Diseases

Thoracolumbar kyphosis in MPS I: A natural history study and an international consensus procedure for the development of a clinical practice guideline

140. Combined intrathecal iduronidase, intravenous iduronidase and transplantation as therapy for Hurler syndrome

X-linked adrenoleukodystrophy (X-ALD) is an inherited, neurodegenerative rare disease that can result in devastating symptoms of blindness, gait disturbances and spastic quadriparesis due to progressive demyelination. Typically, the disease progresses rapidly, causing death within the first decade of life. With limited treatments available, efforts to determine an effective therapy that can alter disease progression or mitigate symptoms have been undertaken for many years, particularly through drug repurposing. Repurposing has generally been guided through clinical experience and small trials. At this time, none of the drug candidates have been approved for use, which may be due, in part, to the lack of pharmacokinetic/pharmacodynamic information on the repurposed medications in the target patient population. Greater consideration for the disease pathophysiology, drug pharmacology and potential drug-target interactions, specifically at the site of action, would improve drug repurposing and facilitate drug development. Incorporating advanced translational and clinical pharmacological approaches in preclinical studies and early-stage clinical trials will improve the success of repurposed drugs for X-ALD as well as other rare diseases.

Paul J. Orchard

Papers

Immunodeficiencies and Metabolic Diseases

Thoracolumbar kyphosis in MPS I: A natural history study and an international consensus procedure for the development of a clinical practice guideline

140. Combined intrathecal iduronidase, intravenous iduronidase and transplantation as therapy for Hurler syndrome

Translational and clinical pharmacology considerations in drug repurposing for X-linked adrenoleukodystrophy-A rare peroxisomal disorder.

205Coronary artery disease in non-Hurler mucopolysaccharidosis