Successful granulocyte-macrophage colony-stimulating factor inhalation therapy for recurrent autoimmune pulmonary alveolar proteinosis after lung transplantation: A case report.

Sargramostim, a recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation therapy, was recently approved for pharmaceutical use in Japan and shows promise as a treatment for autoimmune pulmonary alveolar proteinosis (APAP). For APAP patients with severe respiratory failure due to advanced lung fibrosis, lung transplantation is also a treatment option; however, APAP may recur after the procedure. Here, we report a case of successful sargramostim inhalation therapy for post-transplant APAP relapse in a patient who underwent living lung transplantation owing to severe fibrosis.

Blood DNA virome associates with autoimmune diseases and COVID-19.

Aberrant immune responses to viral pathogens contribute to pathogenesis, but our understanding of pathological immune responses caused by viruses within the human virome, especially at a population scale, remains limited. We analyzed whole-genome sequencing datasets of 6,321 Japanese individuals, including patients with autoimmune diseases (psoriasis vulgaris, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), pulmonary alveolar proteinosis (PAP) or multiple sclerosis) and coronavirus disease 2019 (COVID-19), or healthy controls. We systematically quantified two constituents of the blood DNA virome, endogenous HHV-6 (eHHV-6) and anellovirus.

Repeated inhalation of GM-CSF by nonhuman primates induces bronchus-associated lymphoid tissue along the lower respiratory tract.

Background: Repeated inhalation of granulocyte-macrophage colony-stimulating factor (GM-CSF) was recently approved in Japan as a treatment for autoimmune pulmonary alveolar proteinosis. However, the detailed physiological and pathological effects of repeated inhalation in the long term, especially at increasing doses, remain unclear.

Methods: In this chronic safety study, we administered 24 cynomolgus monkeys (Macaca fascicularis) aged 2-3 years with aerosolized sargramostim (a yeast-derived recombinant human GM-CSF [rhGM-CSF]) biweekly for 26 weeks across four dosing groups (0, 5, 100, and 500 µg/kg/day).

Characterization of the cellular heterogeneity and bone regenerative potential of cultured human periosteal cells.

Introduction: Cell-based bone regenerative therapy exhibits considerable potential in the treatment of bone defects caused by trauma, disease, and congenital anomalies. The periosteum, a fibrous membrane covering the outer surface of bone, plays a crucial role in bone formation and regeneration by sourcing osteoprogenitor cells. The remarkable osteogenic potential of periosteal cells (PCs) has led to the effective clinical implementation of PC-based regenerative therapies and tissue engineering.

Quantitative Evaluation of Changes in Three-Dimensional CT Density Distributions in Pulmonary Alveolar Proteinosis after GM-CSF Inhalation.

Background: A previous clinical trial for autoimmune pulmonary alveolar proteinosis (APAP) demonstrated that granulocyte-macrophage colony-stimulating factor (GM-CSF) inhalation reduced the mean density of the lung field on computed tomography (CT) across 18 axial slice planes at a two-dimensional level. In contrast, in this study, we challenged three-dimensional analysis for changes in CT density distribution using the same datasets.

Methods: As a sub-study of the trial, CT data of 31 and 27 patients who received GM-CSF and placebo, respectively, were analyzed.

Non-destructive, spectrophotometric analysis of the thickness of the cell-multilayered periosteal sheet.

Background: Autologous tissue-engineered periosteal sheets, which have been clinically applied for periodontal regeneration, sinus lift, and alveolar ridge augmentation, are enriched with osteoblast precursor cells and the abundant deposition of collagen type I in the extracellular spaces. Their quality is inspected prior to clinical use; however, most criteria cannot be evaluated without sacrificing samples. To reduce such losses, we developed a non-destructive optical method that can quantitatively evaluate the thickness of the periosteal sheet.

Fluorometric Quantification of Human Platelet Polyphosphate Using 4',6-Diamidine-2-phenylindole Dihydrochloride: Applications in the Japanese Population.

Polyphosphate (polyP), a biopolymer of inorganic phosphate, is widely distributed in living organisms. In platelets, polyP is released upon activation and plays important roles in coagulation and tissue regeneration. However, the lack of a specific quantification method has delayed the in-depth study of polyP.

Genetic determinants of risk in autoimmune pulmonary alveolar proteinosis.

Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6-7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry.

Secondary Pulmonary Alveolar Proteinosis Associated with Primary Myelofibrosis and Ruxolitinib Treatment: An Autopsy Case.

Pulmonary alveolar proteinosis (PAP) is an uncommon lung disorder characterized by the excessive accumulation of surfactant-derived lipoproteins in the pulmonary alveoli and terminal bronchiole. Secondary PAP associated with primary myelofibrosis (PMF) is extremely rare, and to our knowledge, no autopsy case has been reported. We herein report an autopsy case of secondary PAP occurring in a patient with PMF who was treated with the Janus kinase 1/2 inhibitor ruxolitinib.

A Comparative Study of The Effects of Anticoagulants on Pure Platelet-Rich Plasma Quality and Potency.

It is generally accepted that citrate or the A-form of acid-citrate-dextrose (ACD-A) are suitable for preparing platelet-rich plasma (PRP) for regenerative therapy. However, this is based on evidence from blood transfusions and not from regenerative medicine. Thus, we examined the effects of anticoagulants, such as ACD-A, ethylenediaminetetraacetic acid (EDTA), and heparin, on the regenerative quality of PRP to address this gap.

Improvement of native pulmonary alveolar proteinosis after contralateral single living-donor lobar lung transplantation: A case report.

PAP is a rare disease characterized by the accumulation of surfactant materials in the alveolar spaces due to the imbalance of surfactant homeostasis (production and clearance). We herein report a case of an 8-year-old girl who developed PAP after BMT from her mother for the treatment of DBA. The anemia was improved by BMT; however, respiratory dysfunction due to graft-versus-host disease gradually progressed.

Secondary Pulmonary Alveolar Proteinosis Following Treatment with Azacitidine for Myelodysplastic Syndrome.

Secondary pulmonary alveolar proteinosis (sPAP) is a complication of myelodysplastic syndrome (MDS). A 60-year-old woman was diagnosed with MDS with excess blasts-1. Fifty-four months after the initial diagnosis, treatment with azacitidine was initiated.

Platelet Adhesion on Commercially Pure Titanium Plates in Vitro II. Immunofluorescence Visualization of PDGF-B, TGFβ1, and PPARγ Released from Activated Adherent Platelets.

Recent progress in the industrial development of dental implants has improved their surface bio-affinity, while clinical implantologists attempt to improve it through coating with various compounds, including platelet-rich plasma (PRP) in clinical settings. However, it is poorly understood how PRP acts on titanium surfaces. To validate this surface modification method and demonstrate how platelet-derived soluble biomolecules released from the activated adherent platelets act on plain, commercially pure-titanium (-Ti) plates, we evaluated the distribution of biomolecules by immunofluorescence.

Does maternal autoantibody that transfer to newborn cause disease?

Autoimmune pulmonary alveolar proteinosis (aPAP) is associated with excess amount of granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody (GMAb) in the lung and blood. We experienced a female case with severe aPAP who could continue her pregnancy under home oxygen therapy and delivered a newborn by caesarean section. Maternal serum GMAb remained high level for up to one year after the delivery, although aPAP entered remission by whole lung lavage.

Striking Differences in Platelet Distribution between Advanced-Platelet-Rich Fibrin and Concentrated Growth Factors: Effects of Silica-Containing Plastic Tubes.

Compared with platelet-rich plasma, the preparation of platelet-rich fibrin (PRF) is simple and has not been overly modified. However, it was recently demonstrated that centrifugation conditions influence the composition of PRF and that silica microparticles from silica-coated plastic tubes can enter the PRF matrix. These factors may also modify platelet distribution.

Inhaled GM-CSF for Pulmonary Alveolar Proteinosis.

Background: Pulmonary alveolar proteinosis is a disease characterized by abnormal accumulation of surfactant in the alveoli. Most cases are autoimmune and are associated with an autoantibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) that prevents clearing of pulmonary surfactant by alveolar macrophages. An open-label, phase 2 study showed some therapeutic efficacy of inhaled recombinant human GM-CSF in patients with severe pulmonary alveolar proteinosis; however, the efficacy in patients with mild-to-moderate disease remains unclear.

Distribution of platelets, transforming growth factor-β1, platelet-derived growth factor-BB, vascular endothelial growth factor and matrix metalloprotease-9 in advanced platelet-rich fibrin and concentrated growth factor matrices.

Aim: Platelet-rich fibrin (PRF) matrices are compared with regard to their ability to retain and release growth factors. Although this ability is thought to influence regenerative outcomes, it remains unclear how it is regulated. To address this question, we compared advanced PRF (A-PRF) and concentrated growth factor (CGF) matrices in terms of distribution of platelets, transforming growth factor-β1, platelet-derived growth factor-BB, vascular endothelial growth factor and matrix metalloprotease-9 (MMP9).

Evidence for Contamination of Silica Microparticles in Advanced Platelet-Rich Fibrin Matrices Prepared Using Silica-Coated Plastic Tubes.

Platelet-rich fibrin (PRF) therapy has been widely applied in regenerative dentistry, and PRF preparation has been optimized to efficiently form fibrin clots using plain glass tubes. Currently, a shortage of commercially available glass tubes has forced PRF users to utilize silica-coated plastic tubes. However, most plastic tubes are approved by regulatory authorities only for diagnostic use and remain to be approved for PRF therapy.

Memory B cell pool of autoimmune pulmonary alveolar proteinosis patients contains higher frequency of GM-CSF autoreactive B cells than healthy subjects.

The IgG-type neutralizing GM-CSF autoantibody (GMAb) is known to be the causative agent for autoimmune pulmonary alveolar proteinosis (APAP). Previous studies report that serum levels of IgG-GMAb are approximately 50-fold higher in APAP patients than in healthy subjects (HS). Serum levels of IgM-GMAb are also higher in APAP patients than in HS, but this has been assumed to be an etiological bystander.