Kumi Oshima

SHPS-1, a multifunctional transmembrane glycoprotein

Src homology 2 (SH2) domain‐containing protein tyrosine phosphatase substrate 1 (SHPS‐1) is a member of the signal regulatory protein (SIRP) family. The amino‐terminal immunoglobulin‐like domain of SHPS‐1 is necessary for interaction with CD47, a ligand for SHPS‐1, which plays an important role in cell–cell interaction. The intracellular region of SHPS‐1, on the other hand, may act as a scaffold protein, binding to various adapter proteins. Interestingly, increasing evidence has shown that SHPS‐1 is involved in various biological phenomena, including suppression of anchorage‐independent cell growth, negative regulation of immune cells, self‐recognition of red blood cells, mediation of macrophage multinucleation, skeletal muscle differentiation, entrainment of circadian clock, neuronal survival and synaptogenesis. Recent progress has been made in attributing these novel exciting functions. Here we discuss how this interesting molecule works and consider its true role in biology.

A role for SHPS-1/SIRPα1 in IL-1β- and TNFα-dependent signaling

We investigated the role of SHPS-1/SIRPα1 in IL-1β- and TNFα-dependent signaling that leads to the activation of Erk 1/2 and Akt. Treatment of Balb3T3 cells with IL-1β or TNFα activated tyrosine phosphorylation of SHPS-1, its association with SHP-2 and the phosphorylation of Erk 1/2 and Akt. PP1, a specific inhibitor for the Src family protein tyrosine kinases, strongly inhibited tyrosine phosphorylation of SHPS-1 and complex formation of SHPS-1 with SHP-2 by IL-1β. In addition, PP1 substantially inhibited the IL-2β- and TNFα-dependent activation of Erk 1/2 and Akt. Exogenous expression of either SHPS-1 mutants that lack SHP-2 binding function or a dominant negative mutant of SHP-2 markedly inhibited the activation of Erk 1/2 and Akt by IL-1β, whereas wild type SHPS-1 did not. Moreover, IL-1β-stimulation induced association of SHPS-1 with IL-1RAcP, a second subunit of IL-1 receptor, whereas expression of SHPS-1 mutant that lack SHP-2 binding function clearly blocked the association and tyrosine phosphorylation of endogenous SHPS-1. Taken together, our results strongly suggest that activation of Erk 1/2 and Akt by proinflammatory cytokines requires tyrosine phosphorylation of SHPS-1 and subsequent association of SHPS-1 with SHP-2.

Molecular cloning of a novel human gene ( SIRP-B2 ) which encodes a new member of the SIRP/SHPS-1 protein family

AbstractA full-length cDNA encoding a novel protein was isolated and sequenced from a human placental cDNA library. This cDNA consists of 1735 base pairs and has a predicted open reading frame (ORF) encoding 354 amino acids. It possesses a putative signal sequence, a long extracellular domain, a transmembrane region, a short intracellular domain, and no catalytic domain, which is highly homologous to signal-regulatory protein (SIRP)-β, suggesting that it seems to be a new member of the SIRP family. Polymerase chain reaction (PCR)-based mapping with both a monochromosomal hybrid panel and radiation hybrid cell panels placed the gene to human chromosome 20p13 near the marker D20S906.

Association between serum high-molecular-weight adiponectin level and the severity of chronic graft-versus-host disease in allogeneic stem cell transplantation recipients

Recently, a growing body of evidence has suggested that adiponectin, which is secreted by adipose tissues, plays a critical role in obesity-related and autoimmune diseases. We compared the concentrations of adiponectin among 26 normal subjects and 34 allogeneic stem cell transplantation recipients. The concentrations of adiponectin were significantly higher in recipients with chronic graft-versus-host disease (cGVHD) than those in subjects without cGVHD (21.7 ± 11.0 vs 9.1 ± 6.1 μg/mL in females, P < .001; and 10.1 ± 6.8 vs 4.3 ± 2.9 μg/mL in males, P = .003). Multivariate analysis revealed that a higher concentration of adiponectin was associated with female sex (β-coefficient 8.2, P < .0001) and the severity of cGVHD (β-coefficient 6.6, 12.7, and 15.6, P < .01, each for mild, moderate, and severe cGVHD, respectively). In addition, adiponectin levels increased as cGVHD progressed, decreased as cGVHD improved, and did not change with stable cGVHD. In conclusion, adiponectin was associated with the severity of cGVHD and might play a role in the pathophysiology of cGVHD.

Quality of Life after Allogeneic Hematopoietic Cell Transplantation According to Affected Organ and Severity of Chronic Graft-versus-Host Disease

Knowing the impact of chronic graft-versus-host disease (GVHD) on quality of life (QoL) after allogeneic hematopoietic stem cell transplantation (allo-HCT) by GVHD type and severity is critical for providing care to transplant survivors. We conducted a cross-sectional questionnaire study to examine the relationship between patient-reported QoL as measured by the Medical Outcomes Study 36-Item Short-Form Health Survey, Functional Assessment of Cancer Therapy-Bone Marrow Transplant, and visual analogue scale (VAS) and chronic GVHD defined by the National Institutes of Health (NIH) criteria. Recipients of allo-HCT for hematologic disease between 1995 and 2009 aged ≥ 16 years at transplant and ≥20 years at the time of the survey who were relapse-free were eligible. A total of 1140 pairs of patient and physician questionnaires were included in the analysis. By NIH global severity score, QoL scores in all aspects were significantly lower in patients with higher global and organ-specific severity grades, independent of background variables. Compared with patients without GVHD symptoms, those with mild symptoms had impaired physical and general QoL according to global severity score and organ-specific scores except for the genital tract. Mild symptoms in the lungs, gastrointestinal tract, and joints and fascia were associated with clinically meaningful deterioration of physical QoL. VAS scores provided by physicians were generally higher than those provided by patients. Differences between scores reported by patients and physicians were larger for patients with no or mild GVHD symptoms. Our findings based on more than 1000 long-term survivors after HCT enabled us to identify a target of care, informing survivorship care protocols to improve post-transplantation QoL.

Effects of Prophylactic Foscarnet on Human Herpesvirus-6 Reactivation and Encephalitis in Cord Blood Transplant Recipients: A Prospective Multicenter Trial with an Historical Control Group

Cord blood transplantation (CBT) is a distinct risk factor for human herpesvirus-6 (HHV-6) reactivation and HHV-6 encephalitis. In a prospective multicenter trial we investigated the effects of prophylactic foscarnet (90 mg/kg i.v. infusion from days 7 to 27 after CBT) on the occurrence of HHV-6 reactivation, HHV-6 encephalitis, and acute graft-versus-host disease (aGVHD) in CBT recipients. Between 2014 and 2016, 57 patients were included in a foscarnet-prophylaxis group. Outcomes were compared with an historical control group who received CBT between 2010 and 2014 (standard-treatment group, n = 63). The cumulative incidence of high-level HHV-6 reactivation, defined as plasma HHV-6 DNA ≥ 104 copies/mL, at 60 days after CBT was significantly lower in the foscarnet-prophylaxis group than in the standard-treatment group (18.3% versus 57.3%, P < .001). Multivariate analysis revealed that myeloablative preconditioning and standard treatment were significant risk factors for high-level HHV-6 reactivation. The cumulative incidence of HHV-6 encephalitis at 60 days after CBT was not different between the groups (foscarnet-prophylaxis group, 12.4%; standard-treatment group, 4.9%; P = .14). The cumulative incidences of grades II to IV and grades III to IV aGVHD at 60 days after CBT were not different between the groups (grades II to IV aGVHD: foscarnet-prophylaxis group, 42.0%; standard-treatment group, 40.5%; P = .96; grades III to IV aGVHD: foscarnet-prophylaxis group, 14.5%; standard-treatment group, 14.5%; P = 1.00). In the setting of this study foscarnet significantly suppressed systemic HHV-6 reactivation in CBT recipients but failed to prevent the development of HHV-6 encephalitis. Suppression of HHV-6 reactivation by foscarnet did not show any effects against the incidence of aGVHD.

Employment status was highly associated with quality of life after allogeneic hematopoietic cell transplantation, and the association may differ according to patient age and graft-versus-host disease status: analysis of a nationwide QOL survey

Along with the increased number of long-term survivors, the importance of screening and caring for allogeneic hematopoietic cell transplantation (allo-HCT) survivors’ social well-being and quality of life (QOL), as well as late physical effects, has been recognized [1]. Compared to survivors of solid cancers, allo-HCT patients may be more susceptible to critical factors that influence the ability to return to work, including immuno-compromised status, chronic graft-versus-host disease (GVHD), and other late effects [2, 3]. At the same time, because a considerable number of allo-HCT recipients are of working age, workrelated issues are of essential importance in this population, which may impact their QOL. In order to identify targets of care and suitable approaches, we evaluated the relationship of employment status and QOL after allo-HCT using data from a nationwide cross-sectional questionnaire study [4]. To reflect the employment status after allo-HCT, we used two work-related factors, full-time employment or not at survey and career change after allo-HCT, to compare QOL among patients. Eligibility criteria included allo-HCT for hematological disease between 1995 and 2009, ≥16 years at transplant and ≥20 years at survey, and relapse-free status at survey. Consent and response rates were 97 and 95%, respectively (Supplementary Figure 1), and 1140 pairs of patient and