In the interleukin-2 (IL-2) system, intracellular signal transduction is triggered by the beta chain of the IL-2 receptor (IL-2R beta); however, the responsible signaling mechanism remains unidentified. Evidence for the formation of a stable complex of IL-2R beta and the lymphocyte-specific protein tyrosine kinase p56lck is presented. Specific association sites were identified in the tyrosine kinase catalytic domain of p56lck and in the cytoplasmic domain of IL-2R beta. As a result of interaction, IL-2R beta became phosphorylated in vitro by p56lck. Treatment of T lymphocytes with IL-2 promotes p56lck kinase activity. These data suggest the participation of p56lck as a critical signaling molecule downstream of IL-2R via a novel interaction.

Sphingosine-1-phosphate (S1P), a sphingolipid metabolite that is produced inside the cells, regulates a variety of physiological and pathological responses via S1P receptors (S1P1–5). Signal transduction between cells consists of three steps; the synthesis of signaling molecules, their export to the extracellular space and their recognition by receptors. An S1P concentration gradient is essential for the migration of various cell types that express S1P receptors, such as lymphocytes, pre-osteoclasts, cancer cells and endothelial cells. To maintain this concentration gradient, plasma S1P concentration must be at a higher level. However, little is known about the molecular mechanism by which S1P is supplied to extracellular environments such as blood plasma. Here, we show that SPNS2 functions as an S1P transporter in vascular endothelial cells but not in erythrocytes and platelets. Moreover, the plasma S1P concentration of SPNS2-deficient mice was reduced to approximately 60% of wild-type, and SPNS2-deficient mice were lymphopenic. Our results demonstrate that SPNS2 is the first physiological S1P transporter in mammals and is a key determinant of lymphocyte egress from the thymus.

Cytomegalovirus (CMV) infection is a major infectious complication after allogeneic hematopoietic cell transplantation (allo-HSCT). Recently, it was reported that CMV reactivation is associated with a decreased risk of relapse in patients with acute myeloid leukemia (AML). The aim of this study was to evaluate the impact of early CMV reactivation on the incidence of disease relapse after allo-HSCT in a large cohort of patients. The Japan Society for Hematopoietic Cell Transplantation's Transplantation-Related Complication Working Group retrospectively surveyed the database of the Transplant Registry Unified Management Program at the Japan Society for Hematopoietic Cell Transplantation. Patients with AML (n = 1836), acute lymphoblastic leukemia (ALL, n = 911), chronic myeloid leukemia (CML, n = 223), and myelodysplastic syndrome (MDS, n = 569) who underwent their first allo-HSCT from HLA-matched related or unrelated donors between 2000 and 2009 and who survived without disease relapse until day 100 after transplantation were analyzed. Patients who received umbilical cord blood transplantation were not included. Patients underwent surveillance by pp65 antigenemia from the time of engraftment, and the beginning of preemptive therapy was defined as CMV reactivation. Cox proportional hazards models were used to evaluate the risk factors of relapse, nonrelapse, and overall mortality. CMV reactivation and acute/chronic graft-versus-host disease (GVHD) were evaluated as time-dependent covariates. CMV reactivation was associated with a decreased incidence of relapse in patients with AML (20.3% versus 26.4%, P = .027), but not in patients with ALL, CML, or MDS. Among 1836 patients with AML, CMV reactivation occurred in 795 patients (43.3%) at a median of 42 days, and 436 patients (23.7%) relapsed at a median of 221 days after allo-HSCT. Acute GVHD grades II to IV developed in 630 patients (34.3%). By multivariate analysis considering competing risk factors, 3 factors were significantly associated with a decreased risk of AML relapse and 1 factor with an increased risk of AML relapse: CMV reactivation (hazard ratio [HR], .77; 95% confidence interval [CI], .59 to .99), unrelated donor compared with related donor (HR, .59; 95% CI, .42 to .84), development of chronic GVHD (HR, .77; 95% CI, .60 to .99), and pretransplantation advanced disease status compared with standard disease status (HR, 1.99; 95% CI, 1.56 to 2.52). However, CMV reactivation was associated with increased nonrelapse mortality (HR, 1.60; 95% CI, 1.18 to 2.17) and overall mortality (HR, 1.37; 95% CI, 1.11 to 1.69). A beneficial effect of CMV reactivation on subsequent risk of relapse was observed in patients with AML but not in those with other hematological malignancies. However, this benefit was nullified by the increased nonrelapse mortality. The underlying mechanism is unclear; however, immunological activation against CMV reactivation plays an essential role in this association. Thus, immune augmentation treatment options, including vaccination and adopti...

B (2) can be used, within certain limitations, as an effective indicator of viscosity and aggregation propensity of highly concentrated MAb solutions.

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