Naturally occurring CD4⁺CD25⁺ regulatory T cells (Treg) suppress in vitro the proliferation of other T cells in a cell-contact-dependent manner. Dendritic cells (DCs) appear to be a target of ...Treg-mediated immune suppression. We show here that, in coculture of dye-labeled Treg cells and CD4⁺CD25⁻ naïve T cells in the presence of T cell receptor stimulation, Treg cells, which are more mobile than naïve T cells in vitro, out-compete the latter in aggregating around DCs. Deficiency or blockade of leukocyte function-associated antigen-1 (LFA-1) (CD11a/CD18) abrogates Treg aggregation, whereas that of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) (CD152) does not. After forming aggregates, Treg cells specifically down-regulate the expression of CD80/86, but not CD40 or class II MHC, on DCs in both a CTLA-4- and LFA-1-dependent manner. Notably, Treg exerts this CD80/86-down-modulating effect even in the presence of strong DC-maturating stimuli, such as GM-CSF, TNF-α, IFN-γ, type I IFN, and lipopolysaccharide. Taken together, as a possible mechanism of in vitro Treg-mediated cell contact-dependent suppression, we propose that antigen-activated Treg cells exert suppression by two distinct steps: initial LFA-1-dependent formation of Treg aggregates on immature DCs and subsequent LFA-1- and CTLA-4-dependent active down-modulation of CD80/86 expression on DCs. Both steps prevent antigen-reactive naïve T cells from being activated by antigen-presenting DCs, resulting in specific immune suppression and tolerance.
Regulatory T cells (Tregs), either natural or induced, suppress a variety of physiological and pathological immune responses. One of the key issues for understanding Treg function is to determine how ...they suppress other lymphocytes at the molecular level in vivo and in vitro. Here we propose that there may be a key suppressive mechanism that is shared by every forkhead box p3 (Foxp3)+ Treg in vivo and in vitro in mice and humans. When this central mechanism is abrogated, it causes a breach in self-tolerance and immune homeostasis. Other suppressive mechanisms may synergistically operate with this common mechanism depending on the environment and the type of an immune response. Further, Treg-mediated suppression is a multi-step process and impairment or augmentation of each step can alter the ultimate effectiveness of Treg-mediated suppression. These findings will help to design effective ways for controlling immune responses by targeting Treg suppressive functions.
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curable treatment option for adolescent and young adult (AYA) patients with myelodysplastic syndrome (MDS). The study aim was to ...evaluate epidemiological data and identify prognostic factors for AYA patients with MDS undergoing allogeneic HSCT. Here, 645 patients were selected from patients enrolled in a multicenter prospective registry for HSCT from 2000 to 2015. The primary endpoint was 3-year overall survival (OS). Survival rates were estimated using the Kaplan-Meier method. Prognostic factors were identified using the multivariable Cox proportional hazards model. The 3-year OS was 71.2% (95% confidence interval CI: 67.4-74.6%). In multivariable analysis, active disease status (adjusted hazard ratio: 1.54, 95% CI: 1.09-2.18, p = 0.016), poor cytogenetic risk (1.62, 1.12-2.36, p = 0.011), poor performance status (2.01, 1.13-3.56, p = 0.016), human leukocyte antigen (HLA)-matched unrelated donors (2.23, 1.39-3.59, p < 0.001), HLA-mismatched unrelated donors (2.16, 1.09-4.28, p = 0.027), and cord blood transplantation (2.44, 1.43-4.17, p = 0.001) were significantly associated with poor 3-year OS. In conclusion, in AYA patients with MDS the 3-year OS following allogeneic HSCT was 71.2%. Active disease status, poor cytogenetic risk, poor performance status, and donor sources other than related donors were associated with poor 3-year OS.
Graft failure (GF) is a life-threatening complication after allogeneic stem cell transplantation (SCT). Although salvage SCTs can be performed with haploidentical donor (HID) or cord blood (CB), no ...study has compared the performances of these two sources. Using nationwide registration data, we compared the transplant outcomes of patients who developed GF and underwent salvage transplantation from HID (n = 129) and CB (n = 570) from 2007 to 2016. The HID group demonstrated better neutrophil recovery (79.7 vs. 52.5% at 30 days, P < 0.001). With a median follow-up of 3 years, both groups demonstrated similar overall survival (OS) and nonrelapse mortality (NRM; 1-year OS, 33.1 vs. 34.6% and 1-year NRM, 45.1 vs. 49.8% for the HID and CB groups). After adjustments for other covariates, OS did not differ in both groups. However, HID was associated with a lower NRM (hazard ratio, 0.71; P = 0.038) than CB. The incidence of acute graft-versus-host disease (GVHD)-related deaths was significantly higher in the HID group, although infection-related deaths were observed more frequently in the CB group. HID may be a promising salvage SCT option after GF due to its faster engraftment and low NRM.
Background. There is no standard management of reactivation of hepatitis B virus (HBV) infection in HBV-resolved patients without hepatitis B surface antigen (HBsAg), but with antibodies against ...hepatitis B core antigen and/or antibodies against HBsAg (anti-HBs). Methods. We conducted a prospective observational study to evaluate the occurrence of HBV reactivation by serial monthly monitoring of HBV DNA and to establish preemptive therapy guided by this monitoring in B-cell non-Hodgkin lymphoma (B-NHL) treated with rituximab plus corticosteroid-containing chemotherapy (R-steroid-chemo). The primary endpoint was the incidence of HBV reactivation defined as quantifiable HBV DNA levels of ≥11 1U/mL. Results. With a median HBV DNA follow-up of 562 days. HBV reactivation was observed in 21 of the 269 analyzed patients. The incidence of HBV reactivation at 1.5 years was 8.3% (95% confidence interval, 5.5–12.4). No hepatitis due to HBV reactivation was observed in patients who received antiviral treatment when HBV DNA levels were between 11 and 432 IU/mL. An anti-HBs titer of <10 mIU/mL and detectable HBV DNA remaining below the level of quantification at baseline were independent risk factors for HBV reactivation (hazard ratio, 20.6 and 56.2, respectively; P<.001). Even in 6 patients with a rapid increase of HBV due to mutations, the monthly HBV DNA monitoring was effective at preventing HBV-related hepatitis. Conclusions. Monthly monitoring of HBV DNA is useful for preventing HBV reactivation–related hepatitis among B-NHL patients with resolved HBV infection following R-steroid-chemo (UMIN000001299).
Peritoneal lymphomatosis (PL) is a rare presentation of malignant lymphoma cases, many of which are diagnosed as diffuse large B-cell lymphoma (DLBCL) and characterized by aggressive clinical ...courses. We herein report a 63-year-old woman presenting with the rapid development of abdominal distention due to bulky peritoneal tumors. The pathological evaluation of a needle biopsy sample, combined with flow cytometry, yielded the diagnosis of DLBCL. Prompt chemotherapeutic intervention resulted in favorable disease control and sustained complete remission. It is necessary to diagnose cases of DLBCL presenting as PL early to ensure prompt treatment and prevent mortality.
Acquired aplastic anemia is an immune-mediated disease that targets hematopoietic stem cells, which is diagnosed by findings of peripheral blood pancytopenia and hypocellular bone marrow. Although ...the diagnostic definition is simple, differential diagnosis from other overlapping hematopoietic disorders such as hypoplastic myelodysplastic syndrome and inherited bone marrow failure syndrome is not easy. Immune suppressive therapy and allogeneic hematopoietic stem cell transplantation are important treatment approaches for aplastic anemia, and both have advanced in recent years. This issue of Progress in Hematology covers four topics related to aplastic anemia: (1) laboratory markers to identify immune pathophysiology and their role on differential diagnosis and prognosis, (2) the path to combination therapy with horse anti-thymocyte globulin, cyclosporine A, and eltrombopag, (3) more than 60 years of history and recent trends in allogeneic HSCT, and (4) genetic testing for differential diagnosis from IBMFS and novel approaches to transplantation for children including fludarabine/melphalan-based conditioning.
Mitochondria play essential and specific roles during erythroid differentiation. Recently, FAM210B, encoding a mitochondrial inner membrane protein, has been identified as a novel target of GATA-1, ...as well as an erythropoietin-inducible gene. While FAM210B protein is involved in regulate mitochondrial metabolism and heme biosynthesis, its detailed function remains unknown. Here, we generated both knockout and knockdown of endogenous FAM210B in human induced pluripotent stem-derived erythroid progenitor (HiDEP) cells using CRISPR/Cas9 methodology. Intriguingly, erythroid differentiation was more pronounced in the FAM210B-depleted cells, and this resulted in increased frequency of orthochromatic erythroblasts and decreased frequencies of basophilic/polychromatic erythroblasts. Comprehensive metabolite analysis and functional analysis indicated that oxygen consumption rates and the NAD (NAD
+
)/NADH ratio were significantly decreased, while lactate production was significantly increased in FAM210B deletion HiDEP cells, indicating involvement of FAM210B in mitochondrial energy metabolism in erythroblasts. Finally, we purified FAM210B-interacting protein from K562 cells that stably expressed His/biotin-tagged FAM210B. Mass spectrometry analysis of the His/biotin-purified material indicated interactions with multiple subunits of mitochondrial ATP synthases, such as subunit alpha (ATP5A) and beta (ATP5B). Our results suggested that FAM210B contributes prominently to erythroid differentiation by regulating mitochondrial energy metabolism. Our results provide insights into the pathophysiology of dysregulated hematopoiesis.
Abstract
Acquired sideroblastic anemia, characterized by bone marrow ring sideroblasts (RS), is predominantly associated with myelodysplastic syndrome (MDS). Although somatic mutations in
splicing ...factor 3b subunit 1
(
SF3B1
), which is involved in the RNA splicing machinery, are frequently found in MDS-RS, the detailed mechanism contributing to RS formation is unknown. To explore the mechanism, we established human umbilical cord blood-derived erythroid progenitor-2 (HUDEP-2) cells stably expressing SF3B1
K700E
. SF3B1
K700E
expressing cells showed higher proportion of RS than the control cells along with erythroid differentiation, indicating the direct contribution of mutant SF3B1 expression in erythroblasts to RS formation. In SF3B1
K700E
expressing cells,
ABCB7
and
ALAS2,
known causative genes for congenital sideroblastic anemia, were downregulated. Additionally, mis-splicing of
ABCB7
was observed in SF3B1
K700E
expressing cells.
ABCB7
-knockdown HUDEP-2 cells revealed an increased frequency of RS formation along with erythroid differentiation, demonstrating the direct molecular link between ABCB7 defects and RS formation. ALAS2 protein levels were obviously decreased in
ABCB7
-knockdown cells, indicating decreased ALAS2 translation owing to impaired Fe–S cluster export by ABCB7 defects. Finally, RNA-seq analysis of MDS clinical samples demonstrated decreased expression of
ABCB7
by the
SF3B1
mutation. Our findings contribute to the elucidation of the complex mechanisms of RS formation in MDS-RS.
Overexpression of programmed death‐1 (PD‐1) ligands contributes to an immunosuppressive microenvironment. Nivolumab is a PD‐1‐blocking antibody that inhibits the PD‐1 pathway and showed good efficacy ...in several types of malignancy. This phase II study examined the efficacy and safety of nivolumab in 17 Japanese patients with refractory/relapsed classical Hodgkin lymphoma previously treated with brentuximab vedotin. Sixteen patients were included in efficacy analyses and 17 in safety analyses. The primary endpoint was the centrally assessed objective response rate (ORR). The study was commenced in March 2015. We report data obtained at a cutoff of 16 March 2016, at which time 11 patients were still receiving nivolumab. The median (range) duration of treatment and follow‐up were 7.0 (1.4–10.6) months and 9.8 (6.0–11.1) months, respectively. All 17 patients had previously received brentuximab vedotin. The ORR was 81.3% (95% confidence interval CI: 54.4–96.0%; 13/16 patients), with complete remission and partial remission in 4 and 9 patients, respectively. The overall survival (OS) and progression‐free survival (PFS) rates at 6 months were 100 and 60.0% (95% CI: 31.8–79.7%), respectively; the median OS and PFS were not reached. The most common adverse events (AE) were pyrexia (41.2%), pruritus (35.3%), rash (35.3%) and hypothyroidism (29.4%). Four patients (23.5%) experienced grade 3 or 4 AE, but most AE were of grade 1 or 2. In conclusion, nivolumab is a potentially effective and tolerable treatment option for Japanese patients with relapsed/refractory classical Hodgkin lymphoma previously treated with brentuximab vedotin.
We examined the efficacy and safety of nivolumab, a programmed death‐1 (PD‐1)‐blocking antibody, in a phase 1 trial in 17 Japanese patients with refractory/relapsed classical Hodgkin lymphoma previously treated with brentuximab vedotin. The results indicate that nivolumab is a potentially effective treatment option that achieved relevant decreases in tumor size. Nivolumab was also tolerable in this cohort of patients.
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