Raine Tatara

Mesenchymal stromal cells inhibit Th17 but not regulatory T-cell differentiation

BACKGROUND AIMS A previous study has demonstrated that mouse mesenchymal stromal cells (MSC) produce nitric oxide (NO), which suppresses signal transducer and activator of transcription (STAT) 5 phosphorylation and T-cell proliferation under neutral and T helper 1 cells (Th1) conditions. We aimed to determine the effects of MSC on T helper 17 cells (Th17) and regulatory T-cell (T-reg) differentiation. METHODS CD4 T cells obtained from mouse spleen were cultured in conditions for Th17 or Treg differentiation with or without mouse MSC. Th17 and Treg differentiation was assessed by flow cytometry using antibodies against interleukin (IL)-17 and forkhead box P3 (Foxp3), a master regulator of Treg cells. RESULTS MSC inhibited Th17 but not Treg differentiation. Under Th17 conditions, MSC did not produce NO, and inhibitors of indoleamine-2,3-dioxygenase (IDO) and prostaglandin E(2) (PGE2) both restored MSC suppression of differentiation, suggesting that MSC suppress Th17 differentiation at least in part through PGE2 and IDO. CONCLUSIONS Our results suggest that MSC regulate CD4 differentiation through different mechanisms depending on the culture conditions.

Mechanisms of Immunomodulation by Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) have been identified in animals, especially in bone marrow. As stem cells, they have the ability to differentiate into multiple cell types. This potential raises exciting therapeutic possibilities. A recent report described the successful use of MSCs for the treatment of graft-versus-host disease; however, the scientific community has yet to define the molecular mechanisms of immunomodulation by MSCs. This review summarizes what is known and discusses the conflicting data with regard to the mechanisms of immunomodulation by MSCs.

Rituximab plus 70% cyclophosphamide, doxorubicin, vincristine and prednisone for Japanese patients with diffuse large B-cell lymphoma aged 70 years and older

Abstract In the rituximab era, several large studies have suggested that full-dose rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) might be the best treatment for patients with diffuse large B-cell lymphoma (DLBCL) aged 60 years and older. However, it remains unclear whether this is also the case for those aged 70 years and older. Previously untreated patients with DLBCL aged 70 years and older (elderly) were treated with R-70%CHOP, and patients younger than 70 years (younger) were treated with full-dose R-CHOP every 3 weeks, for a total of 6–8 cycles. Complete remission (CR) rates in elderly versus younger patients were 75 vs. 78% (p = 0.7), respectively. The 3-year overall survival, event-free survival and progression-free survival of elderly versus younger patients were 58 vs. 78% (p < 0.05), 45 vs. 70% (p < 0.05) and 64 vs. 72% (p = 0.43), respectively. Severe adverse events were more frequent in the elderly, even with the dose reduction in that age group. Three-year PFS with R-70%CHOP for patients aged 70 years and older was not significantly worse than that with full-dose R-CHOP for younger patients, suggesting that R-70% CHOP might be a reasonable choice for patients with DLBCL aged 70 years and older, especially for those with comorbidities.

IL-21 is critical for GVHD in a mouse model

Immunological effects of IL-21 on T, B and natural killer (NK) cells have been reported, but the role of IL-21 in GVHD remains obscure. Here, we demonstrate that morbidity and mortality of GVHD was significantly reduced after BMT with splenocytes from IL-21R−/− mice compared with those from wild type mice. To further confirm our observation, we generated a decoy receptor for IL-21. GVHD was again less severe in mice receiving BM cells transduced with the IL-21 decoy receptor than control mice These results suggest that IL-21 critically regulates GVHD, and that blockade of the IL-21 signal may represent a novel strategy for the prophylaxis for GVHD.

Altered effector CD4+ T cell function in IL-21R-/- CD4+ T cell-mediated graft-versus-host disease.

We previously showed that transplantation with IL-21R gene-deficient splenocytes resulted in less severe graft-versus-host disease (GVHD) than was observed with wild type splenocytes. In this study, we sought to find mechanism(s) explaining this observation. Recipients of donor CD4+ T cells lacking IL-21R exhibited diminished GVHD symptoms, with reduced inflammatory cell infiltration into the liver and intestine, leading to prolonged survival. After transplantation, CD4+ T cell numbers in the spleen were reduced, and MLR and cytokine production by CD4+ T cells were impaired. These results suggest that IL-21 might promote GVHD through enhanced production of effector CD4+ T cells. Moreover, we found that CD25 depletion altered neither the impaired MLR in vitro nor the ameliorated GVHD symptoms in vivo. Thus, the attenuated GVHD might be caused by an impairment of effector T cell differentiation itself, rather than by an increase in regulatory T cells and suppression of effector T cells.

Lack of IL-21 signal attenuates graft-versus-leukemia effect in the absence of CD8 T-cells.

Previously, we have shown that IL-21R−/− splenocytes ameliorate GVHD as compared with wild-type splenocytes. Here, we investigated whether or not IL-21R−/− splenocytes diminish the graft-versus-leukemia (GVL) effect. Surprisingly, IL-21R−/− splenocytes efficiently eliminate leukemic cells as well as wild-type splenocytes, suggesting the retention of GVL effects in the absence of IL-21 signaling. To compare the GVL effect between IL-21R−/− and wild-type cells, we titrated the number of splenocytes required for the elimination of leukemic cells and found that the threshold of GVL effect was obtained between 5 × 105 and 5 × 106 with both types of splenocytes. Cotransplantation with CD8-depleted splenocytes but not with purified CD8 T-cells resulted in a significant reduction in anti-leukemic effect of IL-21R−/− cells compared with wild-type cells, suggesting that the lack of IL-21 signaling primarily impairs CD4 T-cell rather than CD8 T-cell function and the comparable GVL effect with IL-21R−/− bulk splenocytes results from cooperative compensation by CD8 T-cells.

Clinical features of de novo CD25-positive follicular lymphoma

Abstract CD25 expression in follicular lymphoma (FL) has not yet been investigated. Eighty-five patients with newly diagnosed FL were retrospectively evaluated. On two-color flow cytometric analysis, CD25 was detected on CD19 + and CD20 + lymphoma cells. CD25 expression in FL tended to be higher than in reactive lymphadenopathy, but was lower than in diffuse large B-cell lymphoma. Patients with CD25 + FL (n = 12) showed clinical features of elevated soluble interleukin-2 receptor (IL-2R) levels, B symptoms and an advanced age compared with CD25 − FL (n = 73). The overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) in patients with CD25 + FL were significantly inferior to those with CD25 − FL (ORR, 60 vs. 93%; 2-year PFS, 32 vs. 80.3%; 6-year OS, 47.4 vs. 85.9%, respectively). Multivariate analysis demonstrated that CD25 positivity is an independent prognostic factor for PFS and OS in FL. CD25 + FL may constitute a distinct subgroup associated with aggressiveness and an inferior prognosis.

The bridge treatment selected at the decision for transplantation did not affect the outcomes in patients with MDS.

The optimal treatment for use as a bridge to allogeneic hematopoietic stem cell transplantation at the decision for transplantation has not been established in patients with myelodysplastic syndrome (MDS). We retrospectively evaluated the clinical outcomes after the decision for transplantation in our patients with MDS or acute myeloid leukemia (AML) secondary to MDS, aged more than 15 years, who underwent transplantation between 2007 and 2012. A total of 124 patients were included. We classified patients into two groups according to the bridge treatment selected at the decision for transplantation: Group 1, supportive care (n = 79), immunosuppressive therapy (n = 7), low‐dose chemotherapy (n = 12); Group 2, AML‐type induction chemotherapy (ICT: n = 22), azacitidine (Aza: n = 4). The rate of blasts in the bone marrow significantly influenced the treatment selection at the time of decision. There was no significant difference between the two groups in the rate of overall survival (OS) from the decision (73.1% vs 80.4% at 1 year) or from transplantation (59.0% vs 59.2% at 1 year). A significant difference was not observed even after patients were stratified according to either the rate of blasts in the bone marrow at the time of decision or the propensity score. In conclusion, the bridge treatment selected at the decision for transplantation did not affect the outcomes of transplantation in patients with MDS. However, this analysis did not include patients who could not undergo transplantation after the decision, and thus a prospective study is warranted. Copyright

Intrathecal Administration of High-Titer Cytomegalovirus Immunoglobulin for Cytomegalovirus Meningitis

Cytomegalovirus (CMV) central nervous system disease after hematopoietic stem cell transplantation (HSCT) is a rare but life-threatening complication. Here, we report a patient who developed CMV meningitis after HSCT and was treated with the combination therapy of intrathecal high-titer CMV immunoglobulin and antiviral drugs. A 38-year-old man with myelodysplastic syndrome received a cord blood transplant after graft failure. On day 147, he was diagnosed with CMV meningitis based on pleocytosis and CMV DNA in the cerebrospinal fluid (CSF). Intravenous ganciclovir, foscarnet, and immunoglobulin were administered; however, CMV DNA in the CSF was continuously detected. The addition of intrathecal high-titer CMV immunoglobulin resulted in CMV DNA in the CSF becoming undetectable. On day 241, CMV DNA in the CSF was detected again, but both intrathecal immunoglobulin and intravenous ganciclovir led to its disappearance. No adverse effects related to intrathecal administration were observed. The intrathecal administration of immunoglobulin may be safe and effective for CMV meningitis.

Analysis of hemolysis in collected bone marrow for bone marrow transplantation

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