Mizuha Kosugi-Kanaya

Tracking of intertissue migration reveals the origins of tumor-infiltrating monocytes

Significance Solid tumors contain large numbers of immune cells, including monocytes and monocyte-derived macrophages that promote tumor progression. During tumor development, monocytes accumulate in the spleen. However, the influence of spleen cells on tumor growth remains controversial. Here, we used novel methods for tracking intertissue migration and monitoring hematopoiesis to show that during tumor development the bone marrow dramatically accelerates production of monocytes, rapidly transferring many of these newly formed cells to a reservoir in the spleen. However, these spleen monocytes are less able than their bone marrow counterparts to enter the tumor and make only a minor contribution to the tumor-infiltrating monocyte population. These findings clarify the roles of the spleen and bone marrow in cancer development. Myeloid cells such as monocytes and monocyte-derived macrophages promote tumor progression. Recent reports suggest that extramedullary hematopoiesis sustains a sizable reservoir of tumor-infiltrating monocytes in the spleen. However, the influence of the spleen on tumor development and the extent to which spleen monocytes populate the tumor relative to bone marrow (BM) monocytes remain controversial. Here, we used mice expressing the photoconvertible protein Kikume Green-Red to track the redistribution of monocytes from the BM and spleen, and mice expressing fluorescent ubiquitination-based cell-cycle indicator proteins to monitor active hematopoiesis in these tissues. In mice bearing late-stage tumors, the BM, besides being the major site of monocyte production, supplied the expansion of the spleen reservoir, replacing 9% of spleen monocytes every hour. Deployment of monocytes was equally rapid from the BM and the spleen. However, BM monocytes were younger than those in the spleen and were 2.7 times more likely to migrate into the tumor from the circulation. Partly as a result of this intrinsic difference in migration potential, spleen monocytes made only a minor contribution to the tumor-infiltrating monocyte population. At least 27% of tumor monocytes had traveled from the BM in the last 24 h, compared with only 2% from the spleen. These observations highlight the importance of the BM as the primary hematopoietic tissue and monocyte reservoir in tumor-bearing mice, despite the changes that occur in the spleen monocyte reservoir during tumor development.

Bone Marrow Graft-versus-Host Disease: Evaluation of Its Clinical Impact on Disrupted Hematopoiesis after Allogeneic Hematopoietic Stem Cell Transplantation

Idiopathic cytopenias are frequently observed in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have previously reported the effect of graft-versus-host disease (GVHD) on bone marrow (BM) in murine models, indicating that the osteoblast injury mediated by donor T cells was associated with bone marrow suppression and delayed immune reconstitution. In this study, we prospectively evaluated the relevance of these findings in 51 patients. Patients with chronic GVHD manifested the loss of osteoblasts, contributing to cytopenic symptoms (P = .0427 compared with patients without cytopenic symptoms). The loss of osteoblasts was significantly associated with the extensive type of chronic GVHD (P = .012), and flow cytometric analyses revealed lower numbers of CD19(+) B cells and a significantly increased CD4 to CD8 ratio (P = .0002) in these patients. Our data, for the first time to our knowledge, summarize the detailed analyses of the effect of GVHD on BM in the clinical allo-HSCT patients.

Loss of Lymph Node Fibroblastic Reticular Cells and High Endothelial Cells Is Associated with Humoral Immunodeficiency in Mouse Graft-versus-Host Disease

Graft-versus-host disease (GVHD) is a major risk factor for prolonged humoral immunodeficiency and vaccine unresponsiveness after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the underlying mechanisms for this immunodeficiency are poorly understood. In this article, we describe previously overlooked impacts of GVHD on lymph node (LN) stromal cells involved in humoral immune responses. In major- and minor-mismatched mouse allo-HSCT models, recipients with CD8+ T cell–mediated GVHD suffered severe and irreversible damage to LN structure. These mice were susceptible to pathogenic infection and failed to mount humoral immune responses despite the presence of peripheral T and B cells. These humoral immune defects were associated with the early loss of fibroblastic reticular cells, most notably the CD157+ cell subset, as well as structural defects in high endothelial venules. The disruption to these LN stromal cells was dependent on alloantigens expressed by nonhematopoietic cells. Blockade of the Fas-FasL pathway prevented damage to CD157+ fibroblastic reticular cells and ameliorated LN GVHD. However, blockade of CD62L- or CCR7-dependent migration of CD8+ T cells to the LN was insufficient to prevent stromal cell injury. Overall, our results highlight GVHD-associated loss of functional stromal cells and LN GVHD as a possible explanation for the prolonged susceptibility to infectious disease that is experienced by allo-HSCT patients.

Allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning for mycosis fungoides and Sezary syndrome.

Advanced‐stage mycosis fungoides and Sezary syndrome (MF/SS) have a poor prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT), particularly using a reduced‐intensity conditioning (RIC) regimen, is a promising treatment for advanced‐stage MF/SS. We performed RIC‐HSCT in nine patients with advanced MF/SS. With a median follow‐up period of 954 days after HSCT, the estimated 3‐year overall survival was 85.7% (95% confidence interval, 33.4–97.9%) with no non‐relapse mortality. Five patients relapsed after RIC‐HSCT; however, in four patients whose relapse was detected only from the skin, persistent complete response was achieved in one patient, and the disease was manageable in other three patients by the tapering of immunosuppressants and donor lymphocyte infusion, suggesting that graft‐versus‐lymphoma effect and ‘down‐staging’ effect from advanced stage to early stage by HSCT improve the prognosis of advanced‐stage MF/SS. These results suggest that RIC‐HSCT is an effective treatment for advanced MF/SS. Copyright

Ultra-high level of serum soluble interleukin-2 receptor at diagnosis predicts poor outcome for angioimmunoblastic T-cell lymphoma

Angioimmunoblastic T-cell lymphoma (AITL) is a rare subtype of non-Hodgkin lymphoma and displays an aggressive clinical course with poor outcome. To identify prognostic factors for AITL, we retrospectively analyzed 36 patients with AITL. The median age was 74 years with 83% of the patients having advanced stage. Eighty-three percent received CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)-like chemotherapies, resulting in an overall response rate of 63%. With a median follow-up of 9 years, the estimated overall survival at 5 years was 33.3%. Median serum level of soluble interleukin-2 receptor (sIL-2R) was 5615 U/mL at diagnosis, and over 10 000 U/mL of sIL-2R was identified as a significant poor prognostic factor, independent of the International Prognostic Index, Prognostic Index for peripheral T-cell lymphoma and Prognostic index for AITL (hazard ratio [HR], 4.42; 95% confidence interval [CI], 1.49–13.11; log-rank, p < 0.01). Our study shows that an ultra-high level of serum sIL-2R at diagnosis is a significant poor prognostic biomarker for AITL.

Disseminated toxoplasmosis after hematopoietic stem cell transplantation showing unusual magnetic resonance images

We herein report a patient who had disseminated toxoplasmosis after hematopoietic stem cell transplantation showing atypical clinical presentation and neuroimaging. Parkinsonism symptoms such as muscle rigidity, bradykinesia, tremor, and postural instability were initial manifestations. Magnetic resonance imaging showed diffuse symmetrical lesions of bilateral basal ganglia lacking ringed enhancement. Post‐mortem analysis revealed multiple tachyzoites of Toxoplasma gondii in the basal ganglia, mid brain, cerebellum, and cardiac muscle.

Long-Lasting Graft-Derived Donor T Cells Contribute to the Pathogenesis of Chronic Graft-versus-Host Disease in Mice

Chronic graft-versus-host disease (cGVHD) is a major complication in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Graft-derived T cells (TG) have been implicated in the induction of cGVHD; however, the extent of their contribution to the pathogenesis of cGVHD remains unclear. Using a mouse model of cGVHD, we demonstrate that TG predominate over hematopoietic stem cell-derived T cells generated de novo (THSC) in cGVHD-affected organs such as the liver and lung even at day 63 after allo-HSCT. Persisting TG, in particular CD8+ TG, not only displayed an exhausted or senescent phenotype but also contained a substantial proportion of cells that had the potential to proliferate and produce inflammatory cytokines. Host antigens indirectly presented by donor HSC-derived hematopoietic cells were involved in the maintenance of TG in the reconstituted host. Selective depletion of TG in the chronic phase of disease resulted in the expansion of THSC and thus neither the survival nor histopathology of cGVHD was ameliorated. On the other hand, THSC depletion caused activation of TG and resulted in a lethal TG-mediated exacerbation of GVHD. The findings presented here clarify the pathological role of long-lasting TG in cGVHD.

A combination of anti-CD4 antibody treatment and DLI ameliorates GVHD while preserving GVT effects in murine allo-HSCT

Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is not only a well‐established immunotherapy for hematologic malignancies, but is potentially useful for treating solid tumors refractory to available therapies. However, application of allo‐HSCT to solid tumors is limited, despite the beneficial antitumor effects, by the risk of graft‐versus‐host disease (GVHD). CD4+ T cells have been implicated in several aspects of GVHD, and suppress antitumor CD8+ T‐cell responses. In the present study, we investigated clinically applicable allo‐HSCT protocols designed to maximize antitumor effects while reducing the risk of GVHD. We used a mouse model of allo‐HSCT with s.c. tumors. We found that myeloablative conditioning was associated with better inhibition of tumor growth but with severe acute GVHD. Early treatment with anti‐CD4 mAb substantially ameliorated GVHD while preserving antitumor effects, leading to improved survival in myeloablative allo‐HSCT. Late treatment with anti‐CD4 mAb also ameliorated GVHD to some extent. Donor lymphocyte infusion in GVHD mice treated with anti‐CD4 mAb further suppressed tumor growth without exacerbating GVHD. Collectively, our results suggest that myeloablative allo‐HSCT followed by anti‐CD4 mAb treatment and donor lymphocyte infusion could be a potent and safe immunotherapy for patients with cancers refractory to available therapies.

MALDI-TOF MS in post-transplant bloodstream infections: reliable identification of causative bacteria in the neutropenic phase

MALDI-TOF MS in post-transplant bloodstream infections: reliable identification of causative bacteria in the neutropenic phase

Donor cell leukemia after umbilical cord blood transplantation: recurrent or de novo? The importance of diagnosis for therapeutic decision making.

Title Donor cell leukemia after umbilical cord blood transplantation : recurrent or de novo? The importance of diagnosis for therapeutic decision making Author(s) Shono, Yusuke; Kosugi-Kanaya, Mizuha; Shiratori, Souichi; Sugita, Junichi; Fujimoto, Katsuya; Kondo, Takeshi; Nishio, Mitsufumi; Tanaka, Junji; Imamura, Masahiro Citation International Journal of Hematology, 93(4), 563-565 https://doi.org/10.1007/s12185-011-0814-y Issue Date 2011-04