Tereza Coman

G-CSF mobilizes CD34+ regulatory monocytes that inhibit graft-versus-host disease

G-SCF–mobilized CD34+ monocytes inhibit graft-versus-host disease by the production of nitric oxide and the induction of regulatory T cells. Monocytes suppress GVHD Hematopoietic stem cell transplantation is a highly successful therapy used in patients with bone marrow dysfunction. However, when the stem cell donor cannot be matched to the recipient, the transplanted cells may attack the host in a process called graft-versus-host disease (GVHD). D’Aveni et al. now show that granulocyte colony-stimulating factor (G-CSF)–mobilized stem cells contain a previously uncharacterized population of immunosuppressive CD34+ cells transcriptionally similar to mature monocytes. These cells induce allogeneic T cell death in response to interferon-γ, resulting in regulatory T cell expansion and immunosuppression. The fraction of these CD34+ monocytes in peripheral blood inversely correlates with GVHD in patients, suggesting that expanding these cells before transplant may decrease the risk of GVHD. Granulocyte colony-stimulating factor (G-CSF) is routinely used to collect peripheral blood stem cells (PBSCs) from healthy donors for allogeneic hematopoietic stem cell transplantation (allo-HSCT). We show that, in both humans and mice, G-CSF mobilizes a subset of CD34+ cells with mature monocyte features. These cells, which are phenotypically and functionally conserved in mice and humans, are transcriptionally distinct from myeloid and monocytic precursors but similar to mature monocytes and endowed with immunosuppressive properties. In response to interferon-γ released by activated T cells, these cells produce nitric oxide, which induces allogeneic T cell death both in vitro and in vivo. These apoptotic T cells are engulfed by macrophages that release transforming growth factor–β and promote regulatory T cell expansion. Indeed, the fraction of CD34+ monocytes in peripheral blood CD34+ cells inversely correlates with the incidence of acute graft-versus-host disease (GVHD) in humans. Therefore, G-CSF–mobilized cells are an attractive candidate population to be expanded ex vivo for cellular therapy against GVHD.

Lenalidomide as salvage treatment for multiple myeloma relapsing after allogeneic hematopoietic stem cell transplantation: a report from the French Society of Bone Marrow and Cellular Therapy

Optimal salvage treatment for multiple myeloma relapsing after allogeneic stem cell transplantation remains to be determined. Usually, such patients have been heavily pre-treated and present at relapse with a relatively refractory disease. Immunomodulatory properties of lenalidomide may be beneficial by facilitating a graft-versus-myeloma effect after allogeneic stem cell transplantation. However, the safety of such treatment is still under debate. We conducted a multicenter retrospective study and included 52 myeloma patients receiving lenalidomide alone or in combination with dexamethasone as salvage therapy after allogeneic stem cell transplantation. The first aim was to assess the efficacy and tolerance of this drug. The second aim was to evaluate its potential immunomodulatory effects evaluated on the occurrence of acute graft-versus-host disease under treatment. In this cohort, we show that lenalidomide can induce a high response rate of 83% (including 29% complete response). On lenalidomide therapy, 16 patients (31%) developed or exacerbated an acute graft-versus-host disease, which was the only factor significantly associated with an improved anti-myeloma response. Side effects were mostly reversible, whereas 2 deaths (4%) could be attributed to treatment toxicity and to graft-versus-host disease, respectively. With a median follow up of 16.3 months, the median overall and progression free survival were 30.5 and 18 months, respectively, independently of the occurrence of acute graft-versus-host disease under lenalidomide. Lenalidomide can induce high response rates in myeloma relapsing after allogeneic stem cell transplantation at least in part by triggering an allogeneic anti-myeloma response. Induced graft-versus-host disease has to be balanced against the potential benefit in terms of disease control. Further immunological studies would help us understand lenalidomide immunomodulatory activity in vivo.

Serotonin Is Involved in Autoimmune Arthritis through Th17 Immunity and Bone Resorption

Rheumatoid arthritis is a chronic disease that results in a disabling and painful condition as it progresses to destruction of the articular cartilage and ankylosis of the joints. Although the cause of the disease is still unknown, evidence argues that autoimmunity plays an important part. There are increasing but contradictory views regarding serotonin being associated with activation of immunoinflammatory pathways and the onset of autoimmune reactions. We studied serotonins involvement during collagen-induced arthritis in wild-type and Tph1(-/-) mice, which have markedly reduced peripheral serotonin levels. In wild-type mice, induction of arthritis triggered a robust increase in serotonin content in the paws combined with less inflammation. In Tph1(-/-) mice with arthritis, a marked increase in the clinical and pathologic arthritis scores was noticed. Specifically, in Tph1(-/-) mice with arthritis, a significant increase in osteoclast differentiation and bone resorption was observed with an increase in IL-17 levels in the paws and in Th17 lymphocytes in the draining lymph nodes, whereas T-regulatory cells were dampened. Ex vivo serotonin and agonists of the 5-HT2A and 5-HT2B receptors restored IL-17 secretion from splenocytes and Th17 cell differentiation in Tph1(-/-) mice. These findings indicate that serotonin plays a fundamental role in arthritis through the regulation of the Th17/T-regulatory cell balance and osteoclastogenesis.

APRIL levels are associated with disease activity in human chronic graft-versus-host disease

After allogeneic hematopoietic stem cell transplantation (AHSCT), acute GVHD is almost entirely mediated by donor T cells whereas chronic graft- versus -host disease (cGVHD) also involves donor B cells.[1][1] A breakdown in peripheral B cell homeostasis in cGVHD is in part due to high levels of B

Efficacy and tolerance of ruxolitinib in refractory sclerodermatous chronic graft-versus-host disease

DEAR EDITOR, Chronic graft-versus-host disease (cGVHD) occurs frequently following allogeneic haematopoietic stem cell transplantation (AHSCT). It can often be severe and there is currently an unmet therapeutic need. A recent retrospective study has shown the potential efficacy of ruxolitinib, a selective Janus kinase (JAK)1/2 inhibitor, for the treatment of acute graft-versus-host disease (aGVHD) (n = 54) and cGVHD (n = 41), with an overall response rate of 82% and 85%, respectively. There are no specific studies evaluating the efficacy of ruxolitinib in sclerodermatous cGVHD of the skin, a rare and difficult to treat form of cGVHD. This monocentric retrospective study enrolled patients (n = 12) with severe sclerodermatous cGVHD treated with ruxolitinib between May 2015 and July 2016. Patients with severe sclerodermatous cGVHD were defined as patients who had a modified Rodnan skin score (mRSS) ≥ 10 and were refractory to corticosteroids and at least one other immunosuppressive drug. All of the patients had a stable or worsening mRSS

Clinical profile, biological markers, and comorbidity index as predictors of transplant-related mortality after allo-HSCT

Various pretransplant patient and disease characteristics are associated with treatment-related mortality (TRM) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, TRM cannot yet be satisfactorily predicted. We prospectively investigated the aggregate impact of pretransplant clinical variables (period, donor/recipient age, gender, cytomegalovirus status, disease risk, stem cell source, and HLA matching), comorbidity index scores (Hematopoietic Cell Transplantation Comorbidity Index), and biological markers (telomere length, ferritin, and C-reactive protein) on TRM in single-center patients receiving a first allo-HSCT. From 2006 to 2012, all variables were available for 178 patients. In multivariate analysis, only mismatched unrelated donor (hazard ratio [HR], 2.79; 95% confidence interval [CI], 1.19-6.58; P = .019) and shorter age-adjusted recipient telomere length (HR, 2.17; 95% CI, 1.03-4.57; P = .041) were independently associated with TRM. Pre-allo-HSCT age-adjusted telomere length thus appears to be a useful new predictor of TRM in the setting of HSCT.

Success of haploidentical hematopoietic stem cells transplantation in the treatment of graft failure

Dear Editor, Graft failure (GF), defined as an absolute neutrophil count lower than 0.5×10/l on day 28 with a persistent full recipient chimerism, is a life-threatening complication of allogeneic transplantation (hematopoietic stem cell transplantation (HSCT)) [1]. Its incidence (1 to 20 %) depends on many factors (type of donor, underling disease, HLA identity, stem cell manipulation) [2–5]. Here, we report on a patient who experienced two consecutive graft failures that were successfully managed grace to a haploidentical HSCT. A 63-year-old woman was diagnosed with a MDS type RAEB-T. She had a monosomal and complex karyotype at diagnosis. On June 2014, she underwent HSCT from a 9/10 HLA (mismatching on HLA-B) unrelated donor (UD), upfront without any pre-transplantation treatment. (Donor/ recipient characteristics were sex F/F, group B+/B+, CMV+/+ EBV +/+, and negative HLA-antibodies). Conditioning regimen was busulfan (3.2 mg/kg/day days −6 to −2), fludarabin (30 mg/m/day days −5 to −2), and thymoglobulin (5 mg/kg/day day −3 to −2). Cyclosporine A (CSA) and mycophenolic acid (MMF) were used as GVHD prophylaxis. Peripheral blood stem cells (PBSC) infusion contained 20×10 TNC/kg and 9×10 CD34+/kg. Platelets and neutrophil engraftments were seen on day +12 and +24. Chimerism was 70 % donor, but a few days later, at day +26, she presented undocumented fever and skin rash followed by pancytopenia. A bone marrow biopsy excluded relapse showing no cellularity. A second chimerism (day +37) showed 3 % of donor cells in the setting of persistent pancytopenia. CSA and MMF were stopped but in the absence of hematological recovery, a second HSCT was organized and two unrelated cord blood (CB) units were identified (both 4/6 mismatching) and were infused on day +63. HLA-antibodies were negative. Preparatory regimen consisted of fludarabin (30 mg/m2 day −6 to −4), cyclophosphamide (50 mg/kg/ day −6) and total body irradiation (TBI) 2 Gy. Graft units were 0+ and B+ and had 2.3 and 1.9×10 TNC/kg, respectively, but again, no engraftment was observed in the next 40 days post CB infusion. Since the patient was still in good shape, in October 2014 a third transplant from her son was performed on day +53 and of the second HSCT (day +116 the first one). Conditioning regimen was non-myeloablative according to Baltimore recommendations and consisted of fludarabine 30 mg/m day −6 to −4, pre-transplant cyclophosphamide 14.5 mg/kg day −6 and day −5, and TBI 2 Gy on day −1. GVHD prophylaxis was given by post-transplant cyclophosphamide 50 mg/kg day +3 and +4, CSA, and MMF. PBSC infusion contained 13.6×10 CD34/kg [6]. On day +12 the WBC count rapidly increased with G-CSF stimulation. A full donor chimerism was found. On day +20 grade II (stage III) * Simona Pagliuca smnpag@gmail.com