Bone marrow graft-versus-host disease: early destruction of hematopoietic niche after MHC-mismatched hematopoietic stem cell transplantation

Blood ◽  
2010 ◽  
Vol 115 (26) ◽  
pp. 5401-5411 ◽  
Author(s):  
Yusuke Shono ◽  
Satoshi Ueha ◽  
Yong Wang ◽  
Jun Abe ◽  
Makoto Kurachi ◽  
...  

Abstract Disrupted hematopoiesis and delayed immune reconstitution are life-threatening complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although graft-versus-host disease (GVHD) is a major risk factor for the bone marrow (BM) insufficiency, how GVHD impairs BM hematopoiesis has been largely unknown. We hypothesized that BM stromal niche could be a target of GVHD. In major histocompatibility complex (MHC)–mismatched murine models of GVHD, we have demonstrated the early destruction of osteoblasts that especially affected B-cell lineages. The defective B lymphopoiesis was due to the impaired ability of BM stroma and osteoblasts to support the hematopoiesis, as evidenced by the failure of GVHD-affected BM to reconstitute the hematopoietic cells. The administration of anti-CD4 monoclonal antibody (mAb) ameliorated these effects and improved B lymphopoiesis while preserving graft-versus-tumor effects. Genetic ablation of Fas–Fas ligand signaling also partially restored B lymphopoiesis. Our present study provided evidence of BM GVHD, with the identification of osteoblasts as the main target for GVHD in BM. Moreover, our data showed the potential for mAb therapies to enhance immune reconstitution in vivo for patients undergoing allo-HSCT.

Blood ◽  
2010 ◽  
Vol 115 (6) ◽  
pp. 1296-1302 ◽  
Author(s):  
Pietro Sodani ◽  
Antonella Isgrò ◽  
Javid Gaziev ◽  
Paola Polchi ◽  
Katia Paciaroni ◽  
...  

Abstract Fetomaternal microchimerism suggests immunological tolerance between mother and fetus. Thus, we performed primary hematopoietic stem cell transplantation from a mismatched mother to thalassemic patient without an human leukocyte antigen–identical donor. Twenty-two patients with thalassemia major were conditioned with 60 mg/kg hydroxyurea and 3 mg/kg azathioprine from day −59 to −11; 30 mg/m2 fludarabine from day −17 to −11; 14 mg/kg busulfan starting on day −10; and 200 mg/kg cyclophosphamide, 10 mg/kg thiotepa, and 12.5 mg/kg antithymocyte globulin daily from day −5 to −2. Fourteen patients received CD34+-mobilized peripheral blood and bone marrow progenitor cells; 8 patients received marrow graft–selected peripheral blood stem cells CD34+ and bone marrow CD3/CD19-depleted cells. T-cell dose was adjusted to 2 × 105/kg by fresh marrow cell addback at the time of transplantation. Both groups received cyclosporine for graft-versus-host disease prophylaxis for 2 months after transplantation. Two patients died (cerebral Epstein-Barr virus lymphoma or cytomegalovirus pneumonia), 6 patients reject their grafts, and 14 showed full chimerism with functioning grafts at a median follow-up of 40 months. None of the 14 patients who showed full chimerism developed acute or chronic graft-versus-host disease. These results suggest that maternal haploidentical hematopoietic stem cell transplantation is feasible in patients with thalassemia who lack a matched related donor.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4578-4578
Author(s):  
Ke Zhao ◽  
Zhiping Fan ◽  
Fen Huang ◽  
Shunqing Wang ◽  
Peng Xiang ◽  
...  

Abstract Background Chronic graft-versus-host disease (cGVHD) is the common long-term complication and the leading cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which has a significant impact on patient quality of life. Currently, mesenchymal stromal cells (MSCs) have been considered as a promising therapy for treating refractory acute/chronic GVHD and engraftment failure (EF) or poor graft function (PGF), but the efficacy of MSCs in the prophylaxis of cGVHD is rarely reported. Methods Eighty-two patients who received MSCs treatment after allo-HSCT were enrolled in our study, including 45 patients with refractory aGVHD, 33 patients with EF or PGF and 4 patients with virus infection. In order to evaluate the influence of bone marrow (BM) derived MSCs for the incidence and severity of cGVHD, 308 consecutive patients who underwent allo-HSCT in the same period but without MSCs treatment were considered as the control group. And no statistical significance was found between the two groups for the demographic and transplant characteristics. MSCs were given at a median dose of 1×106 cells/kg once weekly. Results All eighty-two patients in MSC group received a median of 5 (range:3-12) doses of MSCs per patient. In MSC group, seventeen patients (20.7%) had cGVHD, including 14 patients with limited cGVHD and 3 patients with extensive cGVHD. In the control group, 140 patients (45.5%) had cGVHD, including 95 patients with limited and 45 extensive cGVHD. The 2-year cumulative incidence of cGVHD was 26.7% (95%CI: 16.1%-37.5%) in MSC group and 50.4% (95%CI: 37%-63.8%) in the control group (P=0.037). Furthermore, the extensive cGVHD (3/82) in the MSC group were also significantly lower than those (45/308) in the control group (P=0.021). In addition, at a median follow-up time of 189 (range: 112-1035) days post-transplantation, 4 patients relapsed in MSC group and 13 patients relapsed in the control group. The incidence of tumor relapse was not different between the two groups (P=0.629). No short-term toxic side effects were observed and other secondary tumor occurred after MSCs treatment. Conclusion MSCs derived from BM reduce the incidence and severity of cGVHD after allo-HSCT, but not increase the risk of tumour relapse. Disclosures No relevant conflicts of interest to declare.


2019 ◽  
Vol 65 (3) ◽  
pp. 330-336
Author(s):  
Irina Gribkova ◽  
I. Ishmatova ◽  
Mariya Davydovskaya ◽  
K. Kokushkin

The aim of the study was to systematize and summarize the current available data on ruxolitinib use in patients with myelofibrosis (MF) prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) to improve its results. The review includes data from foreign and domestic articles found in the PubMed and elibrary.ru databases describing the results of the use of ruxolitinib in patients with MF prior to allo-HSCT, including clinical cases, original scientific studies and reviews. It is reported that ruxolitinib therapy is safe, reduces mortality in the early post-transplantation period, reduces the incidence of acute and chronic graft-versus-host disease, and decreases the frequency of relapses. Clinical improvement with ruxolitinib therapy prior to allo-HSCT can be considered a prognostically favorable factor.


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