Xiuli Wu

Improvement in poor graft function after allogeneic hematopoietic stem cell transplantation upon administration of mesenchymal stem cells from third-party donors: a pilot prospective study.

Poor graft function (PGF) is a refractory complication that occurs after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the present study, we prospectively evaluated the efficacy and safety of mesenchymal stem cells (MSCs) expanded from the bone marrow of a third-party donor to patients with PGF after allo-HSCT. Twenty patients with PGF (7 with primary and 13 with secondary PGF) received MSCs (1 × 106/kg) one to three times at 28-day intervals. Seventeen patients were responsive to MSCs, whereas three were not. Within the first 100 days after MSC treatment, 13 patients developed 20 episodes of infection. Moreover, five patients experienced cytomegalovirus-DNA viremia, and seven experienced Epstein—Barr virus (EBV)—DNA viremia within the first 100 days after MSC treatment; three of the latter developed EBV-associated posttransplant lymphoproliferative disorders (PTLD) within the follow-up period. Grade II acute graft-versus-host disease (GVHD) occurred in one patient, and local chronic GVHD occurred in two patients after receiving MSC treatment, including one acute GVHD and one chronic GVHD, respectively, after accepting donor lymphocyte infusions due to PTLD. After a follow-up period of an average of 508 days (range 166-904 days) posttransplantation, 11 patients died. No short-term toxic side effects were observed after MSC treatment. Two patients experienced leukemic relapse. With the exception of three patients with PTLD, no secondary tumors occurred. These results indicate that MSCs derived from the bone marrow of a third-party donor are beneficial in the treatment of both primary and secondary PGF that develops after allo-HSCT. However, additional studies will be needed to determine whether such treatment might increase the risk of EBV infection and reactivation or the development of EBV-associated PTLD.

Granulocyte colony-stimulating factor affects the distribution and clonality of TRGV and TRDV repertoire of T cells and graft-versus-host disease

BackgroundThe immune modulatory effect of granulocyte colony-stimulating factor (G-CSF) on T cells resulted in an unexpected low incidence of graft-versus-host disease (GVHD) in allogeneic peripheral blood stem cell transplantation (allo-PBSCT). Recent data indicated that gamma delta+ T cells might participate in mediating graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effect after allogeneic hematopoietic stem cell transplantation. However, whether G-CSF could influence the T cell receptors (TCR) of gamma delta+ T cells (TRGV and TRDV repertoire) remains unclear. To further characterize this feature, we compared the distribution and clonality of TRGV and TRDV repertoire of T cells before and after G-CSF mobilization and investigated the association between the changes of TCR repertoire and GVHD in patients undergoing G-CSF mobilized allo-PBSCT.MethodsThe complementarity-determining region 3 (CDR3) sizes of three TRGV and eight TRDV subfamily genes were analyzed in peripheral blood mononuclear cells (PBMCs) from 20 donors before and after G-CSF mobilization, using RT-PCR and genescan technique. To determine the expression levels of TRGV subfamily genes, we performed quantitative analysis of TRGV I~III subfamilies by real-time PCR.ResultsThe expression levels of three TRGV subfamilies were significantly decreased after G-CSF mobilization (P = 0.015, 0.009 and 0.006, respectively). The pattern of TRGV subfamily expression levels was TRGV II > TRGV I > TRGV III before mobilization, and changed to TRGV I > TRGV II > TRGV III after G-CSF mobilization. The expression frequencies of TRGV and TRDV subfamilies changed at different levels after G-CSF mobilization. Most TRGV and TRDV subfamilies revealed polyclonality from pre-G-CSF-mobilized and G-CSF-mobilized samples. Oligoclonality was detected in TRGV and TRDV subfamilies in 3 donors before mobilization and in another 4 donors after G-CSF mobilization, distributed in TRGV II, TRDV 1, TRDV 3 and TRDV 6, respectively. Significant positive association was observed between the invariable clonality of TRDV 1 gene repertoire after G-CSF mobilization and low incidence of GVHD in recipients (P = 0.015, OR = 0.047).ConclusionsG-CSF mobilization not only influences the distribution and expression levels of TRGV and TRDV repertoire, but also changes the clonality of gamma delta+ T cells. This alteration of TRGV and TRDV repertoire might play a role in mediating GVHD in G-CSF mobilized allo-PBSCT.

Soluble Human Leukocyte Antigen G Molecule Expression in Allogeneic Hematopoietic Stem Cell Transplantation: Good Predictor of Acute Graft-versus-Host Disease

Background: Graft-versus-host disease (GVHD) remains a main complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Human leukocyte antigen G (HLA-G) is a non-classical class I molecule exerting multiple immunoregulatory functions. The aim of this study was to explore the relationship between soluble HLA-G (sHLA-G) and GVHD after allo-HSCT. Methods: The sHLA-G levels were examined using enzyme-linked immunosorbent assay in patients with hematological malignancies (n = 106) before transplantation, on days +15 and +30 after transplantation, as well as healthy volunteers (n = 10). Results: The levels of sHLA-G5, sHLA-G6 and sHLA-G7 in patients on days +15 and +30 after transplantation were all significantly higher than those before transplantation (all p ≤ 0.001). The increased levels of sHLA-G5 on days +15 and +30 after transplantation were both significantly higher in patients with grade 0-I acute GVHD (aGVHD) compared to those with grade II-IV aGVHD (both p < 0.001). The increased levels of sHLA-G5 on days +15 and +30 after transplantation were both negatively correlated with the severity of aGVHD (both p < 0.001). Conclusion: sHLA-G5 might be a predictor of the occurrence and severity of aGVHD, which may help to establish individual prophylaxis against aGVHD and improve the survival for patients after allo-HSCT.

Epstein–Barr virus (EBV) load in cerebrospinal fluid and peripheral blood of patients with EBV‐associated central nervous system diseases after allogeneic hematopoietic stem cell transplantation

To evaluate the diagnostic and prognostic utility of monitoring the Epstein–Barr virus (EBV) load in the cerebrospinal fluid (CSF) and peripheral blood for the patients with EBV‐associated central nervous system (CNS) diseases after allogeneic hematopoietic stem cell transplantation (allo‐HSCT), 172 patients undergoing allo‐HSCT were enrolled in the study.

Idiopathic pneumonia syndrome in mice after allogeneic bone marrow transplantation: association between idiopathic pneumonia syndrome and acute graft-versus-host disease ☆

OBJECTIVE To explore the association between idiopathic pneumonia syndrome (IPS) and acute graft-versus-host disease (aGVHD) in allogeneic hematopoietic stem cell transplantation. METHODS Established acute GVHD model of C57BL/6-->BALB/c mice. Chest computed tomography (CT) scans were dynamically performed in recipient mice after transplant. Lung histopathology and cytokine levels (including TNF-alpha and IFN-gamma) were examined in three experimental groups: mice receiving simple irradiation, syngeneic transplants, and allogeneic transplants. RESULTS All allogeneic transplant mice developed aGVHD. On CT, most aGVHD mice had bilateral diffuse lung infiltrates, while syngeneic transplant mice had normal lungs. On histopathology, aGVHD mice had acute pneumonitis. On immunohistochemistry, the infiltrates were mainly CD4+ T cells during aGVHD onset, but CD8+ T cells predominated during aGVHD progression. Lung TNF-alpha and IFN-gamma levels were higher in the three experimental groups than in normal controls on days +3 and +7 post-transplant. On day +7, TNF-alpha levels were higher in allogeneic than in syngeneic transplant mice; IFN-gamma levels were not different. On days +12 and +16, TNF-alpha levels were higher but IFN-gamma levels were lower in allogeneic mice than in syngeneic transplant mice. CONCLUSIONS The underlying cause of IPS is aGVHD. T cells and TNF-alpha may play a role in the pathogenesis of aGVHD-induced IPS. IPS progression may be associated with decreasing lung IFN-gamma levels.

Effect of granulocyte colony-stimulating factor mobilization on the expression patterns, clonality and signal transduction of TRAV and TRBV repertoire

The immune modulatory effect of granulocyte colony-stimulating factor (G-CSF) on T cells resulted in an unexpected low incidence of graft-versus-host disease (GVHD) in allogeneic peripheral blood stem cell transplantation (allo-PBSCT). Recently, αβ(+) T cells are identified as the primary effector cells for GVHD. However, whether G-CSF could influence the repertoire of αβ(+) T cells (TRAV and TRBV repertoire) and CD3 genes remains unclear. To further characterize this feature, we investigated the effect of G-CSF mobilization on the T cell receptors (TCR) of αβ(+) T cells (TRAV and TRBV repertoire) and CD3 genes, as well as the association between the changes of TCR repertoire and GVHD in patients undergoing G-CSF mobilized allo-PBSCT. We found that G-CSF mobilization had an effect on the expression patterns, clonality and signal transduction of TRAV and TRBV repertoire. This alteration might play a role in mediating GVHD in G-CSF mobilized allo-PBSCT.