Xiaojin Wu

Expression and function of toll‐like receptors in multiple myeloma patients: toll‐like receptor ligands promote multiple myeloma cell growth and survival via activation of nuclear factor‐κB

Toll like receptors (TLRs) are the major agents for innate immunity that recognize invading microbial products and regulate the growth of normal and malignant human B lymphocytes. Multiple myeloma (MM) is a clonal plasma cell malignancy, though the regulatory role of TLRs in MM plasma cells has been reported, the molecular mechanism remains unclear. We first compared the transcripts of TLR1 to TLR10 in MM patients and healthy donors and found that TLR2, ‐4 and ‐9 transcripts were higher in bone marrow mononuclear cells (BMMCs) from patients than those from donors; in addition the expression of TLR4 and TLR9 were higher in MM cells than normal cells as demonstrated by flow cytometric analyses. The ligands of these two TLRs were capable to promote the growth of MM cells and protect them from serum‐deprivation‐induced apoptosis but not normal plasma cells, which could be attenuated with anti‐IL6 neutralizing antibodies or blockage of NF‐κB activities. Further investigation demonstrated that these TLR ligands could trigger the nuclear translocation of NF‐κB p65 and the activated NF‐κB was sufficient to increase the expression of IL6 transcript in MM cells. These data suggested that activated NF‐κB signalling probably plays a crucial role for the ligands of TLR4 and TLR9 to promote the growth and survival of MM cells partially through IL6 autocrine.

Cytomegalovirus Glycoprotein B Genotype in Hematopoietic Stem Cell Transplant Patients from China

Cytomegalovirus (CMV) can be classified into 4 subgroups based on genotype variation of the glycoprotein B (gB) encoded by UL55 gene. Little is known about the CMV gB genotype distribution and its clinical implication in patients who receive hematopoietic stem cell transplant (HSCT) in China. In this study, which comprises 101 HSCT patients with CMV infection, we have found that 36 patients (35.64%) were infected with CMV genotype gB1, 3 patients (2.97%) with gB2, 39 patients (38.61%) with gB3, 1 patient (0.99%) with gB4, and 17 patients (16.83%) were infected with mixed CMV genotypes. We also found that CMV gB3 was associated with a high risk of CMV pneumonitis; nevertheless, there were no significant differences among patients with gB genotypes with respect to the other CMV diseases; no significant differences between patients with gB genotypes with respect to type II-IV acute graft-verses-host disease (aGVHD) and chronic GVHD (cGVHD) was found either. Interestingly, 5 patients (4.95%) were infected with a CMV variant that lacked a signature RsaI digestion site determined by Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), subsequent cloning and sequencing identified this CMV RsaI minus variant to be novel, herein designated as gB5. Overall, these findings suggest that CMV gB1 and gB3 are prevalent among HSCT recipients with CMV infections, and gB3 CMV infection is a risky indicator for CMV pneumonitis; furthermore, a novel CMV variant in a subset of Chinese HSCT recipients is identified and designated as gB5.

The Expression of Th17-Associated Cytokines in Human Acute Graft-versus-Host Disease

The role of Th17 cells and Th17-associated cytokines in the development of acute graft-versus-host disease (aGVHD) in clinical allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients is not well established. In the current study, a cohort of 69 allo-HSCT patients was examined for the percentages of Th17 and FoxP3(+) Treg cells and the expressions of RORγt and FoxP3 in peripheral blood mononuclear cells (PBMCs). The Th17 percentage and RORγt expression were significantly higher, whereas Treg percentage and FoxP3 expression were significantly lower in severe aGVHD (grade 3 to 4) and mild aGVHD (grade 1 to 2) patients than in patients without aGVHD (grade 0) and healthy donors. We then investigated the expressions of Th17-associated cytokines, including TGF-β, IL-6, IL-1β, IL-17, IL-21, IL-22, IL-23, as well as IL-23R in the PBMCs of patients after allo-HSCT. The expressions of IL-17 and IL-22 in CD4(+) T cells were also examined. The results showed that the expressions of IL-6, IL-1β, IL-17, IL-21, IL-23, and IL-23R were all increased, whereas IL-22 expression was decreased in aGVHD patients. The changes were also correlated with the severity of aGVHD. We also investigated the dynamic changes of Th17/Treg cells and Th17-associated cytokines in patients during the onset and resolution of aGVHD. The results demonstrated a reciprocal relationship between Treg and Th17 cells. Th17-associated cytokine expressions, namely IL-17 and IL-23, were closely related to the occurrence and resolution of aGVHD. We conclude that the dynamic balance between the Th17 and FoxP3(+) Treg cells and the changes of Th17-associated cytokines could be the indicators of the disease progression and promising candidates of prognostic biomarkers of aGVHD.

Alterations of hemostatic parameters in the early development of allogeneic hematopoietic stem cell transplantation-related complications

Thrombotic events are common and potentially fatal complications in patients receiving hematopoietic stem cell transplantation (HSCT). Early diagnosis is crucial but remains controversial. In this study, we investigated the early alterations of hemostatic parameters in allogeneic HSCT recipients and determined their potential diagnostic values in transplantation-related thrombotic complications and other post-HSCT events. Results from 107 patients with allogeneic HSCT showed higher levels of plasma plasminogen activator inhibitor-1 (PAI-1), fibrinogen, and tissue-plasminogen activator (t-PA) and a lower level of plasma protein C after transplantation. No change was found for prothrombin time, antithrombin III, d-dimer, and activated partial thromboplastin time following HSCT. Transplantation-related complications (TRCs) in HSCT patients were defined as thrombotic (n = 8), acute graft-versus-host disease (aGVHD, n = 45), and infectious (n = 38). All patients with TRCs, especially the patients with thrombotic complications, presented significant increases in the mean and maximum levels of PAI-1 during the observation period. Similarly, a high maximum t-PA level was found in the thrombotic group. In contrast, apparent lower levels of mean and minimum protein C were observed in the TRC patients, especially in the aGVHD group. Therefore, the hemostatic imbalance in the early phase of HSCT, reflecting prothrombotic state and endothelial injury due to the conditioning therapy or TRCs, might be useful in the differential diagnosis of the thrombotic complication from other TRCs.

Haploidentical allogeneic hematopoietic stem cell transplantation compared to matched unrelated transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia

To investigate the effect of haploidentical allogeneic hematopoietic stem cell transplantation (Haplo-HCT) in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), the outcome of 58 patients with Ph+ ALL who received Haplo-HCT (n=42) or matched unrelated donor transplantation (MUD-HCT) (n=16) during the same period were analyzed retrospectively. All patients received a tyrosine kinase inhibitor (TKI)-based regimen before transplantation, and TKI was resumed primarily after transplantation. At the 3-year follow-up, the overall survival (OS), leukemia-free survival (LFS), the cumulative incidence of relapse (CIR), and non-relapse mortality (NRM) rates in Haplo-HCT group were 69.1, 64.3, 19.0, and 14.3%, respectively, without significant differences from that of MUD-HCT. Haplo-HCT was not related to higher incidences of severe acute graft-versus-host disease (GvHD) (17.6±5.2% vs. 20.0±10.0%, P=0.603) or chronic GvHD (19.5±7.1% vs. 13.3±8.6%, P=0.637) as compared to MUD-HCT. Multivariate analysis showed that chronic GvHD was associated with lower relapse rate in Haplo-HCT group. Haplo-HCT is a promising choice for improving the long-term survival in Ph+ ALL patients.