Comparison analysis between haplo identical stem cell transplantation and matched sibling donor stem cell transplantation for high-risk acute myeloid leukemia in first complete remission

In order to compare the effect between haploidentical(HID) stem cell transplantation(HSCT) and matched sibling donor(MSD)stem cell transplantation for high-risk acute myeloid leukemia(AML) in first complete remission status(CR1), we retrospectively studied 170 cases who received stem cell transplantation from Jan 2008 to Jul 2015 in Peking University People's Hospital. We divided all cases into MSD group(43 cases) and HID(127 cases) group. Patients in HID and MSD group displayed similar baseline characteristics except for age distribution. There were no statistic differences for overall survival(OS), cumulative incidence of relapse, leukemia free survival(LFS), transplantation related mortality(TRM) between HID and MSD group. The 3-year OS, LFS for all patients was 63.9% and 59.7% respectively. Multivariate analysis showed that grade III-IV acute graft versus host disease(aGVHD) was an independent risk factor for treatment related mortality(HR=8.134, 95% CI:3.210–20.611, P0.001), monosomy/complex chromosomal karyotype and white blood cell count more than 50×109 L-1 were two independent factors for relapse(HR=1.533, 95% CI: 1.040–2.260, P=0.031)(HR=1.004, 95% CI: 1.001–1.008, P=0.015).Grade III-IV aGVHD was an independent factor for mortality(HR=3.184, 95% CI: 1.718–5.902, P0.001). These results demonstrated some risk factors for high-risk AML leukemia transplantation and indicated for AML patients in CR1 status, haplo stem cell transplantation could have the same therapeutic effect as MSD transplantation.     

Virus infections and apoptosis: Lessons from HIV

Many viruses establish life-long infections in their natural host with few if any clinical manifestations. The relationship between virus and host is a dynamic process in which the virus has evolved the means to coexist by reducing its visibility, while the host immune system attempts to suppress and eliminate infection without damage to itself. We are now beginning to understand that viruses can employ a variety of strategies to evade host immune responses. These include escape from T cell recognition, resistance to     

WJSC 6th Anniversary Special Issues（2）:Mesenchymal stem cells Mesenchymal stem cells help pancreatic islet transplantation to control type 1 diabetes

Islet cell transplantation has therapeutic potential to treat type 1 diabetes,which is characterized by autoimmune destruction of insulin-producing pancreatic isletβcells.It represents a minimal invasive approach forβcell replacement,but long-term blood control is still largely unachievable.This phenomenon can be attributed to the lack of islet vasculature and hypoxic environment in the immediate post-transplantation period that contributes to the acute loss of islets by ischemia.Moreover,graft failures continue to occur because of immunological rejection,despite the use of potent immunosuppressive agents.Mesenchymal stem cells(MSCs)have the potential to enhance islet transplantation by suppressing inflammatory damage and immune mediated rejection.In this review we discuss the impact of MSCs on islet transplantation and focus on the potential role of MSCs in protecting islet grafts from early graft failure and from autoimmune attack.     

Effector Immune Cell Deployment: a revolutionized concept in cancer immunotherapy

<正>It is estimated that each cell experiences over 20,000 DNA damaging events daily, which are normally repaired. Cells that are beyond repair or acquire malignancy are usually recognized and killed by host immunosurveillance system.However, tumor cells develop mechanisms to thwart immune recognition and response, a dynamic process termed immunoediting, which eventually leads to immune escape.     

Stem cell therapy for retinal diseases

In this review, we discuss about current knowledge about stem cell(SC) therapy in the treatment of retinal degeneration. Both human embryonic stem cell and induced pluripotent stem cell has been growth in culture for a long time, and started to be explored in the treatment of blinding conditions. The Food and Drug Administration, recently, has granted clinical trials using SC retinal therapy to treat complex disorders, as Stargardt’s dystrophy, and patients with geographic atrophy, providing good outcomes. This study ’s intent is to overview the critical regeneration of the subretinal anatomy through retinal pigment epithelium transplantation, with the goal of reestablish important pathways from the retina to the occipital cortex of the brain, as well as the differentiation from pluripotent quiescent SC to adult retina, and its relationship with a primary retinal injury, different techniques of transplantation, management of immune rejection and tumorigenicity, its potential application in improving patients’ vision, and, finally, approaching future directions and challenges for the treatment of several conditions.     

Granulocyte-macrophage colony-stimulating factor （GM-CSF） and T-cell responses： what we do and don＇t know

Granulocyte-macrophage colony-stimulating factor （GM-CSF） is an important hematopoietic growth factor and immune modulator. GM-CSF also has profound effects on the functional activities of various circulating leukocytes. It is produced by a variety of cell types including T cells, macrophages, endothelial cells and fibroblasts upon receiving immune stimuli. Although GM-CSF is produced locally, it can act in a paracrine fashion to recruit circulating neutrophils, monocytes and lymphocytes to enhance their functions in host defense. Recent intensive investigations are centered on the application of GM-CSF as an immune adjuvant for its ability to increase dendritic cell （DC） maturation and function as well as macrophage activity. It is used clinically to treat neutropenia in cancer patients undergoing chemotherapy, in AIDS patients during therapy, and in patients after bone marrow transplantation. Interestingly, the hematopoietic system of GM-CSF-deficient mice appears to be normal; the most significant changes are in some specific T cell responses. Although molecular cloning of GM-CSF was carried out using cDNA library oft cells and it is well known that the T cells produce GM-CSF after activation, there is a lack of systematic investigation of this cytokine in production by T cells and its effect on T cell function. In this article, we will focus mainly on the immunobiology of GM-CSF in T cells.     

Importance of the stem cell microenvironment for ophthalmological cell-based therapy

Cell therapy is a promising treatment for diseases that are caused by cell degeneration or death. The cells for clinical transplantation are usually obtained by culturing healthy allogeneic or exogenous tissue invitro. However, for diseases of the eye, obtaining the adequate number of cells for clinical transplantation is difficult due to the small size of tissue donors and the frequent needs of long-term amplification of cells in vitro, which results in low cell viability after transplantation. In addition, the transplanted cells often develop fibrosis or degrade and have very low survival. Embryonic stem cells(ESCs) and induced pluripotent stem cells(i PS) are also promising candidates for cell therapy. Unfortunately, the differentiation of ESCs can bring immune rejection, tumorigenicity and undesired differentiated cells, limiting its clinical application. Although i PS cells can avoid the risk of immune rejection caused by ES cell differentiation post-transplantation, the low conversion rate, the risk of tumor formation and the potentially unpredictable biological changes that could occur through genetic manipulation hinder its clinical application. Thus, the desired clinical effect of cell therapy is impaired by these factors. Recent research findings recognize that the reason for low survival of the implanted cells not only depends on the seeded cells, but also on the cell microenvironment, which determines the cell survival, proliferation and even reverse differentiation. When used for cell therapy, the transplanted cells need a specific three-dimensional structure to anchor and specific extra cellular matrix components in addition to relevant cytokine signaling to transfer the required information to support their growth. These structures present in the matrix in which the stem cells reside are known as the stem cell microenvironment. The microenvironment interaction with the stem cells provides the necessary homeostasis for cell maintenance and growth. A large number of studies suggest that to explore how to reconstruct the stem cell microenvironment and strengthen its combination with the transplanted cells are key steps to successful cell therapy. In this review, we will describe the interactions of the stem cell microenvironment with the stem cells, discuss the importance of the stem cell microenvironment for cell-based therapy in ocular diseases, and introduce the progress of stem cell-basedtherapy for ocular diseases.     

Adoptive transfer of T cells transduced with a chimeric antigen receptor to treat relapsed or refractory acute leukemia: efficacy and feasibility of immunotherapy approaches

Treatment outcomes of acute leukemia(AL) have not improved over the past several decades and relapse rates remain high despite the availability of aggressive therapies. Conventional relapsed leukemia treatment includes second allogeneic hematopoietic stem cell transplantation(allo-HSCT) and donor lymphocyte infusion(DLI), which in most cases mediate, at best, a modest graft-versus-leukemia effect, although their clinical efficacy is still limited. Although allo-HSCT following myeloablative conditioning is a curative treatment option for younger patients with acute myeloid leukemia(AML) in a first complete remission(CR), allo-HSCT as a clinical treatment is usually limited because of treatment-related toxicity. The overall DLI remission rate is only 15%–42% and 2-year overall survival(OS) is approximately 15%–20%, with a high(40%–60%) incidence of DLI-related graft-versus-host disease(GVHD). Therefore, development of new, targeted treatment strategies for relapsed and refractory AL patients is ongoing. Adoptive transfer of T cells with genetically engineered chimeric antigen receptors(CARs) is an encouraging approach for treating hematological malignancies. These T cells are capable of selectively recognizing tumor-associated antigens and may overcome many limitations of conventional therapies, inducing remission in patients with chemotherapy-refractory or relapsed AL. In this review, we aimed to highlight the current understanding of this promising treatment modality, discussing its adverse effects and efficacy.     

Activation—induced cell death in B lymphocytes

Upon encountering the antigen(Ag),the immune system can either develop a specific immune response of enter a specific state of unresponsiveness,tolerance.The response of B cells to their specific Ag can be activation and proliferation,leading to the immune response,or anergy and activation-induced cell death(AICD),leading to tolerance.AICD in B lymphocytes is a highly regulated event initiated by crosslinking of the B cell receptor (BCR).BCR engagement initiates several signaling events such as activation of PLCγ,Ras,and PI3K,which generally speaking,lead to survival.However,in the absence of survival signals(CD40 or IL-4R engagement),BCR crosslinking can also promote apoptotic signal transduction pathways such as activation of effector caspases,expression of pro-apoptotic genes,and inhibition of pro-survival genes.The complex interplay between survival and death signals determines the B cell fate and, consequently,the immune response.     

Galectin-1-mediated biochemical controls of melanoma and glioma aggressive behavior

Gliomas and melanomas are associated with dismal prognosis because of their marked intrinsic resistance to proapoptotic stimuli,such as conventional chemotherapy and radiotherapy,as well as their ability to escape immune cell attacks.In addition,gliomas and melanomas display pronounced neoangiogenesis.Galectin-1 is a hypoxia-sensitive protein,which is abundantly secreted by glioma and melanoma cells,which displays marked proangiogenic effects.It also provides immune tolerogenic environments to melanoma and glioma cells through the killing of activated T cells that attack these tumor cells.Galectin-1 protects glioma and melanoma cells against cytotoxic insults(including chemotherapy and radiotherapy) through a direct role in the unfolded protein response.Altogether,these facts clearly point to galectin-1 as an important target to be combated in gliomas and melanomas in order to:(1) weaken the defenses of these two types of cancers against radiotherapy,chemotherapy and immunotherapy/vaccine therapy;and(2) reinforce antiangiogenic therapies.In the present article,we review the biochemical and molecular biology-related pathways controlled by galectin-1,which are actually beneficial for melanoma and glioma cells,and therefore detrimental for melanoma and glioma patients.     

Generation of GGTA1 biallelic knockout pigs via zinc-finger nucleases and somatic cell nuclear transfer

Genetically modified pigs are valuable models of human disease and donors of xenotransplanted organs.Conventional gene targeting in pig somatic cells is extremely inefficient.Zinc-finger nuclease(ZFN)technology has been shown to be a powerful tool for efficiently inducing mutations in the genome.However,ZFN-mediated targeting in pigs has rarely been achieved.Here,we used ZFNs to knock out the porcineα-1,3-galactosyl-transferase(GGTA1)gene,which generates Gal epitopes that trigger hyperacute immune rejection in pig-to-human transplantation.Primary pig fibroblasts were transfected with ZFNs targeting the coding region of GGTA1.Eighteen mono-allelic and four biallelic knockout cell clones were obtained after drug selection with efficiencies of 23.4%and 5.2%,respectively.The biallelic cells were used to produce cloned pigs via somatic cell nuclear transfer(SCNT).Three GGTA1 null piglets were born,and one knockout primary fibroblast cell line was established from a cloned fetus.Gal epitopes on GGTA1 null pig cells were completely eliminated from the cell membrane.Functionally,GGTA1 knockout cells were protected from complement-mediated immune attacks when incubated with human serum.This study demonstrated that ZFN is an efficient tool in creating gene-modified pigs.GGTA1 null pigs and GGTA1 null fetal fibroblasts would benefit research and pig-to-human transplantation.     

Armed T cells with CAR for cancer immunotherapy

正The development of genetic engineering has enabled the modification of stem cells and somatic cells.T cells exert immune responses against cancer cells.Efforts to redirect T cell specificity of a chimeric antigen receptor(CAR)to a desired antigen began in the 1990s(Gross et al.,1989;Kuwana et al.,1987).In 2006,the first clinical trial using carbonic anhydrase IX CAR-T cells to fight renal cancer was conducted(Lamers et al.,2006).Until 2011,Porter et al.exploited CD19 CAR-T to treat refractory/relapsed chronic lymphoid leukemia(Porter et al.,2011).Subsequently,trials     

Philadelphia chromosome-positive leukemia stem cells in acute lymphoblastic leukemia and tyrosine kinase inhibitor therapy

Leukemia stem cells(LSCs),which constitute a minority of the tumor bulk,are functionally defined on the basis of their ability to transfer leukemia into an immunodeficient recipient animal.The presence of LSCs has been demonstrated in acute lymphoblastic leukemia(ALL),of which ALL with Philadelphia chromosome-positive(Ph+).The use of imatinib,a tyrosine kinase inhibitor(TKI),as part of front-line treatment and in combination with cytotoxic agents,has greatly improved the proportions of complete response and molecular remission and the overall outcome in adults with newly diagnosed Ph+ ALL.New challenges have emerged with respect to induction of resistance to imatinib via Abelson tyrosine kinase mutations.An important recent addition to the arsenal against Ph+ leukemias in general was the development of novel TKIs,such as nilotinib and dasatinib.However,in vitro experiments have suggested that TKIs have an antiproliferative but not an antiapoptotic or cytotoxic effect on the most primitive ALL stem cells.None of the TKIs in clinical use target the LSC.Second generation TKI dasatinib has been shown to have a more profound effect on the stem cell compartment but the drug was still unable to kill the most primitive LSCs.Allogeneic stem cell transplantation(SCT) remains the only curative treatment available for these patients.Several mechanisms were proposed to explain the resistance of LSCs to TKIs in addition to mutations.Hence,TKIs may be used as a bridge to SCT rather than monotherapy or combination with standard chemotherapy.Better understanding the biology of Ph+ ALL will open new avenues for effective management.In this review,we highlight recent findings relating to the question of LSCs in Ph+ ALL.     

Roles of IκB kinase ε in the innate immune defense and beyond

IκB kinase ε(IKKε) is a non-canonical IκB kinase that is extensively studied in the context of innate immune response. Recently, significant progress has been made in understanding the role of IKKεin interferon(IFN) signaling. In addition to its roles in innate immunity, recent studies also demonstrate that IKKε is a key regulator of the adaptive immune response. Specifically, IKKεfunctions as a negative feedback kinase to curtail CD8 T cell response, implying that it can be a potential therapeutic target to boost antiviral and antitumor T cell immunity. In this review, we highlight the roles of IKKε in regulating IFN signaling and T cell immunity, and discuss a few imminent questions that remain to be answered.     

Myelopoiesis during Zebrafish Early Development

Myelopoiesis is the process of producing all types of myeloid cells including monocytes/macrophages and granulocytes.Myeloid cells are known to manifest a wide spectrum of activities such as immune surveillance and tissue remodeling.Irregularities in myeloid cell development and their function are known to associate with the onset and the progression of a variety of human disorders such as leukemia.In the past decades,extensive studies have been carried out in various model organisms to elucidate the molecular mechanisms underlying myelopoiesis with the hope that these efforts will yield knowledge translatable into therapies for related diseases.Zebrafish has recently emerged as a prominent animal model for studying myelopoiesis,especially during early embryogenesis,largely owing to its unique properties such as transparent embryonic body and external development.This review introduces the methodologies used in zebrafish research and focuses on the recent research progresses of zebrafish myelopoiesis.     

Lactic acid in tumor microenvironments causes dysfunction of NKT cells by interfering with mTOR signaling

Cellular metabolism has been shown to regulate differentiation and function of immune cells.Tumor associated immune cells undergo phenotypic and functional alterations due to the change of cellular metabolism in tumor microenvironments.NKT cells are good candidates for immunotherapies against tumors and have been used in several clinical trials.However,the influences of tumor microenvironments on NKT cell functions remain unclear.In our studies,lactic acid in tumor microenvironments inhibited IFNγ and IL4 productions from NKT cells,and more profound influence on IFNγ was observed.By adjusting the pH of culture medium we further showed that,dysfunction of NKT cells could simply be induced by low extracellular pH.Moreover,low extracellular pH inhibited NKT cell functions by inhibiting mammalian target of rapamycin(mTOR) signaling and nuclear translocation of promyelocytic leukemia zinc-finger(PLZF).Together,our results suggest that tumor acidic microenvironments could interfere with NKT cell functions through metabolic controls.     

Improved clinical outcomes of rhG-CSF-mobilized blood and marrow haploidentical transplantation compared to propensity score-matched rhG-CSF-primed peripheral blood stem cell haploidentical transplantation: a multicenter study

The effects of haploidentical rhG-CSF-mobilized blood and marrow transplantation(HBMT) on hematological malignances are well established. Previous prospective single-center studies have demonstrated better survival after HBMT versus haploidentical rhG-CSF-mobilized peripheral blood stem cell transplantation(HPBSCT) for acute leukemia(AL) not in remission(NR) or in more than the second complete remission(CR2). To test the hypothesis that HBMT is still superior to HPBSCT for patients with AL, multiple myeloma(MM), or non-Hodgkin lymphoma(NHL) in CR1/CR2 and for patients with chronic myeloid leukemia in the first and second chronic phase lacking a matched donor, we designed a propensity score method-based multicenter study.Hematopoietic recovery, acute graft-versus-host disease(aGVHD), and chronic GVHD were comparable between the HBMT group(n=168) and the HPBSCT group(n=42). No significant differences were found in non-relapse mortality rate(20.17%±3.58%and 27.24%±7.16%, P=0.18) or relapse rate(19.96%±3.72% and 28.49%±8.25%, P=0.32) between the HBMT group and the HPBSCT group. HBMT recipients had better overall survival(65.0%±4.2% and 54.2%±8.3%, P=0.037) and disease-free survival(59.9%±4.6% and 44.3%±8.7%, P=0.051). Multivariate analysis showed that HPBSCT was associated with poorer DFS(HR(95%CI), 1.639(0.995–2.699), P=0.052). Our comparisons showed that HBMT was superior to HPBSCT as a post-remission treatment for patients lacking an identical donor.     

Mobilization of CD34~+CD38~- hematopoietic stem cells after priming in acute myeloid leukemia

AIM: To evaluate quantitatively and qualitatively the different CD34+cell subsets after priming by chemotherapy granulocyte colony-stimulating factor(± G-CSF)in patients with acute myeloid leukemia.METHODS: Peripheral blood and bone marrow sampleswere harvested in 8 acute myeloid leukemia patients during and after induction chemotherapy. The CD34/CD38 cell profile was analyzed by multi-parameter flow cytometry. Adhesion profile was made using CXC chemokine receptor 4(CXCR4)(CD184), VLA-4(CD49d/CD29) and CD47.RESULTS: Chemotherapy ± G-CSF mobilized immature cells(CD34+CD38 population), while the more mature cells(CD34+CD38lowand CD34+CD38+populations) decreased progressively after treatment. Circulating CD34+cells tended to be more sensitive to chemotherapy after priming with G-CSF. CD34+cell mobilization was correlated with a gradual increase in CXCR4 and CD47expression, suggesting a role in cell protection and the capacity of homing back to the marrow.CONCLUSION: Chemotherapy ± G-CSF mobilizes into the circulation CD34+bone marrow cells, of which, the immature CD34+CD38-cell population. Further manipulations of these interactions may be a means with which to control the trafficking of leukemia stem cells to improve patients’ outcomes.