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Analysis of T cell receptor beta variable region (TCRBV) gene rearrangement is useful for clonal assessment of abnormal T cell proliferations in various diseases. However, most primer panels previously used can only amplify the third complementarity-determining region. Following IMGT database we established a panel of primers, which can amplify entire sequences of all functional TCRBV families. To confirm the usefulness of this panel of primers, we detected different TCRBV repertoires. In 15 healthy donors, most of the BV families were expressed and appeared as a Gaussian distribution. 13 acute myeloid leukemia patients showed monoclonal or oligoclonal changes of BV15 family, and some of them also had monoclonal or oligoclonal expansion of BV2, BV4, BV6 or BV13 families. In one patient after allo-hematopoietic stem cell transplantation, monoclonal proliferation of BV10 family occurred during graft-versus-host disease. In conclusion, this panel of primers improves our abilities to analyze TCRBV repertoire changes in related diseases.
Mol Biol Rep 2009 Jan
PMID:An improved design of PCR primers for detection of human T cell receptor beta chain repertoire. 1871 97

Hurler syndrome, metachromatic leukodystrophy, globoid-cell leukodystrophy (Krabbe's disease) and X-linked adrenoleukodystrophy are inherited diseases of the CNS that can be cured or arrested by allogeneic hematopoietic stem-cell transplantation (HSCT). Despite significant progress in medical procedures and the availability of banked umbilical cord blood, HSCT is still associated with significant risks of graft failure or GVHD that can lead to death. Transplantation of autologous hematopoietic stem cells genetically modified to express the missing protein may circumvent the majority of the problems associated with allogeneic HSCT. Promising in concept, these strategies are now at a stage to be tested in phase I/II clinical trials to assess safety and potential efficacy.
Curr Opin Mol Ther 2008 Oct
PMID:Hematopoietic stem cell gene therapy in Hurler syndrome, globoid cell leukodystrophy, metachromatic leukodystrophy and X-adrenoleukodystrophy. 1883 Sep 23

The prognosis for thalassemia major has dramatically improved in the last two decades. However, many transfusion-dependent patients continue to develop progressive accumulation of iron. This can lead to tissue damage and eventually death, particularly from cardiac disease. Previous studies that investigated iron chelation treatments, including retrospective and prospective non-randomised clinical trials, suggested that mortality, due mainly to cardiac damage, was reduced or completely absent in patients treated with deferiprone (DFP) alone or a combined deferiprone-deferoxamine (DFP-DFO) chelation treatment. However, no survival analysis has been reported for a long-term randomised control trial. Here, we performed a multicenter, long-term, randomised control trial that compared deferoxamine (DFO) versus DFP alone, sequential DFP-DFO, or combined DFP-DFO iron chelation treatments. The trial included 265 patients with thalassemia major, with 128 (48.3%) females and 137 (51.7%) males. No deaths occurred with the DFP-alone or the combined DFP-DFO treatments. One death occurred due to graft versus host disease (GVHD) in a patient that had undergone bone marrow transplantation; this patient was censored at the time of transplant. Only one death occurred with the DFP-DFO sequential treatment in a patient that had experienced an episode of heart failure one year earlier. Ten deaths occurred with the deferoxamine treatment. The main factors that correlated with an increase in the hazard ratio for death were: cirrhosis, arrhythmia, previous episode of heart failure, diabetes, hypogonadism, and hypothyroidism. In a Cox regression model, the interaction effect of sex and age was statistically significant (p-value<0.013). For each increasing year of age, the hazard ratio for males was 1.03 higher than that for females (p-value<0.013). In conclusion, the results of this study show that the risk factors for predicting mortality in patients with thalassemia major are deferoxamine-treatment, complications, and the interaction effect of sex and age.
Blood Cells Mol Dis
PMID:Improving survival with deferiprone treatment in patients with thalassemia major: a prospective multicenter randomised clinical trial under the auspices of the Italian Society for Thalassemia and Hemoglobinopathies. 1923 92

Graft-versus-host disease is the main complication after hematopoietic stem cells transplantation (HSCT). Non-HLA genotypes, such as cytokines, have been investigated for their potential roles in the occurrence and severity of GVHD as well as for their contribution to overall transplant-related mortality and survival. IL-7 which is secreted by bone marrow stromal cells plays an important role in the development and survival of T cells. Its effect is mediated via interleukin 7 receptor (IL7R). This study investigates the possible links between IL-7alphaR single nucleotide polymorphisms (+510 C/T, +1237 A/G, +2087 T/C and +3110A/G) and transplant outcomes among 116 recipients of HSCT. Genotypes were determined using polymerase chain reaction-sequence-specific primers. No significant differences were observed between the genotypic distributions of IL-7alphaR polymorphisms and incidence of acute or chronic graft versus host disease. Additional studies with larger sample are necessary to further define the influence of IL-7alphaR on the immune response after bone marrow transplantation.
Mol Biol Rep 2010 Jan
PMID:Interleukin-7 receptor-alpha gene polymorphisms in bone marrow transplant recipients. 1925 27

We present an update of our results regarding related HLA-haploidentical and HLA-identical sibling hematopoietic stem cell transplantation (HSCT) in patients with leukemia. We compared the outcomes of 107 patients with leukemia undergoing HLA-identical sibling (n=51) or related HLA-haploidentical (n=56) HSCT performed during the same time period. Patients received BU-CY/CY-TBI in HLA-identical sibling HSCT or TBI+Ara-C+CY+ATG/CCNU+Ara-C+Bu+CY+ATG in haploidentical HSCT as conditioning regimens, followed by unmanipulated marrow and/or peripheral blood (PB) transplantation. All patients achieved full engraftment. The cumulative incidence of grades II through IV acute graft-versus-host disease (aGvHD) in the matched and haploidentical cohorts was 13.7% and 26.8% (P<0.05), respectively. The risk of developing cGvHD was not different between HLA-matched and haploidentical patients (P>0.05). The two-year incidence of treatment-related mortality for matched and haploidentical patients was 7.8% and 12.5%, respectively, with P>0.05, and the incidence of relapse was 17% and 22%, respectively, with P>0.05. The two-year adjusted leukemia-free survival for matched versus haploidentical patients was 76% and 68%, respectively, with P>0.05, and the overall survival for matched versus haploidentical patients was 80% and 70%, respectively, with P>0.05. Multivariate analyses showed that only advanced disease stage and a diagnosis of acute leukemia were related to increased risk of relapse, treatment failure, and overall mortality. In summary, HSCT performed with related HLA-haploidentical donors is a feasible approach with acceptable outcomes.
Blood Cells Mol Dis
PMID:HLA-haploidentical blood and bone marrow transplantation with anti-thymocyte globulin: long-term comparison with HLA-identical sibling transplantation. 1935 56

Acute graft-versus-host disease (GVHD) is an uncommon but often fatal complication following liver transplant. We describe a GVHD case in which a female patient with primary biliary cirrhosis underwent a living-related liver transplant from her son. The human leukocyte antigen typing of the donor was homozygous at all loci. The recipient's human leukocyte antigen type was haplo-identical to that of the donor. A bone marrow aspirate performed for pancytopenia revealed a severely hypoplastic marrow. Fluorescent in situ hybridization (FISH) using X- and Y-chromosome probes demonstrated that 80% of marrow cells were of donor origin. Comparison of Giemsa-stained cell morphology and FISH showed that the erythroid precursor cells were predominantly of male pattern (XY). This report is one of only a few studies that prove the migration of a donor's hematopoietic stem cells to a recipient's bone marrow. We demonstrated that FISH analysis using sex chromosome probes is useful to confirm a diagnosis of GVHD following organ transplantation from a donor of the opposite sex. We also showed that donor hematopoietic stem cells in a liver graft can migrate to the recipient's bone marrow. We suggest that FISH is a rapid and reliable test for confirming the diagnosis of GVHD in a peripheral blood or skin biopsy sample.
J Mol Diagn 2009 Jul
PMID:FISH diagnosis of acute graft-versus-host disease following living-related liver transplant. 1946 Sep 38

Mesenchymal stem cells (MSCs), adherent fibroblastoid cells, present in bone marrow and many other tissues can be easily isolated and expanded in vitro. They are capable of differentiating into different cell types such as osteoblasts, chondrocytes, adipocytes, cardiomyocytes, hepatocytes, endothelial cells and neuronal cells. Such immense plasticity coupled with their ability to modulate the activity of immune cells makes them attractive for stem cell-based therapy aimed at treating previously incurable disorders. Preclinical studies have reported successful use of MSCs for delivering therapeutic proteins and repairing defects in a variety of disease models. These studies highlighted the in vivo potential of MSCs and their ability to home to injury sites and modify the microenvironment by secreting paracrine factors to augment tissue repair. Their therapeutic applicability has been widened by genetic modification to enhance differentiation and tissue targeting, and use in tissue engineering. Clinical trials for diseases such as osteogenesis imperfecta, graft-versus-host disease and myocardial infarction have shown some promise, demonstrating the safe use of both allogeneic and autologous cells. However, lack of knowledge of MSC behaviour and responses in vitro and in vivo force the need for basic and animal studies before heading to the clinic. Contrasting reports on immunomodulatory functions and tumorigenicity along with issues such as mode of cell delivery, lack of specific marker, low survival and engraftment require urgent attention to harness the potential of MSC-based therapy in the near future.
J Cell Mol Med
PMID:Mesenchymal stem cell-based therapy: a new paradigm in regenerative medicine. 1960 34

Immunodeficient mice have been used as recipients of human peripheral blood mononuclear cells (PBMC) for in vivo analyses of human xeno-graft-versus-host disease (GVHD). This xeno-GVHD model system in many ways mimics the human disease. The model system is established by intravenous or intraperitoneal injection of human PBMC or spleen cells into unconditioned or irradiated immunodeficient recipient mice. Recently, the development of several stocks of immunodeficient Prkdc ( scid ) (scid) and recombination activating 1 or 2 gene (Rag1 or Rag2) knockout mice bearing a targeted mutation in the gene encoding the IL2 receptor gamma chain (IL2rgamma) have been reported. The addition of the mutated IL2rgamma gene onto an immunodeficient mouse stock facilitates heightened engraftment with human PBMC. Stocks of mice with mutations in the IL2rgamma gene have been studied in several laboratories on NOD-scid, NOD-Rag1 ( null ), BALB/c-Rag1 ( null ), BALB/c-Rag2 ( null ), and Stock-H2(d)-Rag2 ( null ) strain backgrounds. Parameters to induce human xeno-GVHD in H2(d)-Rag2 ( null ) IL2rgamma ( null ) mice have been published, but variability in the frequency of disease and kinetics of GVHD were observed. The availability of the NOD-scid IL2rgamma ( null ) stock that engrafts more readily with human PBMC than does the Stock-H2(d)-Rag2 ( null ) IL2rgamma ( null ) stock should lead to a more reproducible humanized mouse model of GVHD and for the use in drug evaluation and validation. Furthermore, GVHD in human PBMC-engrafted scid mice has been postulated to result predominately from a human anti-mouse major histocompatibility complex (MHC) class II reactivity. Our recent development of NOD-scid IL2rgamma ( null ) beta2m ( null ) and NOD-scid IL2rgamma ( null ) Ab ( null ) stocks of mice now make it possible to investigate directly the role of host MHC class I and class II in the pathogenesis of GVHD in humanized mice using NOD-scid IL2rgamma ( null ) stocks that engraft at high levels with human PBMC and are deficient in murine MHC class I, class II, or both classes of MHC molecules.
Methods Mol Biol 2010
PMID:Development of novel major histocompatibility complex class I and class II-deficient NOD-SCID IL2R gamma chain knockout mice for modeling human xenogeneic graft-versus-host disease. 2001 95

CD4(+) regulatory T cells (Tregs) play an important role in maintaining immune tolerance by suppressing pathologic immune responses. The generation of large numbers of antigen-specific Tregs ex vivo is critical for the development of clinical immunotherapy based on the adoptive transfer of Tregs. Both CD40-activated B cells (CD40-B) and immature dendritic cells (imDCs) have been used as professional antigen-presenting cells (APCs) to generate antigen-specific Tregs. However, the efficiencies of CD40-B and imDCs to generate CD4(+) Tregs have not been compared directly and the mechanism driving the generation of these Tregs remains largely unknown. In this study, we found that CD40-B exhibited mature phenotypes and were more able to induce and expand CD4(high)CD25(+) Tregs than imDCs. Moreover, Tregs induced by CD40-B had greater suppressive capacity than those induced by imDCs. The generation of CD4(high)CD25(+) Tregs by CD40-B and imDCs is cell-cell contact dependent and partially relies on the expression of human leukocyte antigen (HLA)-DR and CD80/86. Differences in CD4(high)CD25(+) Treg generation efficiency were largely explained by the production of endogenous IL-2 by CD40-B. Our results suggest that CD40-B is better able to generate large numbers of antigen-specific Tregs than imDCs. Additionally, using CD40-B to generate Tregs may accelerate the clinical use of Treg-based immunotherapy in the treatment of allograft rejection, graft versus host disease (GVHD) and autoimmune diseases.
Cell Mol Immunol 2010 Jan
PMID:CD40-activated B cells are more potent than immature dendritic cells to induce and expand CD4(+) regulatory T cells. 2008 75

CD28 is one of the costimulatory molecules crucial for T-cell activation and thus has become an attractive target for therapeutic immunomodulation. Conventional strategies for blocking CD28 activity using monoclonal antibodies, Fab fragments, antagonistic peptide and fusion proteins, have apparent disadvantages such as inherent immunogenicity, unwanted Fc signaling, poor tissue penetration and bioinstability. Recent research has been directed toward the creation of non-natural, sequence-specific biomimetic oligomers with bioinspired structures that capture the amino-acid interface of the targeted proteins. One such family of molecules is the poly-N-substituted glycines or peptoids, which have close structural similarity to peptides but are essentially invulnerable to protease degradation. To screen for peptoids that specifically target CD28, we first designed and chemically synthesized 19 candidate peptoids based on molecular modeling and docking. Using the phage-displaying system that expresses the extracellular domain of the CD28 homodimer and contains the core B7-binding motif, a peptoid (No. 9) with a molecular formula of C(21)H(29)N(3)O(7), was identified to display the highest binding activity to CD28. This peptoid not only inhibited the lymphocyte proliferation in vitro, but suppressed immunoresponses against alloantigens in vivo, and attenuated the graft-versus-host disease in a mouse bone-marrow transplantation model. These results suggested that peptoids targeting CD28 are effective agents for blocking the CD28-mediated costimulation and suitable for development of novel therapeutic approaches for diseases involving this pathway.
Cell Mol Immunol 2010 Mar
PMID:Blockade of CD28 by a synthetical peptoid inhibits T-cell proliferation and attenuates graft-versus-host disease. 2014 6


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