- Successful Outcome in Patients with Fanconi Anemia Undergoing T-Cell Replete Mismatched Related Donor Hematopoietic Cell Transplantation Using Reduced-Dose Cyclophosphamide Post Transplant. [Journal Article]
- BBBiol Blood Marrow Transplant 2019 Jul 12
- Allogeneic Hematopoietic Cell Transplantation (HCT) has been shown to restore normal hematopoiesis in Fanconi anemia (FA) patients with excellent results in matched related donor HCT; outcomes of alt…
Allogeneic Hematopoietic Cell Transplantation (HCT) has been shown to restore normal hematopoiesis in Fanconi anemia (FA) patients with excellent results in matched related donor HCT; outcomes of alternative donor HCT are less favorable. In non-FA patients, several reports documented stable engraftment/low risk of graft-versus-host disease (GVHD) using unmanipulated HLA-mismatched related donors and post HCT cyclophosphamide (PT-CY) for GVHD prophylaxis. In FA patients, data on using this approach are scarce; we therefore launched a study to perform HCT from HLA-mismatched related donors and report here our results on nineteen patients. Conditioning was fludarabine 30mg/m2/day x 5, anti-Thymocyte globulins 5mg/kg/day x 4, total body irradiation (200 cGy). GVHD prophylaxis was cyclosporine and mycophenolate and reduced doses of PT-CY 25 mg/kg on days +3, and +5. Absolute neutrophil count recovery occurred in all patients. Grade III-IV acute GVHD occurred in three patients and chronic GVHD in one. At a median follow-up of 38.3±5.8 months, the five-year probability of overall survival for our patients is 89.2%±7.2%. The regimen was well tolerated; hemorrhagic cystitis occurred in seven patients, and severe mucositis in five. There were two deaths; the primary causes of death were severe GVHD in one patient and leukemia recurrence in the second. We conclude that in FA patients lacking matched related donors, use of mismatched related HCT with low dose PT-CY is a viable option; it is well tolerated with a high rate of engraftment and an acceptable incidence of GVHD.
- Conserved crosstalk between histone deacetylation and H3K79 methylation generates DOT1L-dose dependency in HDAC1-deficient thymic lymphoma. [Journal Article]
- EJEMBO J 2019 Jul 15; 38(14):e101564
- DOT1L methylates histone H3K79 and is aberrantly regulated in MLL-rearranged leukemia. Inhibitors have been developed to target DOT1L activity in leukemia, but cellular mechanisms that regulate DOT1L…
DOT1L methylates histone H3K79 and is aberrantly regulated in MLL-rearranged leukemia. Inhibitors have been developed to target DOT1L activity in leukemia, but cellular mechanisms that regulate DOT1L are still poorly understood. We have identified the histone deacetylase Rpd3 as a negative regulator of budding yeast Dot1. At its target genes, the transcriptional repressor Rpd3 restricts H3K79 methylation, explaining the absence of H3K79me3 at a subset of genes in the yeast genome. Similar to the crosstalk in yeast, inactivation of the murine Rpd3 homolog HDAC1 in thymocytes led to an increase in H3K79 methylation. Thymic lymphomas that arise upon genetic deletion of Hdac1 retained the increased H3K79 methylation and were sensitive to reduced DOT1L dosage. Furthermore, cell lines derived from Hdac1Δ/Δ thymic lymphomas were sensitive to a DOT1L inhibitor, which induced apoptosis. In summary, we identified an evolutionarily conserved crosstalk between HDAC1 and DOT1L with impact in murine thymic lymphoma development.
- [A case of nephrectomy with strong positive HLA antibody undergoing the third renal transplantation]. [Journal Article]
- ZNZhong Nan Da Xue Xue Bao Yi Xue Ban 2019 May 28; 44(5):596-599
- The positive human leukocyte antigen (HLA) antibody present in kidney transplant recipients affects both surgery and rejection, and also affects the long-term survival of the transplanted kidney. Dur…
The positive human leukocyte antigen (HLA) antibody present in kidney transplant recipients affects both surgery and rejection, and also affects the long-term survival of the transplanted kidney. During the third kidney transplant, bilateral axillary fossa and iliac vessel were destroyed. It was very difficult for selection or separation of surgical vessels because the adhesions and scar formation was easy to damage blood vessels and intestinal tubes. A case with strong positive HLA antibody undergoing the third kidney transplant in our hospital was successfully solved the problems, such as less transplant space and vascular scar adhesion. Rituximab, rabbit anti-human thymocyte immunoglobulin, and methylprednisolone treated-antibodies were used in the operation. The immune function test was used to develop individualized treatment after the operation. The postoperative creatinine and urine volume tended to be stable, and the 16-month follow-up renal function was good.
- Jeju ground water containing vanadium induces normal T cell development and immune activation in chronically stressed mice. [Journal Article]
- MBMol Biol Rep 2019 Jul 13
- Containing high concentration of vanadium served by the volcanic bedrock, Jeju ground water has long been known for various implicit health benefits including immune-promotion. Exposure to stress has…
Containing high concentration of vanadium served by the volcanic bedrock, Jeju ground water has long been known for various implicit health benefits including immune-promotion. Exposure to stress has been reported to be associated with immunosuppression such as reducing lymphocyte population or antibody production due to stress hormones. In this study, we aimed at evaluating the effects of Jeju ground water on chronically stressed mice. C57BL/6 mice were subjected to various stressors such as restraint stress, water swimming stress, heat stress, acoustic stress, and Jeju ground water was supplied for 28 days with two different concentrations, S1 (vanadium 15-20 μg/l, pH 8.3) and S2 (vanadium 20-25 μg/l, pH 8.5). Treatment with Jeju ground water increased CD4+CD8- or CD4-CD8+ single-positive thymocytes. It also increased the proliferation of splenocytes and the populations of CD4+ T cells, CD45R/B220+ B cells, CD11b+ macrophages or Gr-1+ granulocytes in spleen. In addition, the production of IgG was increased in chronically stressed mice by treatment with Jeju ground water. These results suggest vanadium-rich Jeju ground water may be helpful in T cell development in thymus and immune cell proliferation and its function in spleen against chronic stress.
- Survival Outcomes of Allogeneic Hematopoietic Cell Transplants with EBV positive or EBV negative Post Transplant Lymphoproliferative Disorder (PTLD), A CIBMTR Study. [Journal Article]
- TITranspl Infect Dis 2019 Jul 12; :e13145
- CONCLUSIONS: There is no difference in survival outcomes for patients with EBVpos or EBVneg PTLD occurring following alloHCT and 1-year survival is poor. Features of conditioning and use of serotherapy remain important. This article is protected by copyright. All rights reserved.
- Effect of a post-hatch lipopolysaccharide challenge in Turkey poults and ducklings after a primary embryonic heat stress. [Journal Article]
- DCDev Comp Immunol 2019 Jul 05; :103436
- The effect of embryonic thermal manipulation on the post-hatch immune response to a lipopolysaccharide (LPS) challenge was studied in Pekin ducklings and turkey poults. Commercial duck and turkey egg…
The effect of embryonic thermal manipulation on the post-hatch immune response to a lipopolysaccharide (LPS) challenge was studied in Pekin ducklings and turkey poults. Commercial duck and turkey eggs were distributed among four treatments: SS-Control (37.5 °C from embryonic day [ED] 1 to 25); SS-LPS (37.5 °C from ED1 to 25 + LPS at D0 [hatch]); HH-LPS (38 °C from ED1 to 25 + LPS at D0; SH-LPS (37.5 °C from ED1 to 10 and 38 °C from ED 11 to 25 + LPS at D0). At ED16 and ED24, the egg shell temperature of the duck and turkey eggs in the HH and SH treatments were higher (P ≤ 0.01) than the SS treatment. Ducklings and poults in the HH treatment had the lowest yolk free body weight at hatch (P ≤ 0.05). At 24, 48, and 72 h post-LPS injection, ducklings and poults in the HH-LPS treatment had significantly reduced BW compared with the SS-Con treatments (P ≤ 0.05). Ducklings and poults in the SH-LPS and HH-LPS treatments had increased plasma heat shock protein 70 (HSP70) and lower splenic HSP70 mRNA amounts than the SS-LPS treatments at 24, and 48 h post-challenge (P ≤ 0.05). At 48 and 72 h, macrophage nitric oxide (NO) production in ducklings and poults in the SH-LPS and HH-LPS treatments was lower than in the SS-LPS treatments (P ≤ 0.05). Ducklings and poults in the SH-LPS treatment had increased thymocyte proliferation compared to the SS-LPS treatment at 24, 48 and 72 h (P ≤ 0.05). At 24 h, ducklings in the SH-LPS treatment had increased splenic IL-10 and reduced IFNγ and IL-6 mRNA abundance. However, both ducklings and poults in the HH-LPS treatment had increased IFNγ, and IL-10 mRNA abundance compared to the SS-LPS treatment (P ≤ 0.05). At 48 h, SH-LPS ducklings and poults had lower splenic IL-10 mRNA abundance (P ≤ 0.05) while the HH-LPS treatment resulted in comparable splenic IL-10 mRNA compared to the SS-LPS treatment (P ≥ 0.05). Ducklings and poults in the SH-LPS treatment had increased thymic and splenic CD8+/CD4+ ratios at 24 h versus the SS-LPS treatment (P ≤ 0.05). In conclusion, embryonic thermal manipulation from ED11-25 increased extracellular HSP70 release, thymocyte proliferation and IL-10 but decreased splenic HSP70 and IFNγ mRNA amounts at 24 h post-LPS injection. This suggests that mild heat stress during the later stages of incubation could potentially prime the embryonic immune system thereby enhances the immune response as earlier than 24 h to eliminate the inflammatory response without affecting the growth performance by increase the extracellular release of HSP70 in both ducklings and poults. Continuous exposure to the small increase in temperature from ED 1-25 (HH) caused an imbalance between pro (IFNγ)- and anti-inflammatory cytokines(IL-10) which affects hatchling responses to an inflammatory challenge and increased mortality. The amount of extracellular HSP70 could potentially play an important role in modulating the immune response against inflammatory challenges.
- On Integrity in Immunity During Ontogeny or How Thymic Regulatory T Cells Work. [Journal Article]
- SJScand J Immunol 2019 Jul 05; :e12806
- The Standard model of T-cell recognition asserts that T-cell receptor (TCR) specificities are positively and negatively selected during ontogeny in the thymus, and that peripheral T-cell repertoire h…
The Standard model of T-cell recognition asserts that T-cell receptor (TCR) specificities are positively and negatively selected during ontogeny in the thymus, and that peripheral T-cell repertoire has mild self-Major Histocompatibility Complex (MHC) reactivity, known as MHC-restriction of foreign-antigen. Thus, the TCR must bind both a restrictive molecule (MHC allele) and a peptide reclining in its groove (pMHC ligand) in order to transmit signal into a T cell. The Standard and Cohn's Tritope model suggest contradictory roles for complementarity-determining regions (CDRs) of the TCRs. Here, I discuss both concepts and propose a different solution to ontogenetic mechanism for TCR-MHC conserved interaction. I suggest that double (CD4+CD8+) positive (DP) developing thymocytes compete with their αβTCRs for binding to self-pMHC on cortical thymic epithelial cells (cTECs) that present a selected set of tissue-restricted antigens (TRA). The competition between DPs involves TCR editing and secondary rearrangements, similar to germinal-centre B-cell somatic hypermutation. These processes would generate cells with higher TCR affinity for self-pMHC, facilitating sufficiently long binding to cTECs to become thymic T regulatory cells (tTregs). Furthermore, CD4+ Foxp3+ tTregs can be generated by mTECs via Aire-dependent and independent pathways, and additionally on thymic bone-marrow derived APCs including thymic Aire-expressing B cells. Thymic Tregs differ from the induced peripheral Tregs (pTregs), which comprise the negative feedback loop to restrain immune responses. The implication of thymocytes' competition for the highest binding to self-pMHC is the co-evolution of species-specific αβTCRV regions with MHC alleles. This article is protected by copyright. All rights reserved.
- Eimeria tenella Elongation Factor-1α (EF-1α) Coadministered with Chicken IL-7 (chIL-7) DNA Vaccine Emulsified in Montanide Gel 01 Adjuvant Enhanced the Immune Response to E. acervulina Infection in Broiler Chickens. [Journal Article]
- ADAvian Dis 2019 Mar 14; 63(2):342-350
- The current study was undertaken to assess the vaccine efficacy of Eimeria tenella EF-1α/chicken IL-7 (chIL-7) DNA vaccine when administered with Montanide Gel 01 adjuvant against live Eimeria acervu…
The current study was undertaken to assess the vaccine efficacy of Eimeria tenella EF-1α/chicken IL-7 (chIL-7) DNA vaccine when administered with Montanide Gel 01 adjuvant against live Eimeria acervulina challenge in commercial broiler chickens. The criteria used for the evaluation of vaccine efficacy were weight gain, duodenal lesion scores, oocyst counts, humoral antibody response, and duodenal proinflammatory cytokine gene expression. Chickens vaccinated with EF-1α (100 µg)/chIL-7 (20 µg) in Gel 01 PR adjuvant showed body weight gain similar to the uninfected control and higher oocyst shedding, a lower gut lesion score, and higher proinflammatory cytokine gene expression than did the infected controls. Moreover, chickens vaccinated with chIL-7 (20 µg) in Gel 01 PR adjuvant shed fewer oocysts with reduced gut lesion scores and produced higher levels of anti-EF-1α serum antibody than did the infected control. Chickens vaccinated with EF-1α (50 µg)/chIL-7 (20 µg) in Gel 01 PR adjuvant showed higher weight gains than did the infected control and shed significantly fewer oocysts than the infected control. Furthermore, chickens vaccinated with EF-1α (100 µg) in Gel 01 PR adjuvant demonstrated the lowest anti-EF-1α serum antibody levels. This study demonstrated the beneficial effects of using EF-1α and/or host cytokine chIL-7 DNA vaccine together with Gel 01 PR adjuvant to improve T-cell-mediated effector function in broiler chickens challenged with live E. acervulina.
- Thy-1 depletion and integrin β3 upregulation-mediated PI3K-Akt-mTOR pathway activation inhibits lung fibroblast autophagy in lipopolysaccharide-induced pulmonary fibrosis. [Journal Article]
- LILab Invest 2019 Jun 27
- Lipopolysaccharide (LPS)-induced autophagy inhibition in lung fibroblasts is closely associated with the activation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin…
Lipopolysaccharide (LPS)-induced autophagy inhibition in lung fibroblasts is closely associated with the activation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K-Akt-mTOR) pathway. However, the underlying mechanism remains unknown. In this study, we demonstrated that LPS activated the PI3K-Akt-mTOR pathway and inhibited lung fibroblast autophagy by depleting thymocyte differentiation antigen-1 (Thy-1) and upregulating integrin β3 (Itgb3). Challenge of the human lung fibroblast MRC-5 cell line with LPS resulted in significant upregulation of integrin β3, activation of the PI3K-Akt-mTOR pathway and inhibition of autophagy, which could be abolished by integrin β3 silencing by specific shRNA or treatment with the integrin β3 inhibitor cilengitide. Meanwhile, LPS could inhibit Thy-1 expression accompanied with PI3K-Akt-mTOR pathway activation and lung fibroblast autophagy inhibition; these effects could be prevented by Thy-1 overexpression. Meanwhile, Thy-1 downregulation with Thy-1 shRNA could mimic the effects of LPS, inducing the activation of PI3K-Akt-mTOR pathway and inhibiting lung fibroblast autophagy. Furthermore, protein immunoprecipitation analysis demonstrated that LPS reduced the binding of Thy-1 to integrin β3. Thy-1 downregulation, integrin β3 upregulation and autophagy inhibition were also detected in a mouse model of LPS-induced pulmonary fibrosis, which could be prohibited by intratracheal injection of Thy-1 overexpressing adeno-associated virus (AAV) or intraperitoneal injection of the integrin β3 inhibitor cilengitide. In conclusion, this study demonstrated that Thy-1 depletion and integrin β3 upregulation are involved in LPS-induced pulmonary fibrosis, and may serve as potential therapeutic targets for pulmonary fibrosis.
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- Risk factors and clinical outcomes of Epstein-Barr virus DNAemia and post-transplant lymphoproliferative disorders after haploidentical and matched-sibling PBSCT in patients with hematologic malignancies. [Journal Article]
- AHAnn Hematol 2019 Jun 26
- In allogeneic hematopoietic stem cell transplantation recipients, reactivation of Epstein-Barr virus (EBV) can cause post-transplantation lymphoproliferative disorder (PTLD), which may rapidly progre…
In allogeneic hematopoietic stem cell transplantation recipients, reactivation of Epstein-Barr virus (EBV) can cause post-transplantation lymphoproliferative disorder (PTLD), which may rapidly progress to multiorgan failure and even death. Development of EBV PTLD correlates very closely with use of anti-thymocyte globulin (ATG) and type of transplant. To assess the incidences and clinical features of EBV DNAemia and PTLD in the setting of stem cell transplantation using unmanipulated G-CSF-primed allogeneic peripheral blood stem cells as graft, we performed a retrospective analysis of stem cell transplantation from HLA-matched sibling donors (MSD-SCT, n = 90) or HLA-haploidentical related donors (HID-SCT, n = 110) in patients with hematological malignancies. All of HID-SCT recipients and 27.8% of MSD-SCT recipients received an ATG-containing conditioning regimen. One-year cumulative incidence of EBV DNAemia was 44.1%, ranging from 4.8% in MSD-SCT recipients not using ATG to 20.0% in MSD-SCT recipients using ATG, and 73.7% in HID-SCT recipients. Risk factors for EBV reactivation included use of ATG (p = 0.008), male donor (p = 0.034), and cytomegalovirus DNAemia (p < 0.001). One-year incidence of EBV PTLD was 11.9%, ranging from 1.8% in recipients of MSD-SCT not using ATG to 4.4% in recipients of MSD-SCT using ATG, and 23.5% in recipients of HID-SCT. Risk factors for PTLD after HID-SCT included in fludarabine-containing conditioning regimen (p = 0.010), cytomegalovirus DNAemia (p = 0.036), and patient's age < 40-yr (p = 0.032). Two-year non-relapse mortality was higher for patients with EBV DNAemia than those without EBV DNAemia (35.8% vs. 15.3%, p = 0.002). One-year relapse-free survival and overall survival among patients with PTLD were 40.2% and 44.9%, respectively, as opposed to 63.4% and 68.4% among patients without PTLD (both p < 0.05). In multivariate analyses, EBV DNAemia predicted a lower risk of relapse (p = 0.025), while PTLD was a marginally significant predictor of relapse (p = 0.092). This study identified patients at risk of EBV reactivation and PTLD after unmanipulated allogeneic peripheral blood stem cell transplantation.