UMLS:C0018133 - FACTA Search

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Query: UMLS:C0018133 (graft-versus-host disease)
18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The goal of this study was to investigate the association of natural killer (NK) cell recovery with clinical outcomes after unmanipulated haploidentical blood and marrow transplantation. We sequentially monitored the reconstitution kinetics of circulating NK cells, CD56(bright) and CD56(dim), in 43 patients by flow cytometry, and the functionality recovery of cytokine or cytotoxicity of NK cells by flow cytometry or lactate dehydrogenase release assay after transplantation. Reconstitution of NK cells was rapid but accompanied by skewing of cell subsets mainly in CD56(bright), which recovered earlier. Linear regression analysis demonstrated that dose of CD34(+) cells in the allografts was inversely correlated with the ratio of T/NK cells (beta = -0.506, P = .003) and CD56(dim)/CD56(bright) cell (beta = -.403, P = .018) by day 14 after hematopoietic stem cell transplantation (HSCT), and the dose of CD3(+) T cells in the allografts was also inversely correlated with the ratio CD56(dim)/CD56(bright) cells by day 14 after HSCT (beta = -0.474, P = .005). Moreover, the dose of CD56(dim) NK cells in the allograft was positively associated with the day 14 CD56(brigh) NK cells (beta = 0.494, P = .032) and inversely correlated with the day 14 ratio of CD56(dim)/CD56(bright) cells (beta = -0.617, P = .005). Compared with nonacute graft-versus-host disease (GVHD) patients, patients with acute GVHD (aGVHD) had a higher level of NK subsets during week 2 posttransplantation. Cox regression analysis revealed that the patients with more CD56(bright) NK cells in the recovery stage had a higher survival rate (hazard risk [HR], 0.406; P = .017) and the patients with a higher ratio of T/NK (>1.0) had a higher chance of getting aGVHD (HR, 3.436; P = .059) and chronic GVHD (HR, 3.925; P = .028). Our results suggest that the recovery of NK cells is and can be used as an indicator to predicate the clinical outcomes after unmanipulated haploidentical transplantation.
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PMID:Effects of the NK cell recovery on outcomes of unmanipulated haploidentical blood and marrow transplantation for patients with hematologic malignancies. 1827 99

Previous studies showed that methylprednisolone (MePDN) down-regulates the surface expression of activating NK receptors and sharply inhibits the NK cytotoxicity both in vitro and in vivo. Since MePDN is administered to patients undergoing hemopoietic stem cell transplant to treat acute graft versus host disease (GvHD), we analyzed whether it could also inhibit the NK cell differentiation from CD34(+) hemopoietic cell precursors, thus interfering with the development of effector cells with anti-leukemic potential. We show that MePDN promotes the in vitro differentiation of CD161+CD56+/- immature NK cells by inducing a rapid expression of NKp46, NKG2D, DNAX-accessory molecule 1 (DNAM-1), leukocyte function-associated antigen-1 and NKG2A and an efficient cytolytic activity. This phenotypic and functional NK cell maturation occurred more rapidly than in parallel control cultures performed in the absence of MePDN. In addition, MePDN induced CD33+CD161-CD56- myeloid precursors to switch toward NK cells. It is also of note that immature NK cells when cultured in the absence (but not in the presence) of MePDN produced high amounts of IL-8. These data indicate that MePDN can accelerate the in vitro NK cell differentiation, thus revealing a dichotomous effect on immature versus mature NK cells; in addition, interference with the in vitro development of myeloid cells occurred. These effects should be further investigated in hemopoietic stem cell transplanted patients receiving steroids to treat GvHD.
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PMID:Methylprednisolone induces preferential and rapid differentiation of CD34+ cord blood precursors toward NK cells. 1831 65

The abundantly available source of stem cells and the low incidence of graft-versus-host disease (GVHD) made cord blood an attractive alternative source of hematopoietic stem cells for transplantation. Besides T cell and NK cell, NKT cell played an important role in low incidence of GVHD during allogeneic transplantation. IL-2 and IL-15 can stimulate T cell and NK cell proliferation, survival and activation in vitro. But they exhibited different effects on the GVHD during allogeneic transplantation. In this study, we explored the different effects of exogenous IL-2 and IL-15 on the expansion of CD3+CD56+ NKT-like cells by in vitro long term culture of cord blood mononuclear cells (CBMCs). The results showed that CD3+CD56+ NKT-like cells were derived from CD34-CD56- CBMCs and IL-2 improved CD3+CD56+ NKT-like cell expansion more strongly than IL-15. Interestingly, CD3+CD56+ NKT-like cells from IL-15-cocultured CBMCs had significantly lower apoptotic frequency and higher levels of activation markers (CD161, CD25, and IFN-gamma) than those from IL-2-cocultured CBMCs. The anti-apoptotic and activating effects of IL-15 on CD3+CD56+ NKT-like cells from CBMCs might possibly explain the pathogenic role of IL-15 in GVHD during allogeneic transplantation.
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PMID:Different roles of IL-15 from IL-2 in differentiation and activation of human CD3+CD56+ NKT-like cells from cord blood in long term culture. 1844

Natural killer (NK) cell-mediated cytotoxicity can control leukemia relapse while protecting patients from graft-versus-host disease (GVHD) after allogeneic stem cell transplant. Cord blood (CB) is rich in NK cell progenitors with similar properties of proliferation and cytotoxicity as adult blood NK cells. Hence, it is attractive to expand and potentially utilize these cells for adoptive immunotherapy. In this study, CB mononuclear cells were CD3-depleted by immunomagnetic microbead selection to remove T cells. This CD3(dep) CB-MNC fraction was then plated for ex vivo expansion, with or without a feeder layer of irradiated umbilical cord mesenchymal stem cells (UC-MSC), with or without cytokines that have been shown to be critical for NK expansion: IL-2, IL-15, IL-3, and FLT-3L. At an average of 2 weeks of culture, there was significantly higher expansion (64.7 +/- 8.4-fold) of CD56(+)/CD3(-) NK cells in the presence of the UC-MSC feeder layer and cytokines compared to controls (no increase with feeder layer only and 6.4 +/- 1.5-fold increase with cytokines only, P < .05). Contact between CD3(dep) CB-MNC cells and UC-MSC augmented NK expansion. The combination of all 4 cytokines was superior to IL-2 alone or 2 cytokines combinations: mean 64.7 +/- 8.4-fold expansion with 4 cytokines combination versus IL-2 alone, IL-2 + FLT-3L, IL-2 + IL-15 or IL-2 + IL-3 (12.2 +/- 2.0, 14.4 +/- 2.4, 10.4 +/- 4.1, 25.2 +/- 8.1 respectively). We also observed that only fresh CD3(dep) CB-MNC preparations could be expanded reliably, whereas frozen and thawed CD3(dep) CB-MNC cells did not expand consistently (mean fold increase 6.5 +/- 3.2). Cytotoxicity of expanded NK cells was compared with NK cells from fresh and overnight IL-2 activated CD3(dep) CB-MNC. Whereas fresh cells displayed no discernible killing, strong cytotoxicity against K562, Raji, REH, and SUP-B15 cells lines was noted after overnight activation in IL-2. Cytotoxicity of expanded NK cells against Raji, REH, and SUP-B15 was lower, which, however, correlated with a predominant expansion of CD56(+)/CD16(-) cells known to have less cytolytic activity than CD56(+)/CD16(+). To test the transfection efficiency in NK cells, fresh or expanded CD3(dep) CB-MNC cells were electroporated with either DNA or mRNA constructs for GFP. DNA had a low transfection efficiency (<10%), whereas the one for mRNA reached 52%, but at the cost of significant cell death. Our results suggest that CB NK cell progenitors can be expanded to obtain large numbers by using an irradiated feeder of UC-MSC. They maintain an elevated cytotoxic profile, and may be genetically manipulated-all characteristics that make them suitable for cellular therapies.
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PMID:Umbilical cord mesenchymal stem cells increase expansion of cord blood natural killer cells. 1872 66

This study was purposed to investigate immune reconstitution at 12 months after allogeneic peripheral blood stem cell transplantation (all-PBSCT) and its relation with the influencing factors such as age, HLA compatibility, graft versus host disease and viral infection. The T lymphocyte subgroups (CD3(+), CD4(+), CD8(+)), B lymphocyte (CD19(+)) and NK (CD16(+)CD56(+)) cells in peripheral blood and serum immunoglobulin concentrations (IgG, IgA and IgM) of 37 patients were analyzed by flow cytometry and scatter turbidimetry, respectively at 1, 3, 6 and 12 months after transplantation. The results showed that CD3(+) cell percentage was (47.5 +/- 23.2)% at 1 month, (75.1 +/- 6.4)% at 3 months, (69.7 +/- 12)% at 6 months and (71.7 +/- 4.2)% at 12 months. CD4(+) cell percentage was (13.3 +/- 6.4)% at 1 month, (20.2 +/- 11.4)% at 3 months, (46.9 +/- 10.3)% at 6 months and (29.1 +/- 18.7)% at 12 months. CD8(+) cell percentage was (43.1 +/- 23.2)% at 1 month, (42.6 +/- 16.9)% at 3 months, (69.7 +/- 12)% at 6 months and (47 +/- 5.6)% at 12 months. CD16(+)56(+) cell percentage was (14.4 +/- 8.4)% at 1 month, (15.9 +/- 7.6)% at 3 months, (14.7 +/- 6.6)% at 6 months and (13.6 +/- 3.4)% at 12 months. CD19(+) cell percentage was (6.4 +/- 5.6)% at 1 month, (11.7 +/- 2.4)% at 3 months, (13.3 +/- 7.3)% at 6 months and (16.7 +/- 5.7)% at 12 months. The serum concentration of IgA was (0.37 +/- 0.14) g/L at 1 month, (0.28 +/- 0.21) g/L at 3 months, (0.42 +/- 0.18) g/L at 6 months and (0.53 +/- 0.34) g/L at 12 months. The serum concentration of IgG was (12.7 +/- 3.8) g/L at 1 month, (16.3 +/- 5.2) g/L at 3 months, (14.3 +/- 6.2) g/L at 6 months and (15.4 +/- 6.9) g/L at 12 months. The serum concentration of IgM was (0.56 +/- 0.24) g/L at 1 month, (0.64 +/- 0.16) g/L at 3 months, (1.1 +/- 0.35) g/L at 6 months and (1.2 +/- 0.28) g/L at 12 months. There were no significant differences between percentage of T lymphocyte subgroups in peripheral blood and serum immunoglobulin concentrations of the patients > or = 45 years old and the patients < 45 years old. The CD19(+) cell percentage of the patients with chronic GVHD at 12 month was less than that of the other ones at 12 months after transplantation. CD4(+) and CD19(+) cell percentage recovery in the patients of haploidentical transplantation was later than that in patients of HLA complete identical transplantation. The CD4(+)/CD8(+) cell ratio and CD4(+) cell percentage of those patients infected with herpes zoster were significantly lower than those without herpes zoster. It is concluded that the CD3(+) cell percentage begins to recover at 3 months after allo-PBSCT. CD4(+) cell percentage begins to recover at 6 months after allo-PBSCT. CD8(+) cell percentage begins to recover at 1 month after allo-PBSCT. B cell percentage recovers at 3 to 6 months after allo-PBSCT. NK cell percentage recovers at 1 to 3 months after allo-PBSCT. The serum concentration of IgG recovers to normal at 1 month after transplantation which is associated with routine infusion of immunoglobulin. The concentration of IgM gradually recovers to normal at 3 months after transplantation. The concentration of IgA does not recover to normal at 12 months after transplantation. The function of B cells recovers slowly in patients with cGVHD. The CD4(+) cell absolute value and CD4(+)/CD8(+) ratio significantly decrease in patients with herpes zoster.
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PMID:[Immune reconstitution after allogeneic peripheral blood stem cell transplantation]. 1892 11

We report 2 patients with plasmacytoid dendritic cell leukemia (pDCL) expressing CD4, CD56, CD33, CD36, HLA-DR, CD123, CD86 and CD83 in the absence of lineage markers (myeloid, B, T or natural killer cells) except for CD33. Culturing leukemic blasts of both cases with IL-3 for 4 days increased the expression of surface molecules associated with antigen presentation, e.g. CD1a and CD40. Leukemic blasts of both cases possessed a considerable level of antigen-presenting ability to allogeneic lymphocytes in mixed leukocyte cultures. Culturing the blasts with IL-3 for 4 days markedly increased allogeneic antigen presenting ability. Combined with data showing evident graft-versus-leukemia effects without graft-versus-host disease in a cord blood stem cell transplanted pDCL case, leukemic cells in pDCL may act as potent antigen presenting cells in vivo, too.
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PMID:Plasmacytoid dendritic cell leukemia with potent antigen-presenting ability. 1894 86

Polyclonal anti-T-lymphocyte globulins (ATG) are used in allogeneic stem cell transplantation (SCT) for the prophylaxis of graft versus host disease (GVHD) by in vivo T cell depletion. In this study we investigated the complement independent induction of apoptosis by rabbit ATG in peripheral blood mononuclear cell (PBMNC) compartments and hematopoetic stem cells (HSC). We also detected antileukemic activity of ATG by measuring apoptosis in myeloid and lymphatic leukemia cell lines and primary leukemia cells. We found ATG to induce apoptosis in T-lymphocytes (CD4(+), CD8+), B-lymphocytes (CD20+), natural killer (NK)-cells (CD56(+)), and monocytes (CD14(+)). HSC, in contrast, were apoptosis resistant and could be growth stimulated by low-dose ATG in the presence of bystander cells. The human leukemia cell lines Jurkat, Daudi, DG-75 (lymphoblastic), and K562, HL-60, KG1, and U937 (myeloblastic) underwent ATG-induced apoptosis, whereas the NK-cell line YT was resistant. Primary leukemia cells from 6 investigated patients with acute lymphoblastic leukemia, 9 of 10 patients with chronic lymphocytic leukemia, and 4 of 8 patients with acute myeloblastic leukemia underwent ATG-induced apoptosis. We conclude apoptosis induction in all PBMNC compartments contributes to GVHD prophylaxis. ATG might support engraftment. Finally, antileukemic activity of ATG could positively influence the transplantation outcome.
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PMID:Rabbit anti T-lymphocyte globulin induces apoptosis in peripheral blood mononuclear cell compartments and leukemia cells, while hematopoetic stem cells are apoptosis resistant. 1916 77

The aim of this study was to investigate the effects of natural killer (NK) cells on transplant outcomes in patients receiving G-CSF-mobilized PBSC grafts and G-CSF-primed BM grafts from HLA-haploidentical donors. Forty-one haploidentical allogeneic hematopoietic SCT patients were analyzed according to the NK cell concentration in relation to acute GVHD (aGVHD), chronic GVHD (cGVHD), TRM and leukemia-free survival. The patients receiving a higher dose of CD56(bright) NK cells (>1.9 x 10(6)/kg) showed a higher incidence of grades II-IV aGVHD (hazard risk (HR), 2.872; P=0.022) and cGVHD (HR, 2.884; P=0.039). A higher CD56(dim)/CD56(bri) NK cell ratio (>8.0) was correlated with a decreased risk of III-IV aGVHD (HR, 0.290; P=0.065) and TRM (HR, 0.072; P=0.012), thereby increasing the rate of leukemia-free survival (HR, 0.174; P=0.007) after haploidentical transplantation without in vitro T-cell depletion. Our results suggest that a high allograft CD56(dim)/CD56(bright) NK cell ratio (>8.0) plays an important role in improving transplant outcomes. A higher dose of CD56(bright) NK cells might be a predictor for a higher incidence of GVHD.
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PMID:Association of natural killer cells in allografts with transplant outcomes in patients receiving G-CSF-mobilized PBSC grafts and G-CSF-primed BM grafts from HLA-haploidentical donors. 1937 16

Post transplant infusion of donor-type natural killer (NK) cells has been shown to have an anti-leukemia-enhancing effect without evoking GVHD in murine hematopoietic cell transplantation (HCT) models. Here, we tested 14 patients (age, 23-65 years), 12 with acute leukemia and 2 with myelodysplastic syndrome, who underwent HLA-mismatched HCT and subsequently received donor NK cell infusions. Cell donors (age, 16-51 years), comprising seven siblings, five offspring, and two mothers of the patients, underwent growth factor-mobilized leukapheresis for 3-5 days. Cells collected on the first 2-4 days were used for HCT, whereas those collected on the last day were CD34 selected by magnetic-activated cell sorting (median, 2.22 x 10(6) cells/kg; range, 0.29-5.66). Donor NK cells were generated from the CD34(+) cells by ex vivo cell culture over a 6-week period (median, 9.28 x 10(6) cells/kg; range, 0.33-24.50; CD122/CD56(+) 64%; CD3(+) 1.0%; and viability 88%). There were no signs of acute toxicity in patients infused with these cells 6-7 weeks post transplant. Overall, one and five patients developed acute and chronic GVHD during post transplant period, respectively. These results showed that clinical-grade donor NK cell production from CD34(+) cells is feasible.
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PMID:Generation of donor natural killer cells from CD34(+) progenitor cells and subsequent infusion after HLA-mismatched allogeneic hematopoietic cell transplantation: a feasibility study. 1988 55

Infusing natural killer (NK) cells following transplantation may allow less infections and relapse with little risk of acute graft-versus-host disease (aGVHD). We delivered 51 total NK cell-enriched donor lymphocyte infusions (DLIs) to 30 patients following a 3-6/6 HLA matched T cell-depleted nonmyeloablative allogeneic transplant. The primary endpoint of this study was feasibility and safety. Eight weeks following transplantation, donor NK cell-enriched DLIs were processed using a CD56(+) selecting column with up to 3 fresh infusions allowed. Toxicity, relapse, and survival were monitored. T cell phenotype, NK cell functional recovery, and KIR typing were assessed for association with outcomes. Fourteen matched and 16 mismatched transplanted patients received a total of 51 NK cell-enriched DLIs. Selection resulted in 96% (standard deviation [SD] 8%) purity and 83% (SD 21%) yield in the matched setting and 97% (SD 3%) purity and 77% (SD 24%) yield in the mismatched setting. The median number of CD3(-) CD56(+) NK cells infused was 10.6 (SD 7.91) x 10(6) cells/kg and 9.21 (SD 5.6) x 10(6) cells/kg, respectively. The median number of contaminating CD3(+)CD56(-) T cells infused was .53 (1.1) x 10(6) and .27 (.78) x 10(6) in the matched and mismatched setting, respectively. Only 1 patient each in the matched (n = 14) or mismatched (n = 16) setting experienced severe aGVHD with little other toxicity attributable to the infusions. Long-term responders with multiple NK cell-enriched infusions and improved T cell phenotypic recovery had improved duration of responses (p = .0045) and overall survival (OS) (P = .0058). A 1-step, high-yield process is feasible, and results in high doses of NK cells infused with little toxicity. NK cell-enriched DLIs result in improved immune recovery and outcomes for some. Future studies must assess whether the improved outcomes are the direct result of the high doses and improved NK cell function or other aspects of immune recovery.
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PMID:Natural killer cell-enriched donor lymphocyte infusions from A 3-6/6 HLA matched family member following nonmyeloablative allogeneic stem cell transplantation. 2018 2

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