Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study, we investigated the inhibitory natural killer cell receptor (NKR) expression of CD94/NKG2A on PBMC after allogeneic bone marrow transplantation (BMT). The proportion of CD94 expression on PBMC was higher in patients without chronic graft-versus-host disease (cGVHD) and also in cGVHD patients with good response to conventional immunosuppressive therapy than in cGVHD patients with poor response. Also, the proportions of CD94+/CD3+ cells and CD94+/CD8+ cells were higher in cGVHD patients showing good response. In addition, the proportion of NKG2A-expressing cells was higher in patients without cGVHD than in patients with cGVHD. Therefore, chronic allostimulation after allo-BMT may augment the proportion of CD94/NKG2A-positive cells, and these cells may play some role in the regulation of alloresponse in some patients.
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PMID:Increased proportion of HLA-class-I-specific natural killer cell receptors (CD94) on peripheral blood mononuclear cells after allogeneic bone marrow transplantation. 1140 10

Analysis of cytokine gene expression in peripheral blood mononuclear cells from patients received allogeneic hematopoietic stem cells transplantation (allo-SCT) showed that type 1 helper T cells (Th1)-derived cytokines increased in severe graft-versus-host disease (GVHD) while Th2-derived cytokines such as IL-4, IL-10, and IL-13 increased in mild GVHD. These results indicate that Th2 cells suppress GVHD although Thl cells augment GVHD. Chimerism analysis showed that mixed chimerism was often observed in younger (<30 years old) patients. Mixed chimerism in older (> or = 30 years old) patients were related to rejection and relapse while this situation is not the case in younger patients, thus indicating that mixed chimerism is an important prognostic factor in older patients. Among the chimerism of various cell populations, donor-derived CD56-positive cells are important in early engraftment when determined in allogeneic nonmyeloablative stem cell transplantation (allo-NST), regardless of the proportion of donor-derived CD3-positive cells. This result suggests that donor-derived CD56-positive cells are a more useful indicator for engraftment and rejection in early time period. Complementary-determining region 3 (CDR3) size spectratyping in T-cell receptor (TCR) chain subfamilies (V beta) showed that high level of diversity in TCR V beta repertoire is important for a late rejection and skewed TCR V repertoire is well correlated to occurrence of GVHD. Expression of inhibitory natural killer (NK) cell receptors such as CD158b and CD94/NKG2A on peripheral CD3-negative and positive cells were increased in parallel with GVHD. Interestingly, these molecules appeared to regulate GVHD while preserving graft-versus-leukemia (GVL) effect.
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PMID:Immunological reconstitution and immunoregulatory cells in hematopoietic stem cell transplantation. 1243 Aug 52

We have evaluated recovery of CD56 positive and other cell types following allogeneic stem cell transplantation and have found that the recovery of CD56 positive cells was faster than other lymphoid cells after allogeneic stem cell transplantation, while the recovery of CD4 positive cells was markedly delayed. Chimerism analysis showed that mixed chimerism was often observed in younger (<30 years old) patients. Mixed chimerism in older (> or =30 years old) patients was associated with rejection and relapse, while this was not found in younger patients. Among the chimerism of various cell populations, donor-derived CD56-positive cells are important in early engraftment when determined in allogeneic nonmyeloablative stem cell transplantation (allo-NST), regardless of the proportion of donor-derived CD3-positive cells. Complementarity-determining region three (CDR3) size spectratyping in T-cell receptor (TCR) chain subfamilies (Vbeta) showed that high level of diversity in TCR Vbeta repertoire is important for a late rejection and skewed TCR Vbeta repertoire is correlated with the occurrence of graft-versus-host disease (GVHD) especially chronic GVHD. Expression of inhibitory natural killer (NK) cell receptors such as CD158b and CD94/NKG2A on peripheral CD3-negative and -positive cells were increased in parallel with GVHD. Interestingly, these cells appeared to control GVHD, while preserving graft-versus-leukemia (GVL) effect. Analysis of cytokine gene expression in peripheral blood mononuclear cells showed that type 1 helper T cells (Th1)-derived cytokines increased in severe GVHD, while Th2-derived cytokines such as IL-4, IL-10 and IL-13 increased in mild GVHD. These results indicate that Th2 cells suppress GVHD, although Th1 cells augment GVHD. Taken together, evaluation of immune reconstitution and tolerance in patients receiving allogeneic stem cell transplantation from the various viewpoints is essential and useful to obtain better clinical outcome.
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PMID:Immune reconstitution and tolerance after allogeneic hematopoietic stem cell transplantation. 1262 23

The study was aimed at the exploration of relationship between T cells expressing killer cell inhibitor receptors (KIR, CD158 and CD94) and graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation. The expression rates of CD158a, CD158b and CD94 on T cells and NK cell were detected by flow cytometry and donor/recipient HLA-Cw was analyzed using PCR after peripheral blood stem cell transplantation (PBSCT) and umbilical cord blood transplantation (UCBT). After both PBSCT and UCBT, the rates of CD3(+)CD158a(+) and CD3(+)CD158b(+) T cells increased, especially the rate of CD8(+)CD158b(+) T cells. In both acute and chronic GVHD groups, the rate of CD3(+)CD158b(+) T cells increased, especially in acute GVHD. The CD94 mainly expressed on CD3(+)CD8(+) T cells. The percentage of the expression of CD94 on CD4(+) and CD8(+) cells after UCBT and PBSCT increased significantly. The expression of KIR in GVHD (early stage of transplantation) increased but the expression of KIR in chronic GVHD (advanced stage of transplantation) decreased. Five patients who HLA-Cw matched had no severe GVHD. In four patients who underwent allo-PBSCT and UCBT from related HLA-matched donors, only 2 patients had no aGVHD. Four patients underwent transplantation from unrelated HLA-matched donors had GVHD. These observations suggested that there is some relationship between GVHD and KIR expression on T cells. CD158b might be an inhibitory molecule of T cell activated at early stage after transplantation. Understanding the mechanism of GVHD with the expression of KIR on T cells, especially those binding the HLA-Cw might shed light on the establishment of the specific immunotolerance for the prevention of GVHD. To pay attention to HLA-Cw typing is very important to reduce GVHD and increase GVL effect in related or unrelated HLA-matched transplantation.
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PMID:Expression of killer cell inhibitor receptors on immunocompetent cells with relation to graft-versus-host disease after hematopoietic stem cell transplantation. 1470 48

Inhibitory natural killer cell receptor (NKR)-expressing cells may induce a graft-versus-leukemia/tumor (GVL/T) effect against leukemic cells and tumor cells that have mismatched or decreased expression of HLA class I molecules and may not cause graft-versus-host disease (GVHD) against host cells that have normal expression of HLA class I molecules. In our study, we were able to expand inhibitory NKR (CD94/NKG2A)-expressing CD8+ T cells from granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells (G-PBMCs) by more than 500-fold using stimulation by an anti-CD3 monoclonal antibody with interleukin 15 (IL-15). These expanded and purified CD94-expressing cells attacked various malignant cell lines, including solid cancer cell lines, as well as the patients' leukemic cells but not autologous and allogeneic phytohemagglutinin (PHA) blasts in vitro. Also, these CD94-expressing cells prevented the growth of K562 leukemic cells and CW2 colon cancer cells in NOD/SCID mice in vivo. On the other hand, the CD94-expressing cells have low responsiveness to alloantigen in mixed lymphocyte culture (MLC) and have high transforming growth factor (TGF)-beta1- but low IL-2- producing capacity. Therefore, CD94-expressing cells with cytolytic activity against the recipient's leukemic and tumor cells without enhancement of alloresponse might be able to be expanded from donor G-PBMCs.
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PMID:Cytolytic activity and regulatory functions of inhibitory NK cell receptor-expressing T cells expanded from granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cells. 1507 36

The effect of natural killer (NK) cell alloreactivity on the outcome of haploidentical hematopoietic stem cell transplantation (HSCT), with or without in vitro T cell depletion, remains controversial. Killer immunoglobulin-like receptors (KIRs) recognize human leukocyte antigen C and B epitopes on target cells, thereby regulating NK cell activity. To examine the recovery of CD94:NKG2A and KIR (CD158a, CD158b, and CD158e) expression by NK cells, we used flow cytometry to evaluate samples from 24 patients and their donors before and in the year following unmanipulated HLA-haploidentical/mismatched blood and marrow transplantation. Linear regression analysis demonstrated that NKG2A recovery was inversely correlated with CD158b recovery in the year following transplant. The doses of T cell subgroups CD4+ and CD8+ were inversely associated with CD158a and CD158e expression during the 2 months following transplantation. Moreover, patients with grades II-IV acute graft-versus-host disease (aGVHD) or who received "high" doses of T cells (>1.37 x 10(8)/kg) showed delayed recovery of KIRs during the 2 months following transplantation. Univariate analysis showed that patients with high CD94 expression by day 60 (>90%) or who received donors with high CD94 expression (>80%) were associated with higher transplantation-related mortality (P = .006 or .067, respectively) and poorer leukemia-free survival (P = .012 or .094, respectively). Thus, the occurrence of aGVHD or the receipt of high doses of T cells in the allograft altered KIR reconstitution. Furthermore, high levels of CD94 expression in donors or in recipients by day 60 might be a good predictor for poor prognosis.
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PMID:Reconstitution of natural killer cell receptor repertoires after unmanipulated HLA-mismatched/haploidentical blood and marrow transplantation: analyses of CD94:NKG2A and killer immunoglobulin-like receptor expression and their associations with clinical outcome. 1753 84

Human umbilical cord blood (CB) has recently been used as a source of stem cells in transplantation. NK cells derived from CB are the key effector cells involved in graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL). It was reported that the activity of CB NK cells was lower than that of adult peripheral blood (PB) NK cells. In this study, we analyzed the expression of some NK cell receptors and cytotoxicity-related molecules in CB and PB NK cells. The expressions of activating NK receptors, CD16, NKG2D and NKp46, did not show significant difference between CB and PB NK cells. But the expression of inhibitory receptor NKG2A/CD94 was significantly higher on CB NK cells. As to the effector function molecules, granzyme B was expressed significantly lower in CB NK cells, but the expressions of intracellular perforin, IFN-gamma, TNF-alpha and cell surface FasL and TRAIL did not show difference between CB and PB NK cells. The results indicated that the high expression of NKG2A/CD94 and low expression of granzyme B may be related with the reduced activity of CB NK cells.
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PMID:High expression of NKG2A/CD94 and low expression of granzyme B are associated with reduced cord blood NK cell activity. 1797 18

T cell receptor excision circles (TRECs) have been suggested to be useful markers of recent thymic output and graft-versus-host disease (GVHD) was thought to have an adverse effect on thymic output. On the other hand, TREC concentrations are diluted with T cell expansion. The C-type lectin superfamily inhibitory receptor CD94 expression on T cells might be a consequence of CD8 T cell expansion. Therefore, this study was designed to analyse TREC DNA level in CD4 and CD8 T cell subset expressing CD94 during GVHD. We investigated TREC DNA copy numbers (TREC levels) of CD4+, CD94+/CD8+ and CD94-/CD8+ T cells in 24 patients who had undergone allogeneic stem cell transplantation and also of in vitro activated and expanded CD94-expressing cells by immobilised anti-CD3 mAb and IL-15. TREC level of CD94+/CD8+ T cells in patients with chronic GVHD was lower than that in patients with no GVHD and with remission status of GVHD. In vitro activated and expanded CD94-expressing cells had a significantly lower TREC level than that in untreated CD8 cells. Therefore, the low TREC level of CD94+/CD8+ T cells is related to chronic GVHD and may reflect T cell expansion during chronic GVHD.
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PMID:T cell receptor excision circle levels in CD94-expressing CD8 T Cells during graft-versus-host disease. 1860 19

A number of experimental studies have shown that natural killer (NK) cells can eliminate cancer cells and the mechanisms involved in this effect have been uncovered during the last two decades. Clinical data from haploidentical haematopoietic stem cell transplantation (haplo-HSCT) revealed that NK cells were responsible for remarkably favourable effects in both adult and paediatric high-risk leukaemias. NK receptors specific for major histocompatibility complex (MHC) class I molecules, including killer immunoglobulin (Ig)-like receptors (KIR) and CD94/NKG2A, play a major role in the anti-leukaemia effect (mediating either inhibitory or activating signals). Haplo- HSCT requires a heavy conditioning regimen for the patient and the use of large numbers of T cell-depleted HSC to be grafted. After transplantation, natural killer cells develop from HSC shortly after engraftment and may include 'alloreactive' NK cells that kill leukaemic cells and prevent graft-versus-host disease (GvHD). Alloreactive NK cells are characterized by the expression of KIR that are not engaged by any of the human leucocyte antigen (HLA) class I alleles expressed by the patient. Their generation is dependent upon the existence of a KIR/HLA class I mismatch between donor and recipient. Novel important information on the function and specificity of different KIR has been obtained recently by the analysis of donor-derived alloreactive NK cells in a cohort of paediatric patients given haplo-HSCT to cure acute, high-risk leukaemias.
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PMID:Activating and inhibitory killer immunoglobulin-like receptors (KIR) in haploidentical haemopoietic stem cell transplantation to cure high-risk leukaemias. 1966 39

Natural killer (NK) cells play a central role in the innate immune system. In allogeneic stem cell transplantation (alloSCT), alloreactive NK cells derived by the graft are discussed to mediate the elimination of leukemic cells and dendritic cells in the patient and thereby to reduce the risk for leukemic relapses and graft-versus-host reactions. The alloreactivity of NK cells is determined by various receptors including the activating CD94/NKG2C and the inhibitory CD94/NKG2A receptors, which both recognize the non-classical human leukocyte antigen E (HLA-E). Here we analyze the contribution of these receptors to NK cell alloreactivity in 26 patients over the course of the first year after alloSCT due to acute myeloid leukemia, myelodysplastic syndrome and T cell Non-Hodgkin-Lymphoma. Our results show that NK cells expressing the activating CD94/NKG2C receptor are significantly reduced in patients after alloSCT with severe acute and chronic graft-versus-host disease (GvHD). Moreover, the ratio of CD94/NKG2C to CD94/NKG2A was reduced in patients with severe acute and chronic GvHD after receiving an HLA-mismatched graft. Collectively, these results provide evidence for the first time that CD94/NKG2C is involved in GvHD prevention.
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PMID:The Activating NKG2C Receptor Is Significantly Reduced in NK Cells after Allogeneic Stem Cell Transplantation in Patients with Severe Graft-versus-Host Disease. 2780 84


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