Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interactions between killer immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I ligands influence development of natural killer (NK) cell repertoire and response to infection, cancer, and allogeneic tissue. As KIRs and HLA class I molecules are highly polymorphic, clinical allogeneic hematopoietic cell transplantation is predicted to frequently involve KIR mismatch, and thus to provide a unique system for study of human NK cell receptor repertoire development. Eighteen leukemia patients undergoing HLA-matched transplantation and their donors were analyzed for KIR genotype. Ten of 13 HLA-identical donor-patient pairs were KIR mismatched and 3 were matched; all HLA-matched unrelated pairs were KIR mismatched. Reconstitution of recipient NK cell repertoire following transplantation was examined using flow cytometry and monoclonal antibodies specific for KIR and CD94:NKG2A. These data form 3 groups. Six to 9 months after transplantation, 8 patients (group 1) reconstituted an NK cell repertoire resembling that of their donor, and for KIR-mismatched transplants, distinct from the recipient before transplantation. In the first year after transplantation, 5 patients (group 2) exhibited a generally depressed frequency of KIR-expressing NK cells and concomitant high frequency of CD94:NKG2A expression. By 3 years after transplantation, the frequency of KIR-expressing NK cells had increased to donor values, in the 3 patients from group 2 analyzed for this period. The remaining 5 patients experienced severe clinical complications following transplantation and displayed unique features in their NK cell receptor reconstitution. These results demonstrate that a majority of HLA-matched hematopoietic cell transplantations involve KIR mismatch and reveal differences in NK cell repertoire having potential impact for immune responsiveness and transplantation outcome.
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PMID:Reconstitution of NK cell receptor repertoire following HLA-matched hematopoietic cell transplantation. 1251 15

T-cell large granular lymphocyte (T-LGL) leukemia is an uncommon disease, with limited information on karyotypic aberrations. No consistent chromosomal changes have thus far been described. We report two cases of T-LGL leukemia who presented with severe anemia. The LGL were CD3+, CD4-, CD8+, CD56-, and CD161-, with variable expression of CD94, CD158a, and CD158b, and had clonal T-cell receptor gene rearrangement. A deletion of the long arm of chromosome 6 was the sole aberration in both cases. This is the first report of a recurrent chromosomal aberration in T-LGL leukemia.
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PMID:Deletion 6q as a recurrent chromosomal aberration in T-cell large granular lymphocyte leukemia. 1254 64

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 diagnosis of granular lymphocytic leukaemia (GLL) requires the presence of an immunophenotypically distinct T-cell (T-GLL) or natural killer-cell (NK-GLL) population. Flow cytometric immunophenotyping was performed on 21 T-GLL patients, 11 NK-GLL patients and 20 normal control subjects using antibodies to T and NK cell-associated antigens in order to accurately identify the distinguishing features of T-GLL and NK-GLL. The NK antigens evaluated included: CD16, CD57, CD94, CD161, and the killing inhibitory receptors (KIRs) CD158a, CD158b and CD158e (p70). Abnormal T-antigen expression was present in all T-GLL patients. CD57 was frequently expressed in T-GLL, however, one-third of patients showed partial CD57 expression similar to that seen in T cells from normal control subjects. Ten T-GLL were KIR positive; all expressed a single KIR isoform. All NK-GLL showed a distinctive, abnormal immunophenotype. Four NK-GLL expressed a single KIR isoform; the remaining seven patients lacked all tested KIRs, which is also a distinct, abnormal finding. Immunoperoxidase staining of bone marrow biopsy specimens from NK-GLL patients with antibodies to CD8, TIA-1 and granzyme B revealed the disease-specific distinctive staining patterns previously found in T-GLL. These studies delineate the unique immunophenotypic features diagnostic of T-GLL and provide strong evidence that NK-GLL, like T-GLL, represents a clonal lymphoproliferative disorder.
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PMID:Demonstration of aberrant T-cell and natural killer-cell antigen expression in all cases of granular lymphocytic leukaemia. 1264 73

Cytokine-induced killer (CIK) cells are a unique population of cytotoxic T lymphocytes (CTL) with the characteristic CD3+CD56+ phenotype. These cells have demonstrated higher proliferative and cytolytic activities in comparison to the reported CD3-CD56+ lymphokine activated killer (LAK) cells that are essentially activated natural killer (NK) cells. CIK cells are non-MHC-restricted in target cell recognition and killing. We have shown the feasibility of generating CIK cells from a series of marrow samples of patients with acute myeloid leukemia (AML) collected at diagnosis. At maturity, the CIK cells exhibit potent cytotoxicity against autologous AML targets as well as allogeneic myeloid leukemia cells, regardless of the HLA types of these targets. This observed cytotoxicity is not entirely due to NK cells as prior pre-absorption of the NK cells cytolytic activities does not abolish the subsequent cytotolytic activities against leukemic targets. It has also been reported by others that CIK cells are cytolytic against chronic myeloid leukemia (CML) cells, both in vitro and in the SCID mouse tumor model. In a mouse transplant model across MHC barrier, the CIK cells generated from the donor do not induce graft vs. host disease as observed for unfractionated donor splenocytes. In comparison to untreated control mice, the infusion of CIK cells results in the prolonged survival of murine leukemia-bearing mice. CIK cells also express CD94, part of the NK receptor comprising of CD94-NKG2 heterodimer. However, only low level of the killer immunoglobulin-like receptors are expressed by the CIK cells. In addition, as reported for the classical CTL, CIK cells could interact with dendritic cells (DC) to result in the enhancement of cytotolytic activities against tumor cells. The characteristic biological properties of the CIK cells would, therefore, enable them to be exploited for anti-leukemic therapy.
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PMID:Cytokine-induced killer cells: NK-like T cells with cytotolytic specificity against leukemia. 1456 44

Individuals lacking natural killer (NK) cells have persistent viral infections and as a consequence die prematurely. In addition, mice with decreased NK cell function are more susceptible to carcinogen-induced cancers. Current evidence strongly suggests that downregulation of MHC by certain tumors and virally-infected cells results in NK cell attack due to the inability to trigger inhibitory Ly49, KIR, and NKG2A/CD94 class Ia and Ib MHC receptors. Extreme haplotype diversity is present in both mouse and human chromosomal segments coding for NK cell class Ia MHC receptors resulting in different numbers and types of receptors being expressed in individuals and different inbred mouse strains. Whether the absence or presence of a particular NK cell receptor gene is advantageous or deleterious for an individual with respect to immunity to pathogens and cancer is a question of paramount importance. Recent advances in our understanding of NK cell function are due to the identification of activating NK cell receptors, such as Ly49H and NKG2D, for specific viral and tumor ligands (m157 and Rae1, respectively). In a clinical setting, such MHC class I receptor diversity is advantageous with respect to preventing leukemic relapse in individuals treated for leukemia and receiving bone marrow transplants. Further delineation of NK cell receptors and tumor ligands will help researchers to exploit the innate immune system to better treat such diseases.
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PMID:Regulation of natural killer cell function. 1468 63

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

CD94/NKG2A is an inhibitory receptor expressed by most human natural killer (NK) cells and a subset of T cells that recognizes human leukocyte antigen E (HLA-E) on potential target cells. To elucidate the cell surface dynamics of CD94/NKG2A receptors, we have expressed CD94/NKG2A-EGFP receptors in the rat basophilic leukemia (RBL) cell line. Photobleaching experiments revealed that CD94/NKG2A-EGFP receptors move freely within the plasma membrane and accumulate at the site of contact with ligand. The enriched CD94/NKG2A-EGFP is markedly less mobile than the nonligated receptor. We observed that not only are lipid rafts not required for receptor polarization, they are excluded from the site of receptor contact with the ligand. Furthermore, the lipid raft patches normally observed at the sites where FcepsilonR1 activation receptors are cross-linked were not observed when CD94/NKG2A was coengaged along with the activation receptor. These results suggest that immobilization of the CD94/NKG2A receptors at ligation sites not only promote sustenance of the inhibitory signal, but by lipid rafts exclusion prevent formation of activation signaling complexes.
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PMID:Exclusion of lipid rafts and decreased mobility of CD94/NKG2A receptors at the inhibitory NK cell synapse. 1513 25

Natural killer (NK) cells play a key role in defense against tumor cells that have the capacity to downregulate human leukocyte antigen (HLA) class I expression. It has been reported that leukemic cells can have downregulated expression of HLA class I molecules. The polymorphic nature of NK cell receptor (NKR) genes generates diverse repertoires in the human population, which display specificity in the innate immune response. In the present study, 11 KIR and two CD94/NKG2 receptors were genotyped by PCR-SSP in 96 leukemic patients and 148 healthy Caucasians. Here, we report a significant increased frequency of the more inhibitory AB killer cell immunoglobulin-like receptor (KIR) phenotype in leukemic patients compared to the controls (31.1% in healthy controls vs 51.0% in leukemic patients, Pc=0.002), which is related to the high prevalence of the inhibitory KIR2DL2 in this population (Pc=0.007). Moreover, two specific KIR phenotypes AB1 and AB9, including all inhibitory KIRs, were significantly associated with leukemic patients. Our study suggests that an important percentage of leukemic patients express a KIR phenotype in favor of escape from NK cell immunity.
Leukemia 2004 Dec
PMID:Identification of natural killer cell receptor phenotypes associated with leukemia. 1547 Apr 87

Natural killer (NK) cell alloreactivity is reported to mediate strong GvL (graft versus leukemia) effect in patients after haploidentical stem-cell transplantation (SCT) for acute myeloid leukemia (AML). Because subsequent immune reconstitution remains a major concern, we studied NK-cell recovery in 10 patients with AML who received haplomismatched SC transplants, among whom no GvL effect was observed, despite the mismatched immunoglobulin-like receptor (KIR) ligand in the GvH direction for 8 of 10 patients. NK cells generated after SCT exhibited an immature phenotype: the cytotoxic CD3- CD56(dim) subset was small, expression of KIRs and NKp30 was reduced, while CD94/NKG2A expression was increased. This phenotype was associated to in vitro lower levels of cytotoxicity against a K562 cell line and against primary mismatched AML blasts than donor samples. This impaired lysis was correlated with CD94/NKG2A expression in NK cells. Blockading CD94/NKG2A restored lysis against the AML blasts, which all expressed HLA-E, the ligand for CD94/NKG2A. Our present study allows a better understanding of the NK-cell differentiation after SCT. These results revealed that the NK cells generated after haplomismatched SCT are blocked at an immature state characterized by specific phenotypic features and impaired functioning, having potential impact for immune responsiveness and transplantation outcome.
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PMID:NK-cell reconstitution after haploidentical hematopoietic stem-cell transplantations: immaturity of NK cells and inhibitory effect of NKG2A override GvL effect. 1568 35


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