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

Mild acid treatment by releasing beta(2)m and antigenic peptides leaves human leukocyte antigen (HLA) class I free heavy chains attached to the cell surface. Acid treatment thus allows detection of the cell surface class I antigens by monoclonal antibodies (mAbs) specific to HLA-free heavy chains. We found that acid treatment also enables detection of the cell surface non-classical HLA-G class I antigen with mAbs specific for HLA-G free heavy chains, including 4H84 mAb recognizing all isoforms. Furthermore, we found that 4H84 mAb, but not other mAbs specific to HLA-G free heavy chains, binds to the surface of 8 out of 16 acid-treated leukemia cell lines. Nevertheless, HLA-G antigen is not present in any of these leukemia cells. This was demonstrated by failure to detect any antigen with 4H84 mAb in immunoblotting as well as by inability to detect HLA-G mRNA by RT-PCR. The antigen recognized by 4H84 mAb in some acid treated leukemia cells was identified by immunoprecipitation as a 45 kDa protein. A number of observations indicate that 45 kDa proteins are none other than classical class I heavy chains. Acid treatment thus induces the ability of the 4H84 mAb to recognize some classical HLA class I molecules. Remarkably, 4H84 determinant on HLA-G is linear but corresponding determinant present on some partially folded classical HLA class I free heavy chains is conformational. In view of the unexpected cross-reactivity, detection of HLA-G with this mAb must be carefully evaluated to avoid false detection.
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PMID:Mild acid treatment induces cross-reactivity of 4H84 monoclonal antibody specific to nonclassical HLA-G antigen with classical HLA class I molecules. 1255 28

Haematopoietic-cell transplantation is a treatment for leukaemia and lymphoma. To reduce the incidence of graft-versus-host disease (GVHD) caused by transplanted T cells, donors and recipients are HLA matched. For patients for whom a matched donor is not available, one option is transplantation from an HLA-mismatched relative who shares one HLA haplotype. This procedure is distinguished by the use of a stronger conditioning regimen for the patient and of a T-cell-depleted graft containing numerous stem cells. After transplantation, natural killer cells are prevalent, and they can include alloreactive cells that kill tumour cells and prevent GVHD. The alloreactions seem to be determined by the mismatched HLA class I ligands and their killer-cell immunoglobulin-like receptors.
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PMID:Alloreactive killer cells: hindrance and help for haematopoietic transplants. 1256 95

Downregulation of MHC class Ia molecule expression is a widespread mechanism used by tumor cells to escape antitumor T-cell-mediated immune responses. However, it is not known why NK cells cannot lyse these MHC class-Ia-deficient tumor targets. Tumors must select additional routes of escape from NK cells. An attractive hypothesis is that the aberrant expression of nonclassical HLA class Ia molecules in tumors provides the required inhibitory signal to NK cells, rendering tumor cells resistant to NK lysis. To analyze the possible role of HLA-E molecules in providing tumor cells with an NK escape mechanism, we studied the cell surface expression of this HLA class Ib molecule in a variety of tumor cell lines with well-defined HLA class Ia alterations. Tests were done with the monoclonal antibody 3D12 recognizing cell surface HLA-E molecules. Our results indicate that HLA-E was mainly detected in leukemia-derived cell lines. In addition, HLA-E was detected in tumor cell lines of different origin. This expression was related with the availability of free beta(2)-microglobulin (beta(2)m) in the cytoplasm of tumor cells. Expression was detected in tumor cell lines showing an imbalance in heavy chain/beta(2)m expression, particularly in tumor cell lines with alterations in the expression of heavy-chain genes. Several lines of evidence favor these conclusions: (1) In the FM55 and NW145 melanoma tumor systems, the reduction in HLA class Ia expression paralleled the increased cell surface detection of HLA-E. (2) A cervical tumor (808) and a melanoma cell line (R22.2) expressing a single HLA-A1 allele also expressed HLA-E. (3) The addition of human beta(2)m to tumor cell lines that expressed the HLA-E(G) allele increased HLA-E cell surface expression. (4) There was no HLA-E cell surface expression in tumor cell lines with total loss of HLA class Ia expression, including cell lines with low transcription of HLA class I heavy chains or with beta(2)m mutations. Our findings suggest that the biological consequences of these cumulative genetic and molecular changes in tumor cells lead to the appearance of HLA-E in a limited number of tumor cell lines with peculiar phenotypic and genotypic characteristics, namely: HLA-class Ia downregulation, free beta(2)m and HLA-E(G) genotype. The aberrant HLA-E expression might be of particular biological relevance in those HLA tumor phenotypes that express a single HLA-A allele when NK inhibition is markedly reduced due to the downregulation of HLA-B and -C alleles.
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PMID:Analysis of HLA-E expression in human tumors. 1261 9

Acute myeloid leukemia (AML) is a clonal disease of hematopoiesis with poor clinical outcome despite recent improvements in chemotherapy and stem cell transplantation regimens. Immunotherapy with dendritic cells (DCs) eliciting specific T cell responses to leukemia-associated antigens (LAAs) might be a therapeutic option. DCs must express HLA class I/II molecules and the costimulatory molecules CD40, CD80 and CD86 to effectively activate T cells for the subsequent lysis of leukemic blasts. The expression of these antigens on DCs generated from 15 AML patients (AML-DCs) and on DCs generated from 15 healthy volunteers (HV-DCs) was analyzed by FACS. All DCs displayed the typical morphology and tested negative for B, T and NK cell markers. The sustained mRNA expression of LAAs such as PRAME, RHAMM or WT-1 proved that the AML-DCs originated from AML blasts. Compared with AML blasts, the expression of CD40, CD80, CD86 and HLA-DR was upregulated during DC culture to a median of 80-98% on AML-DCs. HLA-ABC was preserved on AML-DCs (median 95%). Expression of CD40, CD80 and CD83 remained lower on AML-DCs than on HV-DCs. AML-DCs express at least one LAA and strongly express HLA and costimulatory molecules, the prerequisites for eliciting T cell responses. AML-DCs may play a role in vaccine-based immunotherapies for AML patients.
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PMID:Reconstitution of CD40 and CD80 in dendritic cells generated from blasts of patients with acute myeloid leukemia. 1286 19

Recently, it was demonstrated that transfection of dendritic cells (DCs) with tumor-derived RNA can elicit effective T-cell responses. This technique does not require the definition of the tumor antigen or HLA haplotype of the patients. We applied this approach to induce HLA class I- and class II-restricted T-cell responses directed against malignant cells from patients with chronic lymphocytic leukemia (B-CLL). Here, we show that DCs generated from monocytes of patients with B-CLL induce leukemia-specific cytotoxic and proliferative T-cell responses on transfection with total RNA isolated from autologous leukemic B lymphocytes. Standard 51Cr-release assays showed specific major histocompatibility complex (MHC) class I-restricted cytotoxic activity against the autologous leukemic B cells and DCs transfected with CLL-RNA, whereas nonmalignant B cells were spared. The specificity of the cytotoxic T-lymphocyte (CTL) response was confirmed using cold target inhibition assays and by blocking HLA class I molecules. Furthermore, we established a protocol for the amplification of whole B-CLL mRNA. The use of DCs transfected with in vitro amplified B-CLL mRNA elicited specific T-cell responses similar to the results obtained with native mRNA. These data suggest that vaccinations using DCs transfected with RNA might be a potent new strategy in the treatment of CLL.
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PMID:Induction of chronic lymphocytic leukemia (CLL)-specific CD4- and CD8-mediated T-cell responses using RNA-transfected dendritic cells. 1461 77

Expression of HLA-G on the surface of malignant hematopoietic cells isolated from leukemia patients was analyzed by flow cytometry using monoclonal antibodies (mAbs) recognizing both, intact HLA-G complex (87G, 01G and MEM-G9) as well as HLA-G free heavy chain (4H84, MEM-G/1 and MEM-G/2). Prerequisite of HLA-G detection by mAbs specific to free heavy chain was mild acid treatment, which dissociates intact HLA-G complex. All mAbs, with the exception of 4H84 mAb, did not indicate the presence of HLA-G antigen in leukemia cells. Positive staining with 4H84 mAb was detected in acid-treated cells isolated from 16 out of 30 patients. Intensity of staining increased after IFN-g pre-incubation in most cases. Immunoblot analyses and RT-PCR, however, failed to detect HLA-G antigen or HLA-G transcripts in cells that bind 4H84 mAb after acid-treatment. The binding of 4H84 mAb can be explained by the acid-induced cross-reactivity of this HLA-G specific mAb with classical HLA class I molecules [15]. The results described here further demonstrate that the HLA-G molecule is not expressed in freshly isolated human leukemia cells.
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PMID:Binding analysis of HLA-G specific antibodies to hematopoietic cells isolated from leukemia patients. 1462 85

Dendritic cells (DCs) are potent antigen-presenting cells and play an important role in T-cell-mediated immunity. DCs have been shown to induce strong antitumour immune responses both in vitro and in vivo. One way of providing the DCs with all relevant tumour antigens would be to incubate the DCs with material from dead tumour cells. We have examined the uptake of apoptotic and necrotic K562 leukaemia cells by DCs under different culture conditions. Results from coincubation experiments strongly suggested that uptake of apoptotic K562 cells was dependent upon the addition of autologous serum (AS). Under these conditions, 47-79% of all DCs were shown to ingest apoptotic material. AS also seemed to be important for the expression of functionally important markers, most notably HLA class I, CD86, CCR7 and CD83. The vast majority of DCs were shown to ingest necrotic material from K562 cells, with no additional effect of AS. The results suggest that incubation of DCs with apoptotic material for cell therapeutic purposes may best be performed in the presence of AS.
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PMID:Uptake of Apoptotic K562 Leukaemia Cells by Immature Dendritic Cells is Greatly Facilitated by Serum. 1462 26

Relapse is a major problem after transplantation in children with acute B-lineage leukemias, and new therapies are needed to increase graft-versus-leukemia (GvL) effects without inducing graft-versus-host disease (GvHD). Here, we studied the ability of effector cells recovered from patients after transplantation with positive-selected stem cells from alternative donors to induce antibody-dependent cellular cytotoxicity (ADCC). For this purpose, a chimeric CD19 antibody, CD19-4G7chim, was generated. This antibody efficiently mediated ADCC against primary acute lymphoblastic leukemia (ALL) blasts by using purified natural killer (NK) cells from healthy donors or mononuclear cells from patients as effector cells. Increased lysis was obtained after stimulation of effector cells with interleukin-2 (IL-2). ADCC was not prevented by inhibitory effects mediated by HLA class I. We propose that treatment with chimeric CD19 antibodies leading to ADCC by donor-derived NK cells may become a therapeutic option for the post-transplantation treatment of minimal residual B-lineage ALLs.
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PMID:Chimeric CD19 antibody mediates cytotoxic activity against leukemic blasts with effector cells from pediatric patients who received T-cell-depleted allografts. 1476 38

Human leukocyte antigen (HLA) class I antigen defects may have a negative impact on the growing application of T-cell-based immunotherapeutic strategies for treatment of leukemia. Therefore in the present study, taking advantage of a large panel of HLA class I allele-specific human monoclonal antibodies, we have compared HLA class I antigen expression on leukemic cells with that on autologous and allogeneic normal cells. Down-regulation of HLA-A and/or -B allospecificities was present in the majority of the patients studied. However, down-regulation did not affect all HLA class I alleles uniformly, but was almost exclusively restricted to HLA-A allospecificities and to HLA-B allospecificities which belong to the HLA-Bw6 group. The latter allospecificities, at variance from those that belong to the HLA-Bw4 group, do not modulate the interactions of leukemic cells with natural killer (NK) cells. Therefore, our results suggest that the selective down-regulation of HLA-A and HLA-Bw6 allospecificities associated with HLA-Bw4 preservation provides leukemic cells with an escape mechanism not only from cytotoxic T lymphocytes (CTLs), but also from NK cells. As a result T-cell-based immunotherapeutic strategies for leukemia should utilize HLA-Bw4 alloantigens as restricting elements since a selective HLA-Bw4 allele loss would provide leukemic cells with an escape mechanism from CTLs, but would increase their susceptibility to NK cell-mediated lysis.
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PMID:Down-regulation of HLA-A and HLA-Bw6, but not HLA-Bw4, allospecificities in leukemic cells: an escape mechanism from CTL and NK attack? 1507 Jun 94


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