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)

Cytotoxic T lymphocytes (CTLs) specific for hematopoietic-restricted minor histocompatibility antigens (mHags) are important reagents for adoptive immunotherapy of relapsed leukemia after allogeneic stem cell transplantation. However, expansion of these CTLs to therapeutic numbers is often hampered by the limited supply of antigen-presenting cells (APCs). Therefore, we evaluated whether cell-sized latex beads coated with HLA/mHag complexes HLA-A2/HA-1 or HLA-A2/HA-2 and recombinant CD80 and CD54 molecules can replace professional APCs. The artificial antigen-presenting constructs (aAPCs) effectively stimulated HA-1- and HA-2-specific CTL clones as shown by ligand-specific expansion, cytokine production, and maintenance of cytotoxic activity, without alteration of CTL phenotype. Furthermore, HA-1-specific polyclonal CTL lines were enriched as efficiently by aAPCs as by autologous HA-1 peptide-pulsed dendritic cells. Thus, aAPCs coated with HLA/mHag complexes, CD80, and CD54 may serve as tools for in vitro enrichment of immunotherapeutic mHag-specific CTL lines.
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PMID:Artificial antigen-presenting constructs efficiently stimulate minor histocompatibility antigen-specific cytotoxic T lymphocytes. 1503 Dec 3

The immune system of females is capable of recognizing and reacting against the male-specific minor histocompatibility antigen (mHA), HY. Thus, cytotoxic T-lymphocytes (CTLs) recognizing this antigen may be useful in eradicating leukemic cells of a male patient if they can be generated in vivo or in vitro from a human leukocyte antigen (HLA)-identical female donor. The HLA-A*0201-restricted HY antigen, FIDSYICQV, is a male-specific mHA. Using HLA-A2/HY peptide tetrameric complexes, we reveal a close association between the emergence of HY peptide-specific CD8(+) T cells in peripheral blood and molecular remission of relapsed BCR/ABL(+) chronic myelogenous leukemia in lymphoid blast crisis in a patient who underwent female-to-male transplantation. Assessment of intracellular cytokine levels identified T cells that produce interferon-gamma in response to the HY peptide during the presence of HY tetramer-positive T cells. These results indicate that transplant with allogeneic HY-specific CTLs has therapeutic potential for relapsed leukemia, and that expansion of such T cells may be involved in the development of a graft-versus-leukemia response against lymphoblastic leukemia cells.
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PMID:Expansion and activation of minor histocompatibility antigen HY-specific T cells associated with graft-versus-leukemia response. 1532 66

Mismatches of minor histocompatibility antigens (mHas) between HLA-identical stem cell donors and recipients are known as a major risk factor for graft-versus-host disease (GVHD). We determined the alleles of 5 polymorphic molecules including HA-1 and 4 adhesion molecules in 102 patients who had undergone stem cell transplantation from HLA-identical donors and investigated the association of their mismatches with the relapse rate and incidence of GVHD. We observed relapse rates of 16.1% in patients with at least one or more incompatibilities and 39.4% in patients without incompatibilities (p = 0.018). The respective relapse rates of patients with CD62L, HA-1, CD31 exon 563, CD31 exon 125 and 49b incompatibilities were 6.1%, 14.3%, 11.7%, 20% and 40%. Only patients with CD62L incompatibilities showed a lower relapse rate than patients who received a compatible graft. Since there was no difference between patients with and without incompatibilities as far as the appearance of acute GVHD (> or = 2) was concerned, we conclude that the polymorphic CD62L molecule contributes to graft-versus-leukemia rather than the development of GVHD after HLA-identical stem cell transplantation.
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PMID:[Role of polymorphic adhesion molecules in the development of graft-versus-leukemia effect after HLA-matched allogeneic stem cell transplantation]. 1535 10

Umbilical cord blood transplantation is applied as treatment for mainly pediatric patients with hematologic malignancies. The clinical results show a relatively low incidence of graft-versus-host disease and leukemia relapse. Since maternal cells traffic into the fetus during pregnancy, we questioned whether cord blood has the potential to generate cytotoxic T cells specific for the hematopoietic minor histocompatibility (H) antigen HA-1 that would support the graft-versus-leukemia effect. Here, we demonstrate the feasibility of ex vivo generation of minor H antigen HA-1-specific T cells from cord blood cells. Moreover, we observed pre-existing HA-1-specific T cells in cord blood samples. Both the circulating and the ex vivo-generated HA-1-specific T cells show specific and hematopoietic restricted lysis of human leukocyte antigen-A2(pos)/HA-1(pos) (HLA-A2(pos)/HA-1(pos)) target cells, including leukemic cells. The cord blood-derived HA-1-specific cytotoxic T cells are from child origin. Thus, the so-called naive cord blood can comprise cytotoxic T cells directed at the maternal minor H antigen HA-1. The apparent immunization status of cord blood may well contribute to the in vivo graft-versus-leukemia activity after transplantation. Moreover, since the fetus cannot be primed against Y chromosome-encoded minor H antigens, cord blood is an attractive stem cell source for male patients.
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PMID:Cord blood comprises antigen-experienced T cells specific for maternal minor histocompatibility antigen HA-1. 1549 56

Induction of cytotoxic T lymphocytes (CTLs) for treatment of relapsed leukemia after allogeneic stem-cell transplantation is hindered by the laborious and time-consuming procedure of generating dendritic cells for antigen presentation. Artificial antigen-presenting cells (aAPCs) offer the advantage of being readily available in sufficient numbers, thus allowing for a highly standardized in vitro induction of CTLs. We generated aAPCs coated with anti-CD28 antibody (Ab) and either high-density (HD) or low-density (LD) major histocompatibility complex (MHC) class I molecules loaded with HA-1(H), a nonapeptide derived from the hematopoiesis-restricted minor histocompatibility antigen HA-1. HD- and LD-aAPCs potently induced HA-1(H)-specific CD8+ CTLs from untouched CD8+ T cells of healthy donors. CTLs were subsequently purified by magnetic-activated cell sorting. HD- as well as LD-aAPC-induced CTLs exerted high HA-1H-specific cytotoxicity, resembled T(c)1 effector memory cells, survived a long time in vitro, and were expanded by a factor varying between 8.2 x 10(4) and 51 x 10(4). The T-cell receptor (TCR) repertoire of HA-1H tetramer-positive CTLs was oligoclonal with a prominent usage of Vbeta6. The TCR repertoire of tetramer-positive CTLs was distinct from and more restricted than that of tetramer-negative cells. These findings indicate that aAPCs are attractive tools for the ex vivo generation of HA-1H-specific CTLs suitable for immunotherapy of relapsed leukemia.
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PMID:Cytotoxic minor histocompatibility antigen HA-1-specific CD8+ effector memory T cells: artificial APCs pave the way for clinical application by potent primary in vitro induction. 1573 Nov 81

Minor histocompatibility antigens are allogeneic targets of T-cell mediated graft-versus-tumour effects following allogeneic stem cell transplantation. Recent research has identified several minor histocompatibility antigens as tumour proteins and has also disclosed their unique properties in both the induction and the effector phase of graft-versus-tumour effects. Targeting tumour-specific minor histocompatibility antigens by adoptive immunotherapy will battle against tumour tolerance and evoke allo-immune responses, thereby enhancing graft-versus-tumour effects against leukaemia and solid tumours. Recently acquired knowledge of the role of donor immunisation status, new techniques in the generation of minor histocompatibility antigen-specific cytotoxic T lymphocytes in vitro, and innovative principles in vaccination will help to design clinical trials that exploit minor histocompatibility antigens in the immunotherapy of cancer.
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PMID:Immunotherapy of cancer through targeting of minor histocompatibility antigens. 1576 82

Minor histocompatibility antigens (mHags) can induce T-cell reactivities with important consequences for the graft-versus-leukemia effect and the development of graft-versus-host disease in HLA-matched stem cell transplantation settings. Recently, mHag-specific T cells were also demonstrated in multiparous woman and in solid organ transplant recipients. Microchimeric cells have been detected in the latter settings. To study whether microchimerism is instrumental in the induction and/or maintenance of mHag T cells, we developed an HA-1 allele-specific nested polymerase chain reaction. To optimize and validate the reliability of this method at different levels of microchimerism, serial dilutions of HA-1(H) cells titrated into HA-1(R) cells were tested. We demonstrated that the HA-1(H) allele can be reliably and consistently detected at concentrations as low as 1:10(5) without losing specificity. The developed HA-1-specific nested polymerase chain reaction is an important tool that facilitates the detection of HA-1 microchimerism in various clinical specimens and that promotes investigation of the effects of microchimerism on induction of mHag-specific T cells in the various settings of immunization.
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PMID:Detection of microchimerism by minor histocompatibility antigen HA-1 allele-specific nested polymerase chain reaction. 1584 87

Acute lymphoblastic leukaemia (ALL) responds well to chemotherapy and the majority of children and a significant proportion of adults are cured of their disease after primary therapy. However, a number of patients relapse and allogeneic transplantation following conditioning with chemotherapy and radiotherapy offers the possibility of long-term survival in a proportion of these patients. A significant number of patients with ALL develop disease that is refractory to further therapy. The infusion of unmodified donor lymphocytes (DLI) following relapse after allogeneic transplantation has been shown to be curative in patients with chronic myeloid leukaemia (CML). However, in ALL the success rate is much lower. The results of in vitro and limited in vivo studies suggest that it may be possible to manipulate lymphocytes from the transplant donor to produce cytotoxic T-lymphocytes (CTL) with increased effectiveness in killing patients' ALL cells. This may be done in a number of ways. For example, some strategies utilise the patients dendritic cells (DC) to present tumour antigens to donor lymphocytes and convert them into CTL either by pulsing DC taken in remission with ALL cells or lysate, fusing such 'normal' DC with ALL cells or using DC cultured from the patient's ALL cells. Other approaches include exploiting the expression of leukaemia-specific antigens such as the proteinase PR-3 or the zinc finger transcription factor Wilms tumour-1 protein (WT-1) to stimulate CTL responses. Alternatively, immunotherapeutic strategies might exploit differences in minor histocompatibility antigens such as HA-1 and HA-2 between donor and recipient. These are expressed solely on haemopoietic cells making them suitable targets for donor derived anti-leukaemic cells. In vivo studies to date suggest that educated T-cells may have a role to play in the treatment of relapsed and refractory ALL in the future.
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PMID:Immunotherapeutic strategies in acute lymphoblastic leukaemia relapsing after stem cell transplantation. 1627 19

Identification of a broad array of leukaemia-associated antigens is a crucial step towards immunotherapy of haematological malignancies. However, it is frequently hampered by the decrease of proliferative potential and functional activity of T cell clones used for screening procedures. Transfer of the genes encoding the T cell receptor (TCR) alpha and beta chains of leukaemia-specific clones into primary T cells may help to circumvent this obstacle. In this study, transfer of two minor histocompatibility antigen (minor H antigen)-specific TCRs was performed and the feasibility of the use of TCR-transgenic T cells for identification of minor H antigens through cDNA library screening was investigated. We found that TCR-transgenic cells acquired the specificity of the original clones and matched their sensitivity. Moreover, the higher scale of cytokine-production by TCR-transgenic T cells permits the detection of either small amounts of antigen-positive cells or cells expressing low amounts of an antigen. When applied in equal numbers, TCR-transgenic T cells and the original T cell clones produced similar results in the screening of a cDNA library. However, the use of increased numbers of TCR-transgenic T cells allowed detection of minute amounts of antigen, barely discernible by the T cell clone. In conclusion, TCR-transfer generates a large amount of functional antigen-specific cells suitable for screening of cDNA expression libraries for identification of cognate antigens.
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PMID:T cell receptor-transgenic primary T cells as a tool for discovery of leukaemia-associated antigens. 1636 37

Cytotoxic T lymphocyte (CTL) lines specific for allogeneic antigens were generated by in vitro stimulation of donor-derived peripheral blood mononuclear cells obtained from patients who received human leucocyte antigen (HLA)-matched allogeneic haematopoietic stem cell transplantation (HSCT). One of the allogeneic antigen-specific CD4+ CTL lines, CTL-A, generated from a patient with T cell acute lymphoblastic leukaemia, recognised HLA-DPB1*0501-positive Epstein-Barr virus-immortalised human B cell line (EBV-B cells), phytohaemagglutinin blasts and leukaemia cells, but not interferon-gamma (IFN-gamma) treated HLA-DPB1*0501-positive fibroblasts, indicating that this CD4+ T-cell line recognised a minor histocompatibility antigen (mHa) that is preferentially expressed in haematopoietic cells in an HLA-DPB1*0501-restricted manner. The other CD4+ CTL line, CTL-B, generated from a patient with chronic myeloid leukaemia, recognised mismatched HLA-DQB1*0303 on EBV-B cells and phytohaemagglutinin (PHA) blasts. Interestingly, this CTL line did not recognise IFN-gamma-treated recipient's skin fibroblasts, as HLA-DQ was merely upregulated even after IFN-gamma stimulation in non-haematopoietic cells including fibroblasts, endothelial cells and hepatocytes. These results suggest that these CD4 positive CTLs, specific for mismatch HLA-DQ and mHa that are preferentially expressed on haematopoietic cells, may play an important role in induction of selective graft-versus-leukaemia effect without development of graft-versus-host disease after allogeneic HSCT.
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PMID:Possible involvement of allogeneic antigens recognised by donor-derived CD4 cytotoxic T cells in selective GVL effects after stem cell transplantation of patients with haematological malignancy. 1637 Oct 20


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