Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A study was conducted to clarify the mechanism of donor specific immunological unresponsiveness in renal transplant recipients with a well functioning kidney, since this might provide a clue to the nature of donor specific immunosuppression. Peripheral blood lymphocytes (PBL) were obtained from three renal transplant recipients, the donors (mother), the fathers and healthy volunteers as 3rd party and used in the present study. PBL from one of the three renal transplant recipients, which were donor specific unresponsive in MLR (Mixed Lymphocyte Reaction) and CML (Cell Mediated Lympholysis), suppressed the MLR, CML and synthesis of IL-2 from 3rd party PBL in a double chamber assay only when stimulated by the donor PBL. This suppression was abolished by the treatment with CD3 or CD8 antibodies and complement. RT-PCR was performed to investigate the suppressive effect of the recipient's PBL on IL-2 mRNA expression. In the double chamber MLR, expression of IL-2 mRNA by the PBL from 3rd party was also suppressed only when the recipient's PBL were stimulated by the donor PBL. These results indicate that one of the mechanisms responsible for donor specific immunological unresponsiveness is the presence of donor specific suppressor T cells in recipient's PBL and that these cells project suppressive effect on lymphocytes by producing a humoral suppressive factor(s) that suppress the expression of the IL-2 mRNA only when stimulated by donor PBL.
 ...
PMID:[The mechanism of donor specific unresponsiveness in renal transplant recipients]. 975 14

Three-color flow cytometry immunophenotyping revealed significant increases of CD57+ and CD28- cells among both circulating CD4+ and CD8+ T lymphocytes of untreated hemato-oncological patients (n = 54) as compared to healthy donors (n = 55), with CD57 and CD28 expression on the patients' T cells being largely reciprocal. Marked expansion of CD57+ cells among circulating CD4+ T lymphocytes was frequently detected in patients with chronic leukemia of B cell origin (B-CLL, hairy cell leukemia) but not in patients with chronic myeloid leukemia, suggesting a causal relation with the tumor's major histocompatibility complex class II expression. Using immunomagnetic separation techniques, we further demonstrate that the patients' CD57+/CD28- T cells display a typical Th1-type cytokine secretion profile upon anti-CD3 stimulation, with a markedly higher secretion of the Th1-type cytokines IL-2, IFN-gamma, and TNF-alpha than their CD57-/CD28+ counterparts. Cytotoxic activity of circulating CD8+ T lymphocytes, measured ex vivo in an anti-CD3-redirected assay, was almost exclusively exerted by the CD57+/CD28- subset. Moreover, a marked cytotoxic activity was detected within CD4+CD57+ T cells from some B-CLL patients. Finally, the patients' CD57+/CD28- T cells displayed an increased tendency to apoptosis in culture. Collectively, our results indicate that the expanded CD57+/CD28- T cells in hemato-oncological patients represent differentiated effector cells, similar to their (quantitatively minor) counterpart in healthy donors. The reason for their expansion and their pathophysiologic significance, however, remains unclear.
 ...
PMID:CD57+/CD28- T cells in untreated hemato-oncological patients are expanded and display a Th1-type cytokine secretion profile, ex vivo cytolytic activity and enhanced tendency to apoptosis. 976 2

Chronic myeloid leukemia (CML) is usually treated with either alpha-interferon or hydrea. Median survival is 6 years. Eventually, in most CML patients, the disease evolves to blast phase with clinical and morphologic characteristics of an acute leukemia. This phase is commonly associated with systemic symptoms and the appearance of new cytogenetic abnormalities. Therapy for this phase is of limited value, resulting in a mean survival of 4 months. We describe four consecutive patients seen at our clinic with advanced stage CML (three blast, one accelerated phase) who were treated with interleukin-2 (Proleukin). The mean survival in these patients was 22 months (range 9-35 months) and two are still alive 25 and 35 months after the start of therapy. One patient had a complete cytogenetic response and another a partial response. Toxicity was minimal and no patient had to discontinue therapy because of it.
 ...
PMID:Interleukin-2 therapy for advanced chronic myeloid leukemia. 982 41

To investigate the potential of autologous lymphocytes to eliminate chronic myelogenous leukemia (CML) cells following activation and targeting by CD3-monoclonal antibody, we cultured Ficoll-isolated peripheral blood cells from 11 patients with CML in the chronic phase in permutated combinations of interleukin (IL)-2, CD3-monoclonal antibody (OKT3), and interferon (IFN)gamma. The efficiency of CML cell elimination was studied by means of flow cytometry and reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. Cultures containing only OKT3 and IL-2, with or without IFNgamma, resulted in tumor cell reduction to the level of RT-PCR negativity. The length of the culture period required to reach a RT-PCR-negative state ranged from 3 to 33 days. A 1- to 2-log reduction in leukemic cells could be achieved by culture medium alone. In contrast, 3- to 4-log reductions in CML cells were observed following in vitro culture and ex vivo T cell activation with a given sensitivity for RT-PCR detection of 1 bcr/abl+ cell in 10(4). The feasibility of purging chronic myelogenous leukemia cells in a short time was associated with a low number of platelet counts (r=0.6457; p < 0.05). CML cell reduction was associated with expansion of CD25+/CD4+//CD8+/-/CD56+/- lymphocytes. These findings may be of relevance for immunotherapy procedures.
 ...
PMID:Activation of autologous lymphocytes of patients with chronic myelogenous leukemia in the chronic phase with cytokines and CD3 monoclonal antibody results in bcr/abl- blood leukocyte cultures as determined by reverse transcriptase-polymerase chain reaction. 984 83

The pathogenic mechanisms of immunosuppression leading to susceptibility of Mycobacterium tuberculosis (MT) infection in chronic myelocytic leukemia (CML) are not clear. To address this issue, we measured the proliferative response, variation of T cell subpopulations (CD4+, CD8+, TCR-V delta 2 and TCR-V beta 8 T cells) and the cytokine profile (IL-1 beta, IL-2, IL-4, IL-6, IL-10, TNF-alpha, IFN-gamma) after MT stimulation of peripheral blood mononuclear cells (PBMC) in a patient with concomitant CML and active pulmonary tuberculosis. The results were compared to four patients with active pulmonary tuberculosis and no other coexistent diseases. The immunologic response to phytohemagglutinin (PHA) was also evaluated. In contrast to controls, the CML PBMC failed to proliferate in response to MT antigens. Mycobacterium-reactive CD4+, V delta 2 and V beta 8 T cells did not expand after MT stimulation of the CML PBMC. In MT antigens-stimulated cultures from the CML patient, IL-2 was not produced and mild reduction of IL-1 beta and INF-gamma were observed. In contrast, IL-10 was markedly elevated in these cultures. Similarly, PHA-stimulated PBMC from the CML patient showed no expansion of CD4+ and CD8+. T cells. In these cell cultures, INF-gamma concentration in supernatants was decreased and IL-10 was significantly elevated. This study suggests that patients with CML may present a profound immunosuppression of essential cellular and molecular immune effectors, a scenario which might contribute to the development of active tuberculosis. These findings further support the need of establishing immunotherapeutic modalities with potential value for myeloproliferative disorders.
 ...
PMID:Abnormal immunological response to Mycobacterium tuberculosis antigens in a patient with chronic myelocytic leukemia and active tuberculosis. 1002 42

We designed a phase II study to assess the activity of recombinant interleukin-2 (rIL-2) in patients with chronic myelogenous leukemia (CML). Study population included 11 patients in the chronic phase of CML (6 in hematologic remission and 5 with active disease), 6 patients in the accelerated phase, and 4 in blastic phase of CML. Patients received three 5-day cycles administrated every other week. rIL-2 was given as intravenous bolus infusions of 8 x 10(6) IU/m2 three times a day during cycle 1 and twice a day during cycles 2 and 3. Response to rIL-2 was assessed on day 45. No hematologic response was achieved in the patients with evaluable disease. One patient in hematologic remission with rIL-2 achieved a major response (from 72% to 9% Ph+ metaphases), and two patients had some degree of reduction of Ph+ metaphases. Responses were short-lived (< 6 months), but two of these three patients achieved a new cytogenetic response with interferon given post-rIL-2. A significant immune activation was achieved with rIL-2 including a marked increase in CD3+/CD25+ cells, CD56+ cells, and in natural killer/lymphokine activated killer cell cytotoxic activity. These results confirm preclinical studies, which showed that IL-2 has antileukemic activity in CML. However, the responses observed were short lived and restricted to a subgroup of patients with low disease burden. This invites further studies testing its impact in situations of minimal disease or in combination with other cytokines.
 ...
PMID:Treatment of chronic myelogenous leukemia with interleukin-2: a phase II study in 21 patients. 1009 42

Three different types of anti-T cell antibody were used in patients undergoing haematopoietic stem cell transplantation (HSCT) with an HLA-A, -B and -DR compatible unrelated donor: ATG-Fresenius (ATG-F) (n = 26), Thymoglobuline (TMG) (n = 61) and OKT-3 (n = 45). The groups were comparable regarding diagnosis, stage, age, conditioning and GVHD prophylaxis, Adverse events were less frequent after ATG-F treatment. Levels of IL-2, IL-6, IFN-gamma, TNF-alpha and GM-CSF were increased after OKT-3 infusion. In multivariate analysis OKT-3 treatment (P = 0.01), G-CSF treatment (P = 0.02) and a cell dose >/=2.7 x 108/kg (P = 0.03) gave a faster engraftment. Acute GVHD grades II-IV occurred in 25% of the ATG-F patients, 12% of the TMG-patients and 43% (P < 0.001 vs TMG) of the OKT-3 patients. OKT-3 was associated with acute GVHD in multivariate analysis. TRM was 26% using TMG as compared to 43% in the OKT-3 group (P = 0.03). Patient survival at 4 years was 63%, 50% and 45% in the ATG-F, TMG and OKT-3-treated patients, respectively (NS). Relapses were 8%, 49% and 34%, respectively (ATG-F vs TMG, P = 0.03). Relapse-free survivals were 61%, 40% and 37% (NS). Among CML patients the probability of relapse was 61% in TMG-treated patients, while no patients relapsed in the other two groups. To conclude, the type of anti-T cell antibody affects GVHD and relapse after HSCT using unrelated donors.
 ...
PMID:Effect on cytokine release and graft-versus-host disease of different anti-T cell antibodies during conditioning for unrelated haematopoietic stem cell transplantation. 1051 91

A 3-year-old girl with BCR/ABL-positive CML relapsed after related HLA-identical cord blood transplantation. She was treated with three cycles of donor lymphocyte (DLI) infusion from her 15-month-old brother. Interferon alpha was added after the second DLI, whereas a trial of IL-2 had to be discontinued because of increasing immature myeloid cells in the blood smear. No signs of GVHD were observed, but she developed myelosuppression and needed one platelet and one red blood cell transfusion. She achieved a molecular remission after 6 months with transient molecular relapse followed by sustained remission for 15 months. Thus, DLI with or without interferon alpha might prove to be a promising treatment option with tolerable side-effects in relapsed CML after cord blood transplantation. Bone Marrow Transplantation (2000) 25, 219-222.
 ...
PMID:Successful treatment of relapsed CML after cord blood transplantation with donor leukocyte infusion IL-2 and IFNalpha. 1067 86

Peptide sequences spanning the BCR-ABL protein junction potentially constitute novel leukaemia-specific antigens. 9-mer b3a2 fusion peptides have been reported to bind with high affinity to HLA-A3, -A11 and -B8. We have studied the effect of b3a2 BCR-ABL junctional peptides on the cytotoxic T-cell (CTL) response against normal and chronic myeloid leukaemia (CML) cells. Antigen-presenting cells (APCs) were prepared from HLA-A3- or -B8-positive peripheral blood mononuclear cells (PBMCs) by incubation with phytohaemagglutinin (PHA) and interleukin (IL)-2 for 7 d. These APCs were pulsed with the respective b3a2 junctional peptide in the presence of beta2-microglobulin and were then used to challenge autologous PBMCs at 7-d intervals in the presence of IL-2, IL-6, IL-7 and IL-12. On subsequent exposure to target cells (either further pulsed normal APCs or unpulsed CML cells), specific HLA-restricted CTL responses were observed against all HLA-A3/-B8 matched normal target cells tested, but not to targets that were HLA mismatched. Cytotoxicity was also induced against HLA-A3/-B8 unpulsed CML cells, but not against unmatched CML cells. These data indicate (i) that endogenous BCR-ABL junctional peptides may be presented by CML cells and (ii) that exogenous peptides are potential stimulators of autologous antileukaemic CTLs.
 ...
PMID:b3a2 BCR-ABL fusion peptides as targets for cytotoxic T cells in chronic myeloid leukaemia. 1088 12

Evidence from allogeneic hematopoietic stem cell transplantation indicates a possible immune response against leukemia-associated antigens in patients with either acute myeloid leukemia (AML) or chronic myeloid leukemia (CML). However, autologous immune responses are less evident. We have developed a method using sequential modulation of growth factors (SMGF) to generate specific anti-AML T-cells from primary cultures of mononuclear cells (MNCs) from patients with AML. This culture method induces greater degrees of antigen presentation by inducing dendritic cell (DC) differentiation of AML in the presence of autologous lymphocytes, which are then expanded by interleukin (IL)-2 and costimulatory molecule ligation. MNCs consisting of 92.3% +/- 5.1% AML blasts and 3.4% +/- 3.2% CD3+ T-cells were obtained from AML patients (n = 12) and cultured in AIM-V medium with IL-4 and recombinant granulocyte-monocyte colony-stimulating factor. Recombinant IL-2 was added on day 8. On day 21, culture conditions were changed to anti-CD3/anti-CD28 monoclonal antibodies and IL-2. By day 42, 354 +/- 182-fold CD3+ T-cell expansion had occurred. Cytotoxic T-lymphocyte assays demonstrated that these T-cells caused significant lysis of autologous leukemia cells and AML cell lines, but not of cells of other lineages, in an HLA class I-dependent manner. Specific Vbeta subgroups (Vbeta3, -7, and -12a), possibly representing T-cell clones specific to AML-specific antigens, were expanded in the cultures of cells from 3 AML patients. SMGF can be used to induce and expand autologous T-cells with HLA class I-dependent antileukemia potential from the peripheral blood of AML patients. Adoptive transfer of these expanded T-cells to patients is a possible therapeutic approach for further study.
 ...
PMID:Sequential modulation of growth factors: a novel strategy for adoptive immunotherapy of acute myeloid leukemia. 1243 51


<< Previous 1 2 3 4 5 6 7 Next >>