Numbers and cytotoxicities of CD3+CD56+ T lymphocytes in peripheral blood of patients with acute myeloid leukemia and acute lymphocytic leukemia

Recent reports have highlighted the role of cellular immunity in anti-tumor defenses. T lymphocytes are known to play important part in anti-cancer immunity. The number and function of T lymphocytes are altered in chronic leukemia patients. CD3⁺CD56⁺ T lymphocytes have also been found to be abnormal in cancer patients. We therefore investigated changes in the number and cytotoxicity of CD3⁺CD56⁺ T lymphocytes in the peripheral blood of acute leukemia (AL) patients (excluding acute promyelocytic leukemia), to improve our understanding of the role of this T lymphocyte subset. We analyzed CD3⁺CD56⁺ T lymphocyte numbers and cytotoxicities in healthy controls, AL patients, and AL patients with complete remission. Lymphocyte counts were performed in peripheral blood and flow cytometry was used to determine cell numbers and cytotoxicities. The absolute number of CD3⁺CD56⁺ T lymphocytes was increased in AL patients (including acute myeloid [AML] and acute lymphocytic leukemia [ALL]) compared with healthy controls (P < 0.05), but their functioning was significantly reduced (P < 0.05). The number of CD3⁺CD56⁺ T lymphocytes in AML and ALL patients who achieved remission following chemotherapy was close to healthy controls (P > 0.05), but their functioning was still significantly reduced (P < 0.05). In addition, the number of CD3⁺CD56⁺ T lymphocytes increased significantly in AML patients with increased peripheral blood white blood cell (WBC) counts, and in ALL patients without increased WBCs. These results suggest that cellular immunity may respond to AML and ALL, but that lymphocyte cytotoxicity remains impaired. Dysfunction of CD3⁺CD56⁺ T lymphocytes in AML and ALL patients may contribute to the failure of the host immune response against leukemic blasts.     

Incidence of secondary acute myelogenous leukemia after treatment of childhood acute lymphoblastic leukemia.

BACKGROUND. Recent reports of secondary acute myelogenous leukemia (AML) occurring in children previously treated for acute lymphoblastic leukemia (ALL) prompted a review of patients with ALL treated at the Dana Farber Cancer Institute consortium (DFCI) between 1973 and 1987. Seven hundred fifty-two of 779 children treated for ALL entered complete remission. The mean follow-up time for the 752 patients was 4.4 years. Two children had AML develop 12 and 13 months after the diagnosis of ALL, respectively. METHODS. The estimated overall risk of secondary AML was calculated for the patient population as instances per 1000 patient-years of follow-up. This was compared with recent reported cases from another institution. RESULTS. The estimated overall risk of secondary AML was 0.61 instances per 1000 patient-years of follow-up (95% confidence interval: 0.15, 4.4). The difference between the risk of 0.61 among DFCI patients versus previously reported risk of 5.8 among a differently treated group of patients with ALL was statistically significant (P = 0.0008). No epipodophyllotoxin was used in the patients in the DFCI consortium. In contrast, an epipodophyllotoxin was used in 12 of 13 previously reported patients who had secondary AML develop. CONCLUSIONS. The authors concluded that the use of epipodophyllotoxins may be associated with an increased risk of having secondary AML develop in patients with ALL.     

CD4^＋CD25高表达调节性T细胞与儿童急性淋巴细胞白血病的关系

目的检测急性淋巴细胞白血病（ALL）患儿的CD4^＋CD25调节性T细胞（Treg），探讨其在儿童ALL发生、治疗过程中的意义。方法以40例ALL儿童不同治疗阶段的55份外周血为标本，细胞膜表面抗原采用双色或三色单克隆抗体直接标记法，检测细胞核抗原FoxP3时先标记膜表面抗原，固定破膜后再标记胞核抗原，应用多参数流式细胞仪进行检测。结果ALL患儿的CD4^＋CD25Treg同时表达CD62L和胞核抗原FoxP3。ALL标危组治疗不同阶段儿童的CD4^＋CD25高表达T细胞数值分别为：首次诱导缓解组（1．04±0．33）％，维持治疗组（1．60±0．44）％，持续完全缓解组（1．29±0．30）％；ALL中／高危维持治疗组则为（2．24±0．75）％。结论ALL患儿的CD4^＋CD25Treg数值高于健康儿童，并且与疾病的危险度和治疗的效应有一定的关系；CD4^＋CD25Treg水平升高可能是白血病复发的原因之一。     

The effect of cimetidine mainly increases CD4+ cells of peripheral blood T lymphocytes

Cimetidine, one of the most popular histamine-2 receptor antagonists, has been reported to improve survival in gastrointestinal cancer patients and to activate cell-mediated immune response in surgical patients. NKT cells are a population of T cells that share characteristics with natural killer cells, and their main functions are production of immunoregulatory cytokines and cytolytic activities. In this study, we aimed to investigate the effect of cimetidine on the cell-mediated immunoresponse. Six healthy adult volunteers were given 800 mg of cimetidine per day orally, and their blood samples were taken prior to and at days 1, 3, 5, and 7 days post-administration of cimetidine. Leukocyte counts and differentials were obtained by the conventional hemogram, and the leukocyte subsets were analyzed by flow cytometry. Cimetidine administration caused leukocytosis, dependent on the increase of neutrophils, as well as of the CD3-positive T lymphocytes, and the subset of CD4-positive cells among them. On the other hand, the NK cell subpopulation was decreased, and the NKT cell subpopulation was not affected. The present results suggest that cimetidine is a modulator of the cellular immunity, and may be used as the activator of the tumor specific immunoresponse.     

CXCR4 antagonists mobilize childhood acute lymphoblastic leukemia cells into the peripheral blood and inhibit engraftment.

The role of CXCL12 in the bone marrow (BM) homing and growth of B-cell progenitor acute lymphoblastic leukemia (ALL) has been established. However, the effect of modulating CXCL12/CXCR4 interactions on the retention of ALL cells within the supportive BM microenvironment and the expansion and dissemination of ALL cells in vivo has not been examined. We used mouse models of human childhood and murine leukemia and specific peptide and small molecule CXCR4 antagonists to examine the importance of CXCL12/CXCR4 in the development of leukemia in vivo. CXCR4 antagonists mobilized ALL cells into the peripheral blood (PB). Extended administration of CXCR4 antagonists to mice with leukemia resulted in a reduction in the number of leukemic cells in the PB and spleens of animals compared to control treated animals in three of the five cases tested. There was also a marked reduction in the dissemination of ALL cells to extramedullary sites including liver and kidney in all cases where this occurred. Considering the inhibitory effect of stromal layers on the activity of chemotherapeutic agents and the interactive effect of CXCL12 antagonists with chemotherapeutic agents in vitro, this raises the possibility of using these agents to potentiate the effects of current chemotherapy regimens.     

Decreased cytotoxic potential of fresh and recombinant interleukin 2-cultured large granular lymphocytes in childhood acute lymphoblastic leukemia

Cytotoxic potential (cytotoxic efficiency and binding affinity) of large granular lymphocytes (LGL) in childhood acute lymphoblastic leukemia (ALL) patients was calculated by Michaelis-Menten's kinetic equation. Cytotoxic efficiency (Vmax) of fresh or 3-day recombinant interleukin 2 (IL-2)-cultured LGL, not of similarly cultured T cells, in on-therapy ALL patients was decreased (31% in fresh LGL, P less than 0.05 and 28% in cultured LGL, P less than 0.01) as compared with that in controls, although the binding affinity (Km) of these cells were not decreased. The cytotoxic efficiency and the binding affinity of IL-2-cultured LGL in off-therapy ALL patients was not decreased. These data indicate that the cytotoxic potential of LGL was selectively decreased in on-therapy ALL patients due to the impairment in the post-binding cytotoxic process, not due to the decrease in the binding affinity.     

Recent advance in treatment of childhood acute lymphoblastic leukemia

The five-year event-free survival of nearly 80% in childhood acute lymphoblastic leukemia (ALL) achieved in the 1990 s attested to the effectiveness of risk-directed therapy developed through well-designed clinical trials by 4 groups in clinical study, containing CCLSG, TCCSG, KYCCSG and JACLS. Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) was organized in 2003 and includes all four clinical study groups in Japan. For the purpose of finding the standard treatment, JPLSG protocols have been started for three distinct and rare types of ALL, including mature B-ALL, infant ALL and Ph+ALL. The 2004 ALL protocol of Childhood Cancer and Leukemia Group in Japan (CCLSG) contained a new 2-step stratification based on initial age/WBC count and minimal residual disease at day 91. The JPLSG/ALL committee was started in 2005 for discussing the ongoing need for cooperative clinical study in Japan and the possibility of nelarabine-containing regimen for T-ALL.     

Significance of CD66c expression in childhood acute lymphoblastic leukemia

Upon analyzing 696 childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cases, we identified the characteristics of CD66c expression. In addition to the confirmation of strong correlation with BCR-ABL positivity and hyperdiploid, we further observed that CD66c is frequently expressed in CRLF2-positive (11/15, p < 0.01 against chimeric gene-negative) as well as hypodiploid cases (3/4), whereas it is never expressed in ETV6-RUNX1, MLL-AF4, MLL-AF9, MLL-ENL, and E2A-PBX1-positive cases. Although the expression of CD66c itself is not directly linked to the prognosis, the accompanying genetic abnormalities are important prognostic factors for BCP-ALL, indicating the importance of CD66c expression in the initial diagnosis of BCP-ALL.     

Pregnancy outcome after treatment for acute lymphoblastic leukemia during childhood or adolescence

To evaluate gonadal function and pregnancy outcome after treatment for acute lymphoblastic leukemia during childhood or adolescence, 44 former patients who were less than 20 years of age at diagnosis, 5 or more years from diagnosis, and 18 or more years of age were contacted. Thirty-nine (88%) provided information regarding pregnancy outcome. Gonadal function as estimated by the ability to conceive or sire a pregnancy, was not impaired despite treatment with substantial cumulative doses of methotrexate, 6-mercaptopurine, vincristine, and 1-asparaginase. Twelve patients reported a total of 27 pregnancies. There were four spontaneous abortions, one stillborn, and 22 liveborn infants. The birthweights were 1928 to 4536 g (median, 3430 g). Two infants had congenital anomalies. The childrens' ages ranged from 1 month to 10 years, 2 months (median, 6 years, 1 month). None has been diagnosed with any type of childhood cancer. The results of this study suggest that pregnancy outcome is not affected adversely by treatment received during childhood or adolescence for acute lymphoblastic leukemia.     

Bone marrow recurrence after initial intensive treatment for childhood acute lymphoblastic leukemia

BACKGROUND: The authors studied the clinical outcome of 106 children with acute lymphoblastic leukemia (ALL) who developed a bone marrow recurrence as the first adverse event after contemporary intensified therapy. METHODS: Endpoints were the rates and lengths of second remission, the cumulative incidence of second hematologic recurrence, second event-free survival (EFS), and survival. RESULTS: Bone marrow recurrences were isolated in 79 patients, and combined with an extramedullary site in 27 patients. The median time to recurrence was 2.6 years (range, 0.3-11.6 years). Seventy-six patients (71.7%) attained a second remission (median length, 0.7 year; range, 0.03-13.3 years). The 5-year survival probability among all patients was 24.2% +/- 4.2% (standard error). On multivariate analysis, time to first disease recurrence and blast cell lineage were found to be independent predictors of a second EFS (P = 0.008 and P = 0.028, respectively). The 5-year EFS estimate in patients with an initial disease remission of >/= 36 months was 42.6% +/- 7.8% but was only 12.5% +/- 3.9% among children with a short duration of disease remission (< 36 months). These estimates were 28.7% +/- 4.9% and 5.0% +/- 3.4%, respectively, for B blast and T blast cell lineages. CONCLUSIONS: Despite acceptable long-term second EFS rates for certain subgroups, overall bone marrow recurrence after intensified first-line therapy for childhood ALL signals a poor outcome.     

Infection-related complications during treatment for childhood acute lymphoblastic leukemia

BackgroundComprehensive studies on neutropenia and infection-related complications in patients with acute lymphoblastic leukemia (ALL) are lacking.Patients and methodsWe evaluated infection-related complications that were grade ≥3 on National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0) and their risk factors in 409 children with newly diagnosed ALL throughout the treatment period.ResultsOf the 2420 infection episodes, febrile neutropenia and clinically or microbiologically documented infection were seen in 1107 and 1313 episodes, respectively. Among documented infection episodes, upper respiratory tract was the most common site (n= 389), followed by ear (n= 151), bloodstream (n= 147), and gastrointestinal tract (n= 145) infections. These episodes were more common during intensified therapy phases such as remission induction and reinduction, but respiratory and ear infections, presumably viral in origin, also occurred during continuation phases. The 3-year cumulative incidence of infection-related death was low (1.0±0.9%, n= 4), including 2 from Bacillus cereus bacteremia. There was no fungal infection-related mortality. Age 1–9.9 years at diagnosis was associated with febrile neutropenia (P= 0.002) during induction and febrile neutropenia and documented infection (both P< 0.001) during later continuation. White race was associated with documented infection (P= 0.034) during induction. Compared with low-risk patients, standard- and high-risk patients received more intensive therapy during early continuation and had higher incidences of febrile neutropenia (P< 0.001) and documented infections (P= 0.043). Furthermore, poor neutrophil surge after dexamethasone pulses during continuation, which can reflect the poor bone marrow reserve, was associated with infections (P< 0.001).ConclusionsThe incidence of infection-related death was low. However, young age, white race, intensive chemotherapy, and lack of neutrophil surge after dexamethasone treatment were associated with infection-related complications. Close monitoring for prompt administration of antibiotics and modification of chemotherapy should be considered in these patients.     

Association of peripheral CD4+ CXCR5+ T cells with chronic lymphocytic leukemia

Accumulating evidences indicate that immune dysregulation plays a key role in both lymphomagenesis and patient outcome of chronic lymphocytic leukemia (CLL). Peripheral blood CD4+ CXCR5+ T cells, known as circulating follicular helper T cells (Tfh), can induce B cell activation and production of specific antibody responses. The aim of the study was to investigate changes of circulating Tfh in CLL. Tfh and it subtypes were tested by measuring CD4, CXCR5, CXCR3, and CCR6 in 72 CLL cases and 86 healthy controls using flow cytometry. Data showed that the percentage of Tfh in the peripheral CD4+ T cells was significantly increased in CLL (25.1 %) than in controls (8.4 %) (p?<?0.001). Further analysis revealed that the upregulation of Tfh was contributed by Tfh-th2 subtype and Tfh-th17 subtype. Investigating staging of the cases demonstrated that the prevalence of Tfh was significantly elevated in cases with Binet stage C (37.3 %) than those with stage A (20.1 %) or stage B (23.9 %). In addition, we analyzed Tfh in patients with immunoglobulin variable heavy chain (IGHV) gene mutational status. Results presented that Tfh-th17 subtype had clearly higher frequency in patients with IGHV mutation compared to the unmutated cases (p?=?0.035). This study suggested the involvement of Tfh in the pathogenesis and progression of CLL, and provided a potential target for treating this disease.     

Recovery of blood B-lymphocytes and serum immunoglobulins after chemotherapy for childhood acute lymphoblastic leukemia.

Recovery of humoral immunity after cessation of chemotherapy for childhood acute lymphoblastic leukemia (ALL) was investigated by determining blood leukocyte, lymphocyte and B-lymphocyte, and serum immunoglobulin (Ig) levels and IgG subclasses at 0, 1, 3, 6, 9, and 12 months after cessation of chemotherapy for ALL in 14 patients. Blood B-lymphocytes were analyzed with the use of flow cytometry and monoclonal CD20 antibody. At cessation of chemotherapy, the amount of blood B-lymphocytes was subnormal in most patients but increased to normal levels in 1 month after therapy was discontinued. The recovery of serum Ig, which reflect B-cell function, was slower, but occurred by 6 months after therapy was discontinued in most patients. The authors conclude that by 6 months after cessation of chemotherapy for ALL, a sufficiently functioning immune system by these parameters is established and that prophylactic antibiotics can be withdrawn and immunizations started.     

Prophylaxis and treatment of neoplastic meningeosis in childhood acute lymphoblastic leukemia

The introduction of cranial radiotherapy (CRT) has provided efficient control of overt or subclinical meningeosis in acute leukemia. Especially due to the long-term toxicity of CRT, reduction or elimination of radiotherapy appeared mandatory after cure rates of more than 70% had been achieved in acute lymphoblastic leukemia (ALL). Several large clinical trials of the Berlin-Frankfurt-Münster (BFM) Study Group with more than 3500 patients since 1981 have demonstrated that intensive systemic and intrathecal chemotherapy without or with limited CRT can efficiently prevent central nervous system (CNS) relapses in a large percentage of patients. However, only in low-risk patients prophylactic radiotherapy can be completely and safely replaced by conventional doses of methotrexate. In addition, reduction of chemotherapy in low-risk ALL increased the rate of relapses with CNS involvement. Thus, only a combination of multidrug induction, high-dose methotrexate (HD-MTX) consolidation, and reintensification allowed safe elimination of CRT in low-risk ALL. This approach combined with CRT with 12Gy and 18 Gy in medium and high risk ALL, respectively, reduced the incidence of relapses with CNS involvement to less than 5% (trial ALL-BFM 86). Patients with inadequate response to therapy, or with T-cell ALL, or with overt CNS disease are at particularly high risk for relapse with CNS involvement, and require more systemic and intrathecal chemotherapy combined with cranial irradiation. In B-cell ALL, short intensive chemotherapy pulses including HD-MTX could completely replace radiotherapy. In AML, post-consolidation CRT appears to be advantageous with regard to control of extramedullary as well as systemic relapses.     

Glucocorticoid receptor in childhood acute lymphoblastic leukemia

Glucocorticoid(GC)hasbeenusedinthetreatmentofchildhoodacutelymphoblasticleukenda(ALL)formanyyears.IthasprovedthattheeffectofGCismediatedthroughaglucocortic0idreceptor(GCR)ofthetargetcell.[1]Therefore,manyexpertshaveconcentratdtheirattentiononGCR,butthereisnoreportonthestudyofGCRinchildho0dALLinChina.InununologicalclassificationofALLmaydifferentiatethecelloriginandclustersofdifferentiation(CD)inleukendacell.Itisoneoftheimportantindicatorstoguidecombinationchemotherapyandt0makeapr0gnos…     

Immunologic markers in childhood acute lymphoblastic leukemia

This article details the immunologic diversity of acute lymphoblastic leukemia in children. A historical review of developments in immunophenotyping is followed by a discussion of how major subgroups of leukemia are best defined today. The relationship of immunologic subtypes to stages of normal lymphoid development is explored, and the clinical impact of immunophenotyping is discussed.     

CD4+T细胞与肿瘤免疫

在肿瘤免疫中细胞免疫发挥着重要作用,其中T细胞介导的特异性免疫应答反应更为重要.近年来CD4+T细胞在抗肿瘤免疫中的作用越来越受到重视.在肿瘤免疫中CD4+T细胞启动后可以通过多种机制启动细胞毒性T淋巴细胞(CTL),维持和加强CTL的抗肿瘤反应,并且可以作为效应细胞发挥抗肿瘤作用,CD4+T细胞中的一个亚群细胞CD4+ CD25+T调节细胞对肿瘤免疫有抑制作用.     

CD4+T细胞与肿瘤免疫

在肿瘤免疫中细胞免疫发挥着重要作用,其中T细胞介导的特异性免疫应答反应更为重要.近年来CD4+T细胞在抗肿瘤免疫中的作用越来越受到重视.在肿瘤免疫中CD4+T细胞启动后可以通过多种机制启动细胞毒性T淋巴细胞(CTL),维持和加强CTL的抗肿瘤反应,并且可以作为效应细胞发挥抗肿瘤作用,CD4+T细胞中的一个亚群细胞CD4+ CD25+T调节细胞对肿瘤免疫有抑制作用.