Over-Expression of CD200 In Acute Myeloid Leukemia Mediates the Expansion of Regulatory T-Lymphocytes and Directly Inhibits Natural Killer Cell Tumor Immunity

生物 髓样 髓系白血病 免疫学 FOXP3型 白细胞介素2受体 癌症研究 免疫系统 白血病 T细胞
作者
Steven Coles,Stephen Man,Robert Kerrin Hills,Edward Chung Yern Wang,Alan Kenneth Burnett,Richard Lawrence Darley,Alex Tonks
出处
期刊:Blood [Elsevier BV]
卷期号:116 (21): 491-491 被引量:3
标识
DOI:10.1182/blood.v116.21.491.491
摘要

Abstract Abstract 491 CD200 is a type-1 transmembrane glycoprotein which suppresses inflammatory and autoimmune responses by signalling through its cognate transmembrane receptor homologue (CD200R). Normally, CD200 expression is restricted to immune privileged sites where it enhances immune tolerance through mechanisms that include modulating the expansion of FOXP3+ regulatory T-lymphocytes (T-regs) and suppressing macrophage cytolytic activity. Furthermore, leukocyte associated CD200 has been reported to suppress Natural Killer (NK) cell activity in vivo. Pathologically, we have previously shown that CD200 over-expression on leukemic blasts in around 50% of acute myeloid leukemia (AML) patients is significantly associated with a poor overall survival (Tonks et al, Leukemia, 2007). Given the existing evidence that T-reg frequency and NK cell function influence blast clearance and long-term survival in AML, we investigated the possibility that CD200 expression in AML may be directly suppressing anti-tumor immunity in this disease. Here we present evidence that CD200+ AML can suppress host anti-tumor responses by augmenting the frequency of AML patient T-regs and by direct inhibition of NK cell anti-tumor activity. We also show that targeting the interaction between CD200 and its receptor might provide a new strategy for the treatment of AML. Bone marrow aspirates from 91 diagnostic AML patients were analysed by multiparameter flow cytometry for blast CD200 protein expression. We found that the level of blast CD200 expression directly correlated with an increased frequency of T-regs (CD4+CD25++FoxP3+; R=0.78, p=0.0008). Measuring 3H-thymidine incorporation, we show that T-regs isolated from AML patients by MACS® separation inhibited T-cell proliferation (induced by CD3 and CD28 stimulation) at ratios <0.1%, thus confirming that patients T-regs were functional. In contrast to T-regs, NK cell frequency (CD45+CD19−CD3−CD56+) did not correlate with the level of AML blast CD200 expression (R=0.15, p=0.851), however, NK cell subpopulation bivariate analysis using CD56 and CD16 demonstrated that the CD56dimCD16+ (the principle active NK population) was significantly reduced by over 50% in CD200+ AML patients (36±5% compared to 15±5%, p=0.009). Furthermore, CD200 expression on target cells appeared to have a direct effect on the cytotoxic activity of NK cells; co-culture of NK cells with CD200+ targets resulted in decreased CD107a expression (a marker for cytolytic granules) in NK cells (23±4% vs 12±5%, p=0.038) and decreased apoptosis of the target cells (19±1% vs 10±1%, p=0.041). Since CD200R was detected on NK cells in AML patients, it was likely that CD200 was having a direct effect on suppression of NK cytotoxicity. This was supported by the significant recovery of NK cytolytic activity against CD200+ blasts in the presence of a CD200 blocking antibody (5±1% vs 11±2% CD107a+ NK cells, p=0.046) whereas there was no change seen with CD200− blasts (19±4% vs 19±3%). In conclusion, these findings suggest that CD200 expression on leukemic blasts plays an influential role in suppressing anti-tumor immunity in AML patients through modulating the expansion of functionally suppressive T-regs and directly suppressing NK cell cytolytic activity. In this study blocking CD200 interaction with its receptor was able to recover a significant proportion of patient NK activity, making CD200 a potential therapeutic target for CD200+ AML. Disclosures: No relevant conflicts of interest to declare.

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
1秒前
2秒前
4秒前
5秒前
小马过河应助尼尼采纳,获得10
7秒前
7秒前
7秒前
吾将上下而求索完成签到,获得积分10
7秒前
7秒前
7秒前
科研通AI2S应助LIN采纳,获得10
8秒前
8秒前
8秒前
喜悦的半青完成签到,获得积分10
8秒前
9秒前
好宝宝发布了新的文献求助10
10秒前
上官若男应助程艳采纳,获得80
10秒前
伊可创发布了新的文献求助10
11秒前
Ava应助szh123采纳,获得10
12秒前
锦七发布了新的文献求助10
12秒前
小二郎应助收手吧大哥采纳,获得10
14秒前
15秒前
在水一方应助lm采纳,获得10
15秒前
可爱的函函应助jingjingA采纳,获得10
15秒前
Zdh同学完成签到,获得积分10
16秒前
我是老大应助淡然的铭采纳,获得10
17秒前
girl完成签到,获得积分10
18秒前
19秒前
华仔应助HAHAHA采纳,获得10
19秒前
19秒前
小坤同学发布了新的文献求助10
20秒前
21秒前
musejie应助科研通管家采纳,获得10
21秒前
科研通AI2S应助科研通管家采纳,获得10
21秒前
quhayley应助科研通管家采纳,获得10
21秒前
情怀应助科研通管家采纳,获得10
21秒前
Jasper应助科研通管家采纳,获得10
21秒前
21秒前
21秒前
英俊的铭应助科研通管家采纳,获得10
22秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
‘Unruly’ Children: Historical Fieldnotes and Learning Morality in a Taiwan Village (New Departures in Anthropology) 400
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3988732
求助须知:如何正确求助?哪些是违规求助? 3531027
关于积分的说明 11252281
捐赠科研通 3269732
什么是DOI,文献DOI怎么找? 1804764
邀请新用户注册赠送积分活动 881869
科研通“疑难数据库(出版商)”最低求助积分说明 809021