CTLA4-Ig prevents alloantibody production and BMT rejection in response to platelet transfusions in mice.
CTLA4-Ig prevents alloantibody production and BMT rejection in response to platelet transfusions in mice.
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DOI：
10.1111/j.1537-2995.2011.03550.x
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发表时间：
2012-10
期刊：
影响因子：
2.9
通讯作者：
Zimring JC
中科院分区：
文献类型：
--
作者：
Gilson CR;Patel SR;Zimring JC
血小板输注可诱导体液和细胞同种免疫。抗hla抗体可使患者对随后的输血产生耐药性，同种异体抗体和细胞同种免疫均可导致随后的骨髓移植排斥反应。目前，除了白细胞诱导外，还没有批准的治疗干预措施来防止对血小板输注的同种免疫。靶向阻断T细胞共刺激在移植环境中抑制同种异体免疫方面显示出很大的希望，但尚未在血小板输注的背景下进行探索。我们验证了一个假设，即共刺激阻断试剂CTLA4-Ig可以阻止输注血小板对主要和次要异体抗原的同种异体反应。BALB/c （H-2d）小鼠和C57BL/6 （H-2b）小鼠分别作为血小板供体和输血受体。以BALB/c血小板和脾细胞为靶点，采用间接免疫荧光法检测同种异体抗体。采用BALB/b （H-2b）供体和C57BL/6 （H-2b）受体，在低强度条件下进行骨髓移植，模拟HLA相同的移植。实验组在输注血小板前或输注血小板后给予CTLA4-Ig，对照组给予同型匹配抗体。CTLA4-Ig消除了体液异体免疫（抗h -2d抗体）和输血诱导的骨髓移植排斥反应。虽然在输注时单剂量的CTLA4-Ig可以阻止对后续血小板输注的同种异体免疫，但在初始血小板输注后给予CTLA4-Ig无效。将治疗推迟到输血小板后才进行，未能预防骨髓移植排斥反应。这些发现证明了一种使用FDA批准的药物的新策略，该药物有可能预防血小板输注同种免疫的临床后遗症。
Platelet transfusions can induce humoral and cellular alloimmunity. Anti-HLA antibodies can render patients refractory to subsequent transfusion, and both alloantibodies and cellular alloimmunity can contribute to subsequent bone marrow transplant rejection. Currently, there are no approved therapeutic interventions to prevent alloimmunization to platelet transfusions other than leukoreduction. Targeted blockade of T cell costimulation has shown great promise in inhibiting alloimmunity in the setting of transplantation, but has not been explored in the context of platelet transfusion. We tested the hypothesis that the costimulatory blockade reagent CTLA4-Ig would prevent alloreactivity against major and minor alloantigens on transfused platelets. BALB/c (H-2d) mice and C57BL/6 (H-2b) mice were used as platelet donors and transfusion recipients, respectively. Alloantibodies were measured by indirect immunofluorescence using BALB/c platelets and splenocytes as targets. Bone marrow transplants were carried out under reduced intensity conditioning using BALB/b (H-2b) donors and C57BL/6 (H-2b) recipients to model HLA identical transplants. Experimental groups were given CTLA4-Ig (before or after platelet transfusion) with control groups receiving isotype matched antibody. CTLA4-Ig abrogated both humoral alloimmunization (anti-H-2d antibodies) and transfusion induced bone marrow transplant rejection. Whereas a single dose of CTLA4-Ig at time of transfusion prevented alloimmunization to subsequent platelet transfusions, administration of CTLA4-Ig after initial platelet transfusion was ineffective. Delaying treatment until after platelet transfusion failed to prevent bone marrow transplant rejection. These findings demonstrate a novel strategy using an FDA approved drug that has the potential to prevent the clinical sequela of alloimmunization to platelet transfusions.
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影响因子：
15.9
作者：
Patel, Seema R.;Cadwell, Chantel M.;Zimring, James C.
通讯作者：
Zimring, James C.
影响因子：
8.7
作者：
Rudd CE;Taylor A;Schneider H
通讯作者：
Schneider H
影响因子：
20.3
作者：
SEMPLE, JW;SPECK, ER;FREEDMAN, J
通讯作者：
FREEDMAN, J
影响因子：
20.3
作者：
Bang, A;Speck, ER;Semple, JW
通讯作者：
Semple, JW
影响因子：
20.3
作者：
Semple, JW;Milev, Y;Freedman, J
通讯作者：
Freedman, J