Targeting of B and T lymphocyte associated (BTLA) prevents graft-versus-host disease without global immunosuppression.
Targeting of B and T lymphocyte associated (BTLA) prevents graft-versus-host disease without global immunosuppression.
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DOI：
10.1084/jem.20102017
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发表时间：
2010-11-22
期刊：
影响因子：
--
通讯作者：
Murphy KM
中科院分区：
文献类型：
--
作者：
Albring JC;Sandau MM;Rapaport AS;Edelson BT;Satpathy A;Mashayekhi M;Lathrop SK;Hsieh CS;Stelljes M;Colonna M;Murphy TL;Murphy KM
一次性使用BTLA抗体治疗移植物抗宿主病可提供长期保护，而不会影响效应器T细胞对肿瘤或病原体的反应。移植物抗宿主病(GVHD)在异基因造血干细胞移植(AHSCT)中引起显著的发病率和死亡率，阻碍了其在非危及生命的疾病中的广泛应用。我们发现，单次注射针对共抑制免疫球蛋白受体、B和T淋巴细胞相关(BTLA)的非耗竭单抗，在进行HSCT时给予GVHD是永久性的。一旦GVHD建立，抗BTLA治疗不能逆转疾病，这表明其机制发生在移植后早期。抗BTLA治疗预防GVHD不依赖其配体，即共刺激肿瘤坏死因子受体疱疹病毒进入介质(HVEM)，并要求供者来源的T细胞表达BTLA。此外，与预先承诺的天然来源的CD 4+Foxp3+调节性T细胞(T−)相比，抗BTLA治疗导致了CD 4+叉头盒P3−(FOXP3 REG细胞)效应T细胞(T Eff细胞)的相对抑制，并允许移植物抗肿瘤效应以及对病原体的强烈反应。这些结果表明，BTLA激动剂重新平衡了HSCT后淋巴细胞减少宿主中T细胞的扩张，从而在没有全局免疫抑制的情况下预防了GVHD。因此，在HSCT治疗开始时使用单抗靶向BTLA可能会减少组织相容性带来的限制，并允许更广泛地应用于非危及生命的疾病的治疗。
One-time treatment with an antibody against BTLA provides long-term protection against graft-versus-host disease without affecting effector T cell responses to tumors or pathogens. Graft-versus-host disease (GVHD) causes significant morbidity and mortality in allogeneic hematopoietic stem cell transplantation (aHSCT), preventing its broader application to non–life-threatening diseases. We show that a single administration of a nondepleting monoclonal antibody specific for the coinhibitory immunoglobulin receptor, B and T lymphocyte associated (BTLA), permanently prevented GVHD when administered at the time of aHSCT. Once GVHD was established, anti-BTLA treatment was unable to reverse disease, suggesting that its mechanism occurs early after aHSCT. Anti-BTLA treatment prevented GVHD independently of its ligand, the costimulatory tumor necrosis factor receptor herpesvirus entry mediator (HVEM), and required BTLA expression by donor-derived T cells. Furthermore, anti-BTLA treatment led to the relative inhibition of CD4+ forkhead box P3− (Foxp3−) effector T cell (T eff cell) expansion compared with precommitted naturally occurring donor-derived CD4+ Foxp3+ regulatory T cell (T reg cell) and allowed for graft-versus-tumor (GVT) effects as well as robust responses to pathogens. These results suggest that BTLA agonism rebalances T cell expansion in lymphopenic hosts after aHSCT, thereby preventing GVHD without global immunosuppression. Thus, targeting BTLA with a monoclonal antibody at the initiation of aHSCT therapy might reduce limitations imposed by histocompatibility and allow broader application to treatment of non–life-threatening diseases.
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DOI：
10.1084/jem.20071160
发表时间：
2008-06-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Steinberg MW;Turovskaya O;Shaikh RB;Kim G;McCole DF;Pfeffer K;Murphy KM;Ware CF;Kronenberg M
通讯作者：
Kronenberg M
影响因子：
32.4
作者：
Fontenot, JD;Rasmussen, JP;Rudensky, AY
通讯作者：
Rudensky, AY
影响因子：
20.3
作者：
Taylor, PA;Lees, CJ;Blazar, BR
通讯作者：
Blazar, BR
影响因子：
4.4
作者：
Blazar, BR;Carreno, BM;Taylor, PA
通讯作者：
Taylor, PA
影响因子：
4.8
作者：
Rehemtulla, A;Stegman, LD;Ross, BD
通讯作者：
Ross, BD