Combined inhibition of c-Abl and PDGF receptors for prevention and treatment of murine sclerodermatous chronic graft-versus-host disease.
Combined inhibition of c-Abl and PDGF receptors for prevention and treatment of murine sclerodermatous chronic graft-versus-host disease.
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联合抑制c-Abl和PDGF受体防治小鼠硬皮病慢性移植物抗宿主病
DOI：
10.1016/j.ajpath.2012.07.017
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Distler J.H.
中科院分区：
文献类型：
--
作者：
Zerr P;Distler A;Palumbo-Zerr K;Tomcik M;Vollath S;Dees C;Egberts F;Tinazzi I;Del Galdo F;Distler O;Schett G;Spriewald B.M;Distler J.H.
慢性移植物抗宿主病（cGvHD）是同种异体骨髓移植的常见并发症，对长期预后有重要影响。cGvHD的分子机制只被部分揭示，分子靶向治疗尚未建立临床应用。我们研究了联合抑制Abelson激酶（c-Abl）和血小板衍生生长因子受体（PDGFR）在实验性硬皮性cGvHD中的作用。使用伊马替尼或尼洛替尼治疗可消除c-Abl和PDGFR的异常活化，并可防止实验性cGvHD。使用伊马替尼或尼洛替尼的预防性治疗抑制硬化性cGvHD的发展。在接受伊马替尼或尼洛替尼治疗的小鼠中，体重减轻、脱发和皮肤溃疡等临床特征以及真皮增厚和胶原蛋白积累的组织学特征显著减少，但在接受泼尼松治疗的小鼠中则没有。值得注意的是，伊马替尼和尼洛替尼对于已经临床表现的实验性cGvHD也有效。综上所述，联合抑制c-Abl和PDGFR可有效预防和治疗实验性硬皮性cGvHD。考虑到与cGvHD相关的高发病率，缺乏临床使用的有效分子治疗方法，以及伊马替尼非对照研究的首次阳性信号，联合抑制c-Abl和PDGFR可能是未来治疗硬化性cGvHD的一种有希望的策略。
Chronic graft-versus-host disease (cGvHD) is a common complication of allogeneic bone marrow transplantation, and has a major effect on the long-term prognosis. The molecular mechanisms underlying cGvHD have been only partially revealed, and molecular targeted therapies have not yet been established for clinical use. We examined the effects of the combined inhibition of the Abelson kinase (c-Abl) and platelet-derived growth factor receptors (PDGFR) in experimental sclerodermatous cGvHD. Treatment using imatinib or nilotinib abolished the aberrant activation of c-Abl and PDGFR and protected against experimental cGvHD. Preventive therapy using imatinib or nilotinib inhibited the development of sclerodermatous cGvHD. Clinical features such as weight loss, alopecia, and skin ulcers, and histologic features with dermal thickening and accumulation of collagen were significantly reduced in mice that received imatinib or nilotinib therapy, but not in mice that received prednisone therapy. Of note, imatinib and nilotinib were also effective for treatment of experimental cGvHD that had already been clinically manifested. In summary, the combined inhibition of c-Abl and PDGFR is effective for prevention and treatment of experimental sclerodermatous cGvHD. Considering the high morbidity associated with cGvHD, the lack of efficient molecular therapies for clinical use, and first positive signals from uncontrolled studies of imatinib, combined inhibition of c-Abl and PDGFR might be a promising future strategy for treatment of sclerodermatous cGvHD.
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影响因子：
20.3
作者：
K. Yamashita;U. Choi;Patricia C. Woltz;Susan F. Foster;M. Sneller;F. Hakim;D. Fowler;M. Bishop;S. Pavletic;M. Tamari;K. Castro;A. Barrett;R. Childs;G. Illei;S. Leitman;H. Malech;M. Horwitz
通讯作者：
K. Yamashita;U. Choi;Patricia C. Woltz;Susan F. Foster;M. Sneller;F. Hakim;D. Fowler;M. Bishop;S. Pavletic;M. Tamari;K. Castro;A. Barrett;R. Childs;G. Illei;S. Leitman;H. Malech;M. Horwitz
影响因子：
3.6
作者：
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通讯作者：
Cortes, Jorge
影响因子：
20.3
作者：
Kahner, Bryan N.;Dorsam, Robert T.;Kunapuli, Satya P.
通讯作者：
Kunapuli, Satya P.
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DOI：
10.1111/j.1365-2257.2005.00699.x
发表时间：
2005
期刊：
Clinical and laboratory haematology
影响因子：
--
作者：
A. Wechalekar;T. Cranfield;D. Sinclair;M. Ganzckowski
通讯作者：
M. Ganzckowski
尼洛替尼的活性和耐受性
影响因子：
6.2
作者：
M. Koren;P. le Coutre;J. Duyster;C. Scheid;P. Panayiotidis;W. Prejzner;J. Rowe;M. Schwarz;N. Goldschmidt;A. Nagler
通讯作者：
A. Nagler