2012-05-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/643464摘要：在器官移植的領域，排斥是器官失去功能主要的原因之一。目前預防器官排斥的藥物使用，主要是預防T 淋巴球活化以及分裂複製。包括calcineurin inhibitor, mTORinhibitor, 或是mycophenolate mofetil 之類的藥物。可是，一旦發生急性排斥，目前使用的這些藥物對於治療急性排斥沒有幫助。淋巴細胞消除藥物目前常使用來治療或是預防急性排斥而且也被證實可以有效對於治療移植器官的急性排斥。例如，anti-CD20(Rituximab, Roche) 經常用來除去體內B 型淋巴球來治療抗體性排斥，而 anti-CD3(OKT3, Janssen-Cilag) 或是anti-thymocyte globulin (rabbit ATG, Genzyme; equine ATG,Pfizer) 常用來除去體內T 型淋巴球來治療對於大量類固醇治療無效的急性細胞性排斥。可是，這些目前的除去淋巴球的抗體製劑的問題是一旦使用後，這些抗體製劑會在體內留存一段時間，這段時間會使病患暴露於感染的風險。這些抗體製劑使用上有過敏的風險，重複使用可能會引發人體免疫反應產生中和性抗體。因此，發展新型口服可依投與劑量高低來達成不同藥效的淋巴球去除劑，對於治療移植器官急性排斥有其重要性。在細胞內，IkB kinase (IKK) 複合物是由兩個催化型副單元，IKKα 和 IKKβ，以及一個調控型副單元 IKKγ (NEMO)所組成。 IKK 複合物可以催化IκB 的磷酸化以及Ubiquitin 鏈的鍵結造成IkB 的分解並釋放出NFκB 到細胞核內去活化下游免疫反應。IKK/NFκB 系統是調控免疫發炎反應、癌化反應重要的系統之一。有研究報告指出IKK 抑制劑 BMS-345541 (4(2′-aminoethyl)amino-1,8-dimethylimidazo (1,2-a)quinoxaline) 是高度專一性的IKK 抑制劑，可以抑制NF-κB 下游發炎性基因的轉錄。在我們最近初步的小鼠實驗發現，每天餵食BMS-345541 可以隨著投與劑量增加而使小鼠血液中淋巴球數目下降但不影響血液裡中性球 (neutrophil) 的數目。因此我們提出假設這個IKK 抑制劑可能可以是理想的口服型淋巴球去除劑。因此我們提出這個計畫來發展新型口服淋巴球去除劑來應用在器官移植急性排斥的治療。<br> Abstract: Rejection is the major cause of graft failure in solid organ transplantation. The currentregimen for the prophylaxis of graft rejection includes prevention of the activation orproliferation of T cells, including calcineurin inhibitor, mTOR inhibitor or mycophenolatemofetil. These reagents, however, were not effective once acute rejection happened.Lymphocyte-depleting agents are 3 frequently used in organ transplantation to treat or preventrejection episodes and have demonstrated the great success in improvement of acute rejection.For example, anti-CD20 (Rituximab, Roche) is frequently used to deplete B cells fortreatment of antibody-mediated rejection and anti-CD3 (OKT3, Janssen-Cilag) oranti-thymocyte globulin (rabbit ATG, Genzyme; equine ATG, Pfizer) for depletion of T cellsfor treatment of steroid-resistant acute cellular rejection. However, the major problem ofcurrent regimen of immunoglobulin is that it's all-or-none. Once the patients are administered,the effect would last a long time. They could not use these antibodies repeatedly, otherwisethe patients would generate neutralizing antibody. Therefore, a new and improved medicationthat could deplete lymphocytes in a dose-dependent manner reversibly and could beadministered per orally is needed.The IκB kinase (IKK) complex, composed of two catalytic subunits, IKKα and IKKβ,and a regulatory subunit IKKγ (NEMO), catalyzes the phosphorylation and then a subsequentubiquitination and proteolysis of IκB, releasing NF-κB to translocate to the nucleus andactivate the expression of downstream pro-inflammatory genes in response to stimuli. TheIKK/NFκB system is a master regulator of a diverse array of cellular actions covering a widespectrum of immune/inflammatory reactions, carcinogenesis, neurodegenerative processesand vascular responses. It was reported that the IKK inhibitor, BMS-345541(4(2′-aminoethyl)amino-1,8-dimethylimidazo (1,2-a)quinoxaline), is a highly selectiveinhibitor of IKK that inhibits NF-κB-dependent transcription of pro-inflammatory cytokinesboth in vitro and in vivo.We recently found that mice received daily BMS-345541 administration and theirlymphocyte, but not myeloid cell, counts showed a significant decrease suggesting that IKKinhibitor BMS-345541 might become an ideal lymphocyte depleting agent. We propose toundertake a series of studies to develop novel lymphocyte-depleting agents for organtransplantation and lymphoma.