器官移植後的排斥現象是無法避免的，而且必須長期服用FK506以及CsA等免疫抑制劑。但服用這類的免疫抑制劑通常會產生嚴重性的副作用。然而，任意終止免疫抑制劑的治療可能產生移植排斥作用而導致器官衰竭。所以發展安全且更有效用的免疫抑制劑可以更進一步改善器官移植後的存活率。
跟其他器官移植相比較，同種異體器官移植後具有耐受性卻不產生排斥現象幾乎只發生在臨床及實驗動物模式的肝臟移植中。已有報告指出在大鼠同位肝臟移植模式中，受肝者術後的血清具有免疫抑制的效果，並且可以克服排斥的產生。然而在受肝者術後前期的血清中，這些具有免疫抑制功能的分子之界定仍舊未明。在我們先前的研究裡，我們證明了同種異體肝臟移植耐受性的產生是和肝臟移植後血清中具免疫抑制活性的抗組蛋白H1抗體之被誘導生成有關聯。我曾經研究過組蛋白H1和抗組蛋白H1抗體對各種細胞的免疫調控作用，特別是對T細胞，ASCs及DCs之間的細胞作用加以探討。因此，本研究主題的具體目標將探討組蛋白H1在移植及再生免疫學上的角色。
首先，我將從DC，T細胞，LAK細胞以及NK細胞而來探討組蛋白H1的免疫抑制活性。在ConA blast實驗中加入抗組蛋白H1抗體，不但不會對細胞產生毒性，而且可以抑制細胞増生，並會增加CD4+CD25+ T細胞比例。當DC接受抗組蛋白H1抗體的作用時，會降低CD80/CD86，IL-1β以及 IL-6的表現。另外，加入抗組蛋白H1抗體到LAK細胞一起培養時，會減少NKR-P1的比例以及降低iNOS，IL-2和IFN-γ的表現。LAK 細胞和NK細胞接受抗組蛋白H1抗體作用後，其毒殺效果也會降低。我們發現當封鎖組蛋白H1的表現時，DC會傾向耐受性的狀態並且降低LAK細胞和NK細胞的毒殺作用，而且會誘導CD4+CD25+Foxp3 T細胞的產生。我們也證實存在細胞質與細胞培養液中的組蛋白H1，可以活化DC的反應。當組蛋白H1被封鎖後會降低DC中訊息傳遞的功能以及MAPKs的表現，並且抑制DC的活性。換言之，DC接受組蛋白H1刺激後，會增加MHC II、CD80及CD86的表現，而且會增加MAPKs的表現。這些結果顯示要促使DC成熟及活化，須組蛋白H1從細胞核轉移到細胞質並且釋出。
近期動物研究顯示幹細胞由骨髓遷徙到肝臟移植片扮演著調控免疫耐受及再生的重要角色。另外，已有研究指出核蛋白會增進幹細胞的遷徙及後續的再生能力。因此，我一直在探討組蛋白H1 對幹細胞的作用。我們發現移植耐受性模式的肝臟中有組蛋白H1的大量表現，相反的，移植排斥模式的肝臟中並未有組蛋白H1的表現。因此，我將先從體外模式研究來證明組蛋白H1對ASCs免疫調節及遷徙能力的影響。由我們研究的結果發現組蛋白H1可以誘導ASCs免疫調節抑制及分化。接下來，將探討肝臟移植後組蛋白H1對於肝臟再生的影響。由這些結果顯示抗組蛋白H1抗體可以發展成有效的免疫抑制藥物；另外，組蛋白H1也可以應用在ASCs組織工程方面，成為有潛能的療法。

In solid organ transplantation, rejection is inevitable and must be treated with long-term immunosuppressive agents, such as tacrolimus (FK506) and cyclosporine A (CsA), which cause deleterious side effects. However, it is unethical to randomly terminate immunosuppressive therapy, which leads to allograft failure. The development of safer and more effective immunosuppressants would result in further improvement of organ transplantation.
Allograft tolerance can be observed almost exclusively in clinical and experimental liver transplantation compared to other organ transplantation. In a rat model of orthotopic liver transplantation (OLT), recipient serum after OLT (post-OLT serum) has been reported to have immunosuppressive activity and contribute to overcome allograft rejection. However, the molecular identities of immunosuppressive factors, which are in the early stage of post-OLT, remain elusive. We previously demonstrated that liver allograft tolerance is associated with the immunosuppressive activity of anti-histone H1 antibody (Ab) induced in the serum of liver transplantation. I have been researching the effect of histone H1 and its Ab on individual immune responsible cells such as DCs, T cells, NK cells and adipose-derived stem cells (ASCs). Especially, cross-talk among T cells, ASCs and DCs is currently being paid attention. Therefore, the specific aims of this study focus here upon the significance of histone H1 and its Ab in transplantation immunology and regeneration immunobiology.
Firstly, the mechanisms underlying the immunosuppressive activity by anti-histone H1 Ab was explored in immune responsible cells including DCs, T-cells, LAK cells, and NK cells. The addition of anti-histone H1 Ab to Concanavalin A (ConA) blast inhibited the proliferation of 5-(6)-carboxy-fluorescein succinimidyl ester (CFSE)-labeled lymphocytes without toxicity but increased the population of CD4+CD25+ T-cells. DCs treated with anti-histone H1 Ab expressed lower levels of CD80/CD86, interleukin (IL)-1β, and IL-6. The addition of anti-histone H1 Ab to LAK cells culture decreased the percentages of NKR-P1 populations and down-regulated levels of inducible nitric oxide synthase (iNOS), IL-2, and interferon (IFN)-γ in RT-PCR. The cytotoxicity of LAK cells and NK cells was lower after treated with anti-histone H1 Ab compared to treat with control IgG. We found that the blockade of histone H1 modulated DCs toward tolerogenic status, decreased the cytotoxicity of LAK and NK cells, and induced CD4+CD25+ T-cells. We also focus upon the significance of histone H1 on DCs in terms of the intracellular signalling pathway of DCs. Our immunostaining and immunoblot studies demonstrated that histone H1 was detected in cytoplasm and culture supernatants upon the activation of DCs. Histone H1 blockage by anti-histone H1 Ab down-regulated the intracellular activation of mitogen-activated protein kinases (MAPKs) (p38) and IkBα of DCs, and inhibited DC activity in the proliferation of CD4+ T cells. On the other hand, the addition of histone H1 without endotoxin stimulation up-regulated major histocompatibility complex class (MHC) II, the CD80 and CD86 surface markers of DCs and the activation of MAPKs (p38 and extracellular-regulated kinase (ERK) 1/2) and IkBα. These results suggest that the translocation of histone H1 from nuclei to cytoplasm and the release of their own histone H1 are necessary for the maturation of DCs and the activation for T lymphocytes.
Recent experimental studies suggest that stem cells from bone marrow to liver allograft play an important role of immunological tolerance and regeneration in the donor graft. Additionally, nuclear proteins have been reported to enhance migration of stem cells and subsequent regeneration. Therefore, I have been investigating the effect of histone H1 on stem cells. In the experimental setting of liver transplantation, the expression of histone H1 in donor graft can be observed exclusively in tolerogeneic OLT while no hepatic expression of histone H1 was observed in donor grafts of rejector OLT. Therefore, I firstly performed in vitro studies demonstrating the effect of histone H1 on immunosuppression potential and migration ability of ASCs. Our in vitro studies showed that histone H1 does not alter immunological status but that histone H1 enhanced wound healing and migration ability accompanied with increased IL-6 expression. In the present study, the role of histone H1 on post-transplant liver regeneration is also discussed. In conclusion, these results suggest that the use of anti-histone H1 Abs might be a useful strategy for the development of a form of immunosuppression and histone H1 may be useful for induction of ASCs in tissue engineering and future potential ASCs therapies for transplantation.

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