本文選題：組織工程皮膚　切入點(diǎn)：免疫原性　出處：《第三軍醫(yī)大學(xué)》2008年博士論文

【摘要】： 組織工程皮膚是目前治療難治性潰瘍、大面積燒傷等皮膚缺損性疾病最有效的方法之一。組織工程皮膚是采用組織工程學(xué)方法,體外分離自體或異體細(xì)胞并長(zhǎng)期培養(yǎng)和擴(kuò)增后,與其他天然或合成材料共同構(gòu)建而成。采用自體細(xì)胞雖然避免了免疫排斥反應(yīng),但為患者造成了新的創(chuàng)面,并限制了組織工程皮膚的商品化。異體細(xì)胞經(jīng)體外長(zhǎng)期培養(yǎng)后是否被受體免疫系統(tǒng)識(shí)別即免疫原性如何,仍然存在爭(zhēng)論。目前構(gòu)建組織工程皮膚主要使用角質(zhì)形成細(xì)胞(keratinocyte,KC)、成纖維細(xì)胞(fibroblast,FB)作為種子細(xì)胞。一般認(rèn)為這兩種細(xì)胞正常情況下僅表達(dá)MHC-Ⅰ類(lèi)抗原,不表達(dá)MHC-Ⅱ類(lèi)抗原及共刺激分子,本身不具備遞呈抗原能力,因此免疫原性較弱。但有實(shí)驗(yàn)顯示在炎癥因子如干擾素-γ(interferon-γ,IFN-γ)的作用下,上述細(xì)胞能誘導(dǎo)HLA-DR的表達(dá)。HLA-DR屬于MHC-Ⅱ分子,是專(zhuān)職抗原遞呈細(xì)胞(antigen presenting cell,APC)呈遞抗原的重要結(jié)構(gòu)之一。還有研究者認(rèn)為KC可通過(guò)誘導(dǎo)表達(dá)B7分子來(lái)向T淋巴細(xì)胞傳遞協(xié)同刺激信號(hào),從而激活T淋巴細(xì)胞。因此KC、FB能否成為APC,從而激活T細(xì)胞需要實(shí)驗(yàn)加以明確�；旌狭馨图�(xì)胞培養(yǎng)試驗(yàn)是以研究細(xì)胞免疫為主,一定程度上模擬體內(nèi)免疫識(shí)別途徑,廣泛應(yīng)用于研究免疫排斥反應(yīng)的實(shí)驗(yàn)中。本實(shí)驗(yàn)將不同代KC、FB與異體淋巴細(xì)胞混合培養(yǎng),觀察淋巴細(xì)胞的增殖程度,反映異體KC、FB在體外培養(yǎng)的過(guò)程中免疫原性的變化情況。 異體細(xì)胞移植后是否被受體免疫系統(tǒng)排斥,另一個(gè)關(guān)鍵之處在于其能否被受體的專(zhuān)職APC所識(shí)別。朗格漢斯細(xì)胞(langerhans cell, LC)是專(zhuān)職APC,長(zhǎng)期定植于皮膚、呼吸道上皮及消化道粘膜上皮中,攝取抗原后向局部淋巴組織遷移,在那里最終分化成熟,激活初始T淋巴細(xì)胞,啟動(dòng)免疫反應(yīng)或誘導(dǎo)免疫耐受。LC如何識(shí)別抗原,激活淋巴細(xì)胞的具體機(jī)制目前尚不完全清楚。隨著LC的體外培養(yǎng)成功,對(duì)于LC能否識(shí)別異體KC、FB的問(wèn)題能夠進(jìn)一步深入研究。本實(shí)驗(yàn)采用多種細(xì)胞因子聯(lián)合誘導(dǎo)培養(yǎng)LC,將培養(yǎng)的LC與異體KC、FB混合培養(yǎng)后,觀察LC的表型變化情況,反映LC對(duì)異體KC、FB的識(shí)別情況。 組織工程皮膚支架材料也是影響其免疫原性的一個(gè)重要因素,組織工程皮膚采用的支架材料主要分為合成高分子材料及天然高分子材料,目前的研究主要集中于支架材料的生物毒性和降解性等,對(duì)其免疫原性的研究較少。動(dòng)物膠原屬于天然高分子材料,是由動(dòng)物細(xì)胞合成,是細(xì)胞外間質(zhì)的主要成分,因其易于獲取,在組織工程皮膚支架材料中的應(yīng)用最為廣泛,雖然不同種類(lèi)的動(dòng)物分離出來(lái)的膠原極其相似,但畢竟屬于異種蛋白,植入后是否具有免疫原性,有必要系統(tǒng)地研究。 組織工程皮膚免疫原性的研究進(jìn)展緩慢,其中一個(gè)主要原因就是移植于人體的臨床研究受到倫理學(xué)等多方面的制約;另外長(zhǎng)期缺乏一種良好的能夠模擬人體免疫內(nèi)環(huán)境的實(shí)驗(yàn)動(dòng)物也影響了深入研究。重度聯(lián)合免疫缺陷(severe combined immunodeficiency,SCID)鼠是細(xì)胞免疫、體液免疫均缺陷的動(dòng)物,容易植入人的免疫細(xì)胞和組織,構(gòu)建人的免疫系統(tǒng)。有實(shí)驗(yàn)顯示植入SCID鼠的人淋巴細(xì)胞能夠長(zhǎng)期存活,仍然保持排斥異體移植物的特性。另有實(shí)驗(yàn)將人皮膚移植于SCID鼠后,移植的人皮膚能長(zhǎng)期維持正常的皮膚結(jié)構(gòu),以上特點(diǎn)將使SCID鼠成為研究組織工程皮膚免疫原性的一個(gè)有力工具。本實(shí)驗(yàn)將組織工程皮膚、人皮膚和無(wú)細(xì)胞真皮支架移植于SCID鼠后,植入異體人脾淋巴細(xì)胞后觀察組織工程皮膚三者的免疫排斥跡象,從組織水平反映組織工程皮膚的免疫原性�，F(xiàn)將本實(shí)驗(yàn)方法、結(jié)果和結(jié)論分述如下: 方法: 1.采用組織工程的方法分離培養(yǎng)KC、FB,并不斷傳代。將不同代的KC、FB與異體淋巴細(xì)胞混合培養(yǎng),觀察淋巴細(xì)胞的增殖程度。CD1a標(biāo)記LC,流式細(xì)胞儀測(cè)不同代數(shù)KC中混雜的LC的變化情況,以及KC在不同培養(yǎng)體系下細(xì)胞表面CD80、CD86的變化情況,從細(xì)胞水平觀察組織工程皮膚種子細(xì)胞的免疫原性。 2.體外采用多種細(xì)胞因子聯(lián)合誘導(dǎo)外周血單核細(xì)胞分化發(fā)育為L(zhǎng)C,流式細(xì)胞儀測(cè)細(xì)胞表面CD1a、HLA-DR、CD80、CD86和CD83的表達(dá)情況,電鏡鑒定培養(yǎng)的細(xì)胞為L(zhǎng)C。將純化的KC、FB分別與LC共培養(yǎng)后測(cè)LC的細(xì)胞表型的變化情況,從細(xì)胞水平觀察LC對(duì)異體KC、FB的識(shí)別情況。 3.將體外分離的不同數(shù)量的人脾淋巴細(xì)胞注入SCID鼠腹腔內(nèi),觀察SCID鼠的生長(zhǎng)情況,流式細(xì)胞測(cè)鼠血中人淋巴細(xì)胞的分類(lèi)情況,ELISA法測(cè)鼠血中人IgG的含量,摸索出一條穩(wěn)定植入人脾淋巴細(xì)胞的實(shí)驗(yàn)方法。 4.將組織工程皮膚、人包皮、無(wú)細(xì)胞真皮支架移植于SCID鼠,隨后植入異體人脾淋巴細(xì)胞后,用組織學(xué)和免疫組織化學(xué)的方法觀察組織工程皮膚等的免疫排斥跡象,從組織水平反映組織工程皮膚整體的免疫原性。 結(jié)果: 1.原代～4代KC、原代FB能顯著刺激異體淋巴細(xì)胞增殖。流式細(xì)胞儀分析顯示KC中混雜的LC逐漸減少,5代后無(wú)法測(cè)出LC的存在。KC刺激異體淋巴細(xì)胞增殖與其中混雜的LC明顯相關(guān)。5代KC在無(wú)血清、有血清和PHA存在的培養(yǎng)體系均無(wú)法檢測(cè)出細(xì)胞表面CD80、CD86的表達(dá)。 2.人外周血單核細(xì)胞在GM-CSF、IL-4、TGF-β1的聯(lián)合誘導(dǎo)下,分化發(fā)育為L(zhǎng)C,流式細(xì)胞儀顯示細(xì)胞高表達(dá)CD1a,低表達(dá)HLA-DR、CD80、CD86,不表達(dá)CD83,電鏡下觀察到LC的特殊結(jié)構(gòu)birbeck小體。與純化的KC、FB共培養(yǎng)后LC的CD80、CD86和CD83無(wú)明顯改變,也不能明顯刺激同源淋巴細(xì)胞增殖。 3.將3×107人脾淋巴細(xì)胞植入SCID鼠后,動(dòng)物無(wú)明顯的移植物抗宿主反應(yīng)。2周至10周鼠血中分離出的淋巴細(xì)胞均測(cè)得T細(xì)胞、B細(xì)胞、NK細(xì)胞。其中T、B細(xì)胞的百分比8周達(dá)到峰值,分別為18.2±0.4%和7.5±0.3%。鼠血中人IgG10周達(dá)到182.51±4.96 ug/ml。 4.組織工程皮膚、人包皮移植于SCID鼠后能維持其正常人皮膚組織結(jié)構(gòu),植入異體淋巴細(xì)胞后,組織工程皮膚未發(fā)生明顯的免疫排斥反應(yīng),人包皮則發(fā)生了明顯的免疫排斥反應(yīng)。 結(jié)論:本實(shí)驗(yàn)將組織工程皮膚種子細(xì)胞與異體淋巴細(xì)胞混合培養(yǎng),純化后種子細(xì)胞不能顯著刺異體激淋巴細(xì)胞的增殖;純化的種子細(xì)胞與體外誘導(dǎo)培養(yǎng)的不成熟LC混合培養(yǎng)后,也不能明顯上調(diào)LC CD80、CD86和CD83的表達(dá)。將人脾淋巴細(xì)胞植入SCID鼠后,人淋巴細(xì)胞能繼續(xù)增殖和分化,仍具有分泌人IgG等功能。組織工程皮膚移植于SCID鼠后植入異體淋巴細(xì)胞,未發(fā)生明顯排斥反應(yīng)。綜上所述,本實(shí)驗(yàn)構(gòu)建的組織工程皮膚免疫原性較弱,不易引起機(jī)體的免疫排斥反應(yīng)。
[Abstract]:The skin tissue engineering is the treatment of refractory ulcers, burns and other methods of large area skin defect disease. One of the most effective skin tissue engineering is by tissue engineering method, in vitro autologous or allogeneic cells and long term culture and amplification, and other natural or synthetic materials constructed by autologous cells can avoid. Immune rejection, but caused a new wound for patients, and limit the commercialization of tissue engineered skin. Allogeneic cells after long-term in vitro cultivation is the immune system of receptor recognition is immunogenic, is still controversial. The main use of tissue engineering skin keratinocytes (keratinocyte, KC), a fiber cells (fibroblast, FB) as seed cells. Generally these two kinds of cells normally only the expression of MHC- class I antigen, the expression of MHC- class II antigens and costimulatory molecules That does not have antigen-presenting ability, so the weak immunogenicity. But some experiments showed that in inflammatory cytokines such as interferon gamma (interferon- y, IFN- y) under the effect of the expression of.HLA-DR cells can induce HLA-DR belongs to the MHC- II molecule is professional antigen presenting cells (antigen presenting cell, APC) important the structure of antigen presentation. And researchers believe that KC can also induce the expression of B7 molecules to T cells transmit costimulatory signal to activate T lymphocytes. So KC, FB can become APC, which activates T cells need to clear. The mixed lymphocyte culture test is to study the cell immune, immune to a certain extent in the way of recognition simulation, widely applied in the study of immune rejection in the experiment. In the experiment of different generations of KC, cultured with allogeneic lymphocytes in mixed FB lymphocytes proliferation, degree of observation, reflection The changes of immunogenicity during the culture of KC and FB in vitro.
Allogeneic cell transplantation is rejected by host immune system, another key lies in whether it can be a full-time receptor identified in the APC. Hans Lange (Langerhans cell, LC cells) is a full-time APC, long-term colonization in the skin, respiratory and digestive tract epithelial mucosa, migrate to the local lymph tissue uptake of antigen after the final where the initial differentiation, activation of T lymphocytes, immune response or immune tolerance induced by.LC antigen recognition, the specific mechanism of activated lymphocytes remains unclear. With the LC cultured in vitro successfully, for LC can identify allogeneic KC, FB problem can be further studied. This experiment adopts a variety of cytokines induced by the combination of culture LC, LC and KC in cultured allogenic FB, mixed culture, to observe the phenotype change of LC and LC reflect on allogeneic KC, identification of FB.
Scaffold materials of tissue engineering skin is also an important factor affecting the immunogenicity of the scaffold material of tissue engineering skin used consists of synthetic polymer materials and natural polymer materials, the present study focuses on the scaffold materials for biological toxicity and degradation, study on the immunogenicity of small animal collagen belongs to natural. Polymer materials are synthesized by animal cells, is the main component of extracellular matrix, because of its easy access and application in tissue engineering scaffold material in the skin is the most widely used, although different animal separated collagen is very similar, but after all, belongs to the heterogeneous protein is immunogenic after implantation, it is necessary to to study.
Research progress of tissue engineering skin immunogenicity is slow, clinical study of one of the main reasons is transplanted into the body is restricted by ethics and other aspects; another long-term lack of a good environment to mimic human immune animal also studied. Effects of severe combined immunodeficiency (severe combined, immunodeficiency, SCID) in cellular immunity, humoral immune defects in animal, easy implantation of human immune cells and tissues, construct the human immune system. Some experiments showed that human lymphocytes transplanted in SCID mice could still maintain long-term survival, graft rejection characteristics. The human skin transplanted to SCID mice after skin transplantation can the normal skin structure maintained for a long time, the above features make SCID mice become a powerful tool to study tissue engineering skin immunogenicity. This experiment will be organized Engineering skin, human skin and acellular dermal scaffold were transplanted to SCID rats, observe signs of rejection immune tissue engineering skin of the three implanted allogenic human splenic lymphocytes, reflect the immunogenicity of tissue engineering skin from the organizational level. The experimental methods, results and conclusions are as follows:
Method:
1. using tissue engineering methods for isolation of KC, FB, and continuously passaged. Different generation of KC culture, mixed with allogenic lymphocytes FB,.CD1a marker LC lymphocyte proliferation were observed, the changes of LC mixed flow cytometry test in different generations of KC, and KC cells in different culture systems under the surface of CD80 and the change of CD86, observe the immunogenicity of seed cells for skin tissue engineering from the cell level.
2. in vitro by cytokines induced by peripheral blood mononuclear cells and differentiation of LC cells was measured by flow cytometry on CD1a, HLA-DR, CD80, CD86 and CD83 expression of the cultured cells were identified by electron microscopy, LC. purified KC, FB changes respectively after cultured with LC LC fine test the cell phenotype, from the cell level to observe the effect of LC on allogeneic KC, identification of FB.
3. in vitro separation of different number of human spleen lymphocytes in SCID mice by intraperitoneal injection, to observe the growth of SCID rats, the classification of flow cytometric measurement of blood lymphocytes, determination of blood IgG ELISA method, and find out a stable implantation of human spleen lymphocytes experiment method.
4. of the tissue engineering skin, human foreskin acellular dermal scaffold were transplanted to SCID rats, then implanted in allogenic human splenic lymphocytes, using histological and immunohistochemical observation of immune rejection of the tissue engineering skin signs reflect the immunogenicity of tissue engineering skin tissue from the whole level.
Result:
The 1. primary to the 4 generation KC, primary FB could stimulate the proliferation of allogeneic lymphocytes. KC analysis showed that in mixed LC gradually decreased flow cytometry after 5 generations could not be detected in the presence of LC.KC to stimulate the proliferation of allogeneic lymphocytes and mixed with LC was significantly related to.5 generation KC in serum-free culture system, there exists the serum and PHA were unable to detect cell surface CD80, CD86 expression.
IL-4 2. in human peripheral blood mononuclear cells in GM-CSF, TGF-, and beta 1 induced differentiation, LC, flow cytometry showed that the cells with high expression of CD1a and low expression of HLA-DR, CD80, CD86, the expression of CD83 were observed by electron microscope LC Birbeck special structure bodies. With purified KC. After LC CD80 co culture FB, CD86 and CD83 had no obvious change, and could not stimulate homologous lymphocyte proliferation.
3. 3 x 107 human splenic lymphocytes transplanted in SCID mice after T cells were measured in isolated animal lymphocytes had no obvious graft-versus-host reaction of.2 to 10 weeks of blood B cells, NK cells. In T, the percentage of B cells reached the peak in 8 weeks, 0.4% and 7.5 respectively 18.2. 0.3%. + in the blood of mice IgG10 weeks to reach 182.51 + 4.96 ug/ml.
4., tissue engineered skin and human foreskin transplanted to SCID mice can maintain their normal skin tissue structure. After implantation of allogenic lymphocytes, no obvious immune rejection is found in tissue-engineered skin, and there is a significant immunological rejection in human foreskin.
Conclusion: the tissue engineering skin seed cells and allogeneic mixed lymphocyte culture, purified seed cells significantly stimulate allogenic lymphocytes proliferation; immature LC mixed culture cultured seed cells and purified in vitro after not significantly up-regulated LC expression of CD80, CD86 and CD83. The human spleen lymphocytes implanted SCID after, people can continue to lymphocyte proliferation and differentiation, still has secrete human IgG. Tissue engineering skin transplantation in SCID rats after implantation of allogeneic lymphocytes, no obvious rejection. In conclusion, this experiment is the primary tissue engineering skin immune building, is not easy to cause immune rejection.

【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2008
【分類(lèi)號(hào)】：R392

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