Kupffer细胞和IL-15对HBV免疫耐受的作用机制研究
摘要
肝脏是一个独特的器官,它既是人体最大的代谢和解毒器官,同时也被认为是机体重要的免疫器官。与其它免疫器官主要诱导免疫应答不同,肝脏更倾向于诱导免疫耐受如口服免疫耐受,肝脏移植耐受等。一些病原菌如乙型肝炎病毒(Hepatitis B Virus, HBV)、丙型肝炎病毒(Hepatitis C Virus, HCV)和疟疾等利用肝脏诱导免疫耐受的特性在肝脏局部形成慢性感染,严重危害人类健康。
HBV主要感染肝实质细胞,部分人群感染HBV后会导致终生携带,HBV携带者对HBV疫苗处于免疫耐受状态。长期以来,人们对于HBV诱导免疫耐受的机理研究主要基于HBV转基因鼠,但HBV转基因鼠免疫系统从胚胎期对HBV病毒就完全处于免疫耐受状态,与人类后天感染HBV状态有较大差别。本研究中我们采用pAAV/HBV1.2质粒高压注射的方式建立HBV慢性携带小鼠动物模型,研究了HBV慢性携带诱导外周免疫耐受的机理和HBV感染初期肝脏局部微环境改变对HBV免疫耐受的影响。一方面,我们发现Kupffer细胞在诱导HBV携带鼠外周免疫耐受过程中发挥重要作用；另一方面,肝脏过表达IL-15能够预防pAAV/HBV1.2质粒高压注射形成的免疫耐受状态。
本研究中,我们采用对C57BL/6小鼠高压注射pAAV/HBV1.2质粒的方式建立HBV持续携带动物模型,模拟人类HBV慢性感染状态。运用放射免疫方法定量检测血清中HBsAg、HBeAg、Anti-HBs含量,免疫组化方法检测肝脏组织HBcAg表达,荧光定量PCR方法检测血清中HBV DNA含量,利用以上指标评价pAAV/HBV1.2质粒高压注射后HBV携带情况；通过细胞清除、细胞纯化和细胞转输实验观察特定细胞亚群在HBV诱导外周免疫耐受过程中的作用；采用构建重组表达质粒和高压注射的方式在小鼠体内内源性过表达IL-15；利用流式细胞术检测各细胞亚群的变化特征；利用ELISA方法检测血清中细胞因子含量的变化。采用上述研究方法,我们得到了以下结果：
Kupffer细胞介导HBV免疫耐受。
pAAV/HBV1.2质粒高压注射小鼠后血清中能检测到HBsAg、HBeAg持续表达,高压注射6周后肝脏组织仍可以检测到HBcAg蛋白,血清转氨酶在HBV质粒携带过程中一直维持在正常水平,这暗示HBV质粒携带鼠的免疫状态与处于免疫耐受状态的人类慢性HBV携带者的免疫状态相似。与人类HBV感染现象相一致,我们发现HBV疫苗预先免疫可以促进小鼠排斥HBV; HBV质粒携带鼠在HBV疫苗免疫后,不能产生Anti-HBs, HBV疫苗免疫也不能促进HBV质粒携带鼠排斥HBV,这表明肝脏表达HBV诱导外周对HBV疫苗处于免疫耐受状态。进一步我们对HBV质粒携带鼠免疫非HBV蛋白抗原OVA,发现HBV携带鼠可以对OVA产生免疫应答,这说明肝脏表达HBV诱导外周免疫耐受只针对HBV蛋白,是抗原特异性的。
我们将HBV质粒携带鼠和对照鼠的脾脏淋巴细胞转输到获得性免疫系统缺陷的Rag1-/-鼠中,在Rag1-/-鼠上分别重建它们的外周免疫系统,观察重建的免疫系统对HBV疫苗的反应。实验结果表明,重建了对照鼠免疫系统的Rag1-/-鼠能对HBV疫苗产生应答,而重建了HBV携带鼠免疫系统的Rag1-/-鼠不能对HBV疫苗产生应答。接着,我们将HBV携带鼠脾脏淋巴细胞中的CD4+T细胞替换为对照鼠的CD4+T细胞,再转输给Rag1-/-,发现对照鼠的CD4+T细胞能辅助HBV携带鼠的获得性免疫系统对HBV疫苗产生免疫应答。这暗示HBV携带鼠免疫耐受状态可能是由于其CD4+T细胞功能缺陷造成的。
肝脏抗原递呈细胞被证明在诱导肝脏免疫耐受过程中起重要作用。HBV携带鼠的非实质细胞转输到Naive鼠中能诱导受者鼠对HBV疫苗低免疫应答,进一步将肝脏非实质细胞分为Kupffer细胞和非Kupffer细胞再分别进行转输,我们发现Kupffer细胞具有很强的诱导受者鼠低免疫应答的能力,这表明Kupffer细胞介导了HBV免疫耐受。不过,检测Kupffer细胞在pAAV/HBV1.2质粒高压注射前后的变化情况,我们发现Kupffer细胞的状态并没有显著改变,这暗示肝脏Kupffer细胞一直处于诱导免疫耐受的状态。
肝脏过表达IL-15诱导产生IFN-β预防HBV免疫耐受
为了研究IL-15对HBV免疫耐受的影响,我们构建了含IL-15基因表达框的pLIVE-IL-15质粒,通过高压注射的方式使pLIVE-IL-15质粒在小鼠体内过表达IL-15。实验结果表明,pLIVE-IL-15质粒高压注射小鼠后能在体内长期表达。若将pLIVE-IL-15质粒或对照质粒pLIVE-EGFP与pAAV/HBV1.2质粒一起注射到小鼠体内,我们发现对照质粒组小鼠血清中长期表达HBsAg和HBeAg,而pLIVE-IL-15质粒注射组血清中低表达HBsAg和HBeAg并且HBV最终会被清除。这表明IL-15能有效预防HBV免疫耐受状态形成。
IL-15是一种多能性细胞因子,对天然免疫系统细胞和获得性免疫系统细胞都具有调节作用。pLIVE-IL-15质粒在Rag1-/-鼠中仍能有效地抑制HBV表达,这表明IL-15发挥抗HBV功能不依赖于获得性免疫系统。尽管脾脏和肝脏NK细胞在IL-15质粒注射后数目有较大提升,但采用PK136抗体清除NK/NKT细胞并不影响IL-15抗HBV功能,采用IL-2Rγc-/-鼠实验也表明IL-15抗HBV能力不依赖于NK细胞。
IFN-γ和IFN-α/β均可以抑制HBV表达。IL-15在IFN-γ缺陷鼠中仍具有抗HBV功能,这表明IL-15抗HBV能力不依赖于IFN-γ。研究发现,肝脏IFN-β mRNA和血清IFN-β蛋白水平在IL-15质粒注射后显著上调,而肝脏IFN-amRNA和血清IFN-α蛋白水平在IL-15质粒注射后变化不明显。进一步采用Anti-IFNAR1抗体阻断IFN-β功能可以完全逆转IL-15的抗HBV作用,这说明IL-15抗HBV功能依赖于IFN-β。Clodronate Lyposomes青除巨噬细胞不会改变IL-15的抗HBV作用,暗示IFN-β并不是由IL-15作用于巨噬细胞产生的。
结论：pAAV/HBV1.2质粒高压注射模型很好地模拟了人类HBV慢性感染状况,可以用于研究HBV感染诱导外周免疫耐受的现象及机理。我们发现HBV免疫耐受状态与CD4+T细胞功能缺陷相关,Kupffer细胞在诱导HBV免疫耐受过程中发挥关键作用。细胞因子IL-15通过诱导产生IFN-β有效预防HBV免疫耐受状态的形成。本研究对于认识肝脏独特的免疫耐受特性,对于理解HBV慢性感染诱导外周免疫耐受的机理及HBV治疗都具有一定意义。
The liver is the largest internal organ in body and plays an important role in maintaining normal metabolism and detoxifying the body. Also, the liver has been recognized as a unique immune organ which favours the induction of immune tolerance rather than immunity, such as oral tolerance, liver transplant tolerance. Some liver pathogens (HBV, HCV, and malaria) can establish persistent/chronic infections in the liver that lead to inflammatory liver disease.
HBV infects the liver as its primary target. The immune system of HBV infected patient has become tolerant to HBV and shows no response to periphery HBV vaccine. Up to now, most in vivo studies on the mechanisms of HBV tolerance have been performed by using HBV transgenic mice; however, HBV transgenic mice are inherently tolerant to HBV virus and are not suitable for studying the mechanisms of HBV tolerance in HBV infected patient who is infected after birth and have limitations in addressing the factors at the onset of infection that influence the final outcomes of chronic HBV infection. Hydrodynamic injection of pAAV/HBV1.2leads to a persistent HBV gene expression in mice, which mimics human chronic HBV infections in the immune tolerant stage. So in the current study, we used this model to study the mechanism of HBV induced immune tolerance and examine the effects of IL-15on immune response to HBV.
In this study, a mouse model for HBV tolerance was established by hydrodynamical injection of pAAV/HBV1.2plasmid into C57BL/6mice. The serum levels of HBsAg、HBeAg and Anti-HBs were measured by radioimmunoassay. Intrahepatic HBcAg expression was determined by immunohistochemistry. Serum HBV DNA was measured by quantitative PCR. In experiments of cell depletion, cell purification and cell transfer, we examined the exact role of specific cell population in HBV immune tolerance. With the aim to investigate the immunomodulatory effects of IL-15in vivo, we constructed a gene transfer vector to endogenously overexpress IL-15in mice. The status of lymphocyte subsets was analyzed with flow cytometer. Serum levels of cytokines were measured by ELISA. Our major findings are shown as follows:
Involvement of Kupffer cells in HBV-induced immuntolerance
Hydrodynamic delivery of the plasmid pAAV/HBV1.2into mouse liver allowed persistent HBV viremia and antigenemia in C57BL/6mice. Secretion of HBsAg and HBeAg into the serum remained high6weeks post pAAV/HBV1.2administration. Both cytoplasmic and nucleic HBcAg were detected in the livers of HBV-carrier mice at6weeks after injection. There were no detectable anti-HBs antibodies in the sera of these animals. The animal model mimics human chronic HBV infections in the immune tolerant stage. If mice were immunized with HBsAg vaccine ahead of tail vein hydrodynamic injection, all HBsAg-vaccinated mice could eliminated HBV virus by decreasing HBsAg and HBeAg in their sera and HBcAg in liver tissues. However, if HBV-carrier mice were immunized with HBsAg vaccine, serum anti-HBs can not be detected in HBV carrier mice and HBsAg vaccine can not cure HBV persistence in HBV carrier mice. Thus, HBV persistence in liver could induce peripheral immune tolerance. Meanwhile, the HBV-carrier mice preserved a strong immune response to other antigen such as OVA, so that peripheral tolerance toward HBsAg was antigen-specifically induced in HBV-carrier mice.
Splenocytes from naive or HBV carrier mice were transferred to ragl-/-mice. After being challenged with HBV vaccine, ragl-/-mice with the immune system of naive mice developed protective levels of anti-HBs, whereas anti-HBs levels were nearly undetectable in ragl-/-mice with the immune system of HBV carrier mice. If we replaced CD4+T cells of splenocytes from HBV carrier mice with CD4+T cells from naive mice and transferred the reconstructive splenocytes to ragl-/-mice and vaccined with HBsAg, we found the reconstructive immune system could response to HBsAg, indicating that the immune tolerant status of HBV carrier mice was associated with the dysfunction of CD4+T cells.
The inherent tolerogenicity of the liver are mediated by tolerogenic antigen-presenting cells. Although phenotype of kupffer cells has no obvious change after pAAV/HBV1.2injection, the mice received NPCs or only KCs from HBV carrier mice secreted obvious low anti-HBs levels after HBsAg immunization, suggesting that kupffer cells are critical in induction of immune tolerance.
Prevention of hepatitis B virus-induced immunotolerance by liver over-expression of interleukin-15via promoting IFN-beta production
With the aim to investigate the immunomodulatory effects of IL-15in vivo, we constructed a gene transfer vector to endogenously overexpress IL-15in mice. We found that hydrodynamic injection of the plasmid pLIVE-IL-15resulted in a sustained concentration of IL-15in serum. Liver IL-15over-expression resulted in great suppression of HBsAg and HBeAg expression early after pAAV/HBV1.2injection and even eliminated HBV virus at five weeks post injection. So, IL-15liver gene transfer induced enhanced immune responses to HBV.
IL-15is a pleiotropic cytokine known to modulate both innate and adaptive immune cells. Over-expression of IL-15similarly decreased HBsAg and HBeAg levels in Ragl-/-mice, suggesting that IL-15exerted anti-HBV activity in a T-cell and B-cell independent manner. Interestingly, despite an increase in NK cell numbers in both spleen and liver of IL-15-expression mice, the anti-HBV effect of IL-15was neither dependent on presence of NK cells in mAb depletion experiment and by using NK-deficient mice (IL-2Rγc-/-).
Type Ⅰ IFNs (IFN-α/β) and IFN-y are known to inhibit HBV gene expression noncytopathically. IL-15inhibits HBV gene expression in IFN-γ-/-mice, suggesting that IFN-y did not play a critical role in IL-15-mediated anti-HBV activity. IL-15treatment increased intrahepatic IFN-β mRNA expression as well as circulating serum IFN-β levels, whereas IFN-a mRNA and protein levels were unchanged. Blockade of IFN-β function led to a significant increase in expression of HBsAg and HBeAg in IL-15treated mice, indicating the anti-HBV activity of IL-15was probably mediated by IFN-β. Depletion of macrophages with clodronate lyposomes did not block the ability of IL-15to inhibit HBV expression in our study, suggesting that IFN-β was not produced by macrophages.
Conclusion:The characteristics of the mouse model for HBV-induced immuntolerance are analogous to those of human chronic HBV infections. The status of HBV induced immuntolerance is associated with dysfunction of CD4+T cells. Kupffer cells play an important role in inducing periphery immune tolerance. Liver over-expression of IL-15prevents HBV-induced immune tolerance in an IFN-β-dependent manner. So, the study on the mechanism of HBV-induced immuntolerance and a novel function of IL-15in anti-HBV immunity might provide an implication in clinical practice.
HBV主要感染肝实质细胞,部分人群感染HBV后会导致终生携带,HBV携带者对HBV疫苗处于免疫耐受状态。长期以来,人们对于HBV诱导免疫耐受的机理研究主要基于HBV转基因鼠,但HBV转基因鼠免疫系统从胚胎期对HBV病毒就完全处于免疫耐受状态,与人类后天感染HBV状态有较大差别。本研究中我们采用pAAV/HBV1.2质粒高压注射的方式建立HBV慢性携带小鼠动物模型,研究了HBV慢性携带诱导外周免疫耐受的机理和HBV感染初期肝脏局部微环境改变对HBV免疫耐受的影响。一方面,我们发现Kupffer细胞在诱导HBV携带鼠外周免疫耐受过程中发挥重要作用；另一方面,肝脏过表达IL-15能够预防pAAV/HBV1.2质粒高压注射形成的免疫耐受状态。
本研究中,我们采用对C57BL/6小鼠高压注射pAAV/HBV1.2质粒的方式建立HBV持续携带动物模型,模拟人类HBV慢性感染状态。运用放射免疫方法定量检测血清中HBsAg、HBeAg、Anti-HBs含量,免疫组化方法检测肝脏组织HBcAg表达,荧光定量PCR方法检测血清中HBV DNA含量,利用以上指标评价pAAV/HBV1.2质粒高压注射后HBV携带情况；通过细胞清除、细胞纯化和细胞转输实验观察特定细胞亚群在HBV诱导外周免疫耐受过程中的作用；采用构建重组表达质粒和高压注射的方式在小鼠体内内源性过表达IL-15；利用流式细胞术检测各细胞亚群的变化特征；利用ELISA方法检测血清中细胞因子含量的变化。采用上述研究方法,我们得到了以下结果：
Kupffer细胞介导HBV免疫耐受。
pAAV/HBV1.2质粒高压注射小鼠后血清中能检测到HBsAg、HBeAg持续表达,高压注射6周后肝脏组织仍可以检测到HBcAg蛋白,血清转氨酶在HBV质粒携带过程中一直维持在正常水平,这暗示HBV质粒携带鼠的免疫状态与处于免疫耐受状态的人类慢性HBV携带者的免疫状态相似。与人类HBV感染现象相一致,我们发现HBV疫苗预先免疫可以促进小鼠排斥HBV; HBV质粒携带鼠在HBV疫苗免疫后,不能产生Anti-HBs, HBV疫苗免疫也不能促进HBV质粒携带鼠排斥HBV,这表明肝脏表达HBV诱导外周对HBV疫苗处于免疫耐受状态。进一步我们对HBV质粒携带鼠免疫非HBV蛋白抗原OVA,发现HBV携带鼠可以对OVA产生免疫应答,这说明肝脏表达HBV诱导外周免疫耐受只针对HBV蛋白,是抗原特异性的。
我们将HBV质粒携带鼠和对照鼠的脾脏淋巴细胞转输到获得性免疫系统缺陷的Rag1-/-鼠中,在Rag1-/-鼠上分别重建它们的外周免疫系统,观察重建的免疫系统对HBV疫苗的反应。实验结果表明,重建了对照鼠免疫系统的Rag1-/-鼠能对HBV疫苗产生应答,而重建了HBV携带鼠免疫系统的Rag1-/-鼠不能对HBV疫苗产生应答。接着,我们将HBV携带鼠脾脏淋巴细胞中的CD4+T细胞替换为对照鼠的CD4+T细胞,再转输给Rag1-/-,发现对照鼠的CD4+T细胞能辅助HBV携带鼠的获得性免疫系统对HBV疫苗产生免疫应答。这暗示HBV携带鼠免疫耐受状态可能是由于其CD4+T细胞功能缺陷造成的。
肝脏抗原递呈细胞被证明在诱导肝脏免疫耐受过程中起重要作用。HBV携带鼠的非实质细胞转输到Naive鼠中能诱导受者鼠对HBV疫苗低免疫应答,进一步将肝脏非实质细胞分为Kupffer细胞和非Kupffer细胞再分别进行转输,我们发现Kupffer细胞具有很强的诱导受者鼠低免疫应答的能力,这表明Kupffer细胞介导了HBV免疫耐受。不过,检测Kupffer细胞在pAAV/HBV1.2质粒高压注射前后的变化情况,我们发现Kupffer细胞的状态并没有显著改变,这暗示肝脏Kupffer细胞一直处于诱导免疫耐受的状态。
肝脏过表达IL-15诱导产生IFN-β预防HBV免疫耐受
为了研究IL-15对HBV免疫耐受的影响,我们构建了含IL-15基因表达框的pLIVE-IL-15质粒,通过高压注射的方式使pLIVE-IL-15质粒在小鼠体内过表达IL-15。实验结果表明,pLIVE-IL-15质粒高压注射小鼠后能在体内长期表达。若将pLIVE-IL-15质粒或对照质粒pLIVE-EGFP与pAAV/HBV1.2质粒一起注射到小鼠体内,我们发现对照质粒组小鼠血清中长期表达HBsAg和HBeAg,而pLIVE-IL-15质粒注射组血清中低表达HBsAg和HBeAg并且HBV最终会被清除。这表明IL-15能有效预防HBV免疫耐受状态形成。
IL-15是一种多能性细胞因子,对天然免疫系统细胞和获得性免疫系统细胞都具有调节作用。pLIVE-IL-15质粒在Rag1-/-鼠中仍能有效地抑制HBV表达,这表明IL-15发挥抗HBV功能不依赖于获得性免疫系统。尽管脾脏和肝脏NK细胞在IL-15质粒注射后数目有较大提升,但采用PK136抗体清除NK/NKT细胞并不影响IL-15抗HBV功能,采用IL-2Rγc-/-鼠实验也表明IL-15抗HBV能力不依赖于NK细胞。
IFN-γ和IFN-α/β均可以抑制HBV表达。IL-15在IFN-γ缺陷鼠中仍具有抗HBV功能,这表明IL-15抗HBV能力不依赖于IFN-γ。研究发现,肝脏IFN-β mRNA和血清IFN-β蛋白水平在IL-15质粒注射后显著上调,而肝脏IFN-amRNA和血清IFN-α蛋白水平在IL-15质粒注射后变化不明显。进一步采用Anti-IFNAR1抗体阻断IFN-β功能可以完全逆转IL-15的抗HBV作用,这说明IL-15抗HBV功能依赖于IFN-β。Clodronate Lyposomes青除巨噬细胞不会改变IL-15的抗HBV作用,暗示IFN-β并不是由IL-15作用于巨噬细胞产生的。
结论：pAAV/HBV1.2质粒高压注射模型很好地模拟了人类HBV慢性感染状况,可以用于研究HBV感染诱导外周免疫耐受的现象及机理。我们发现HBV免疫耐受状态与CD4+T细胞功能缺陷相关,Kupffer细胞在诱导HBV免疫耐受过程中发挥关键作用。细胞因子IL-15通过诱导产生IFN-β有效预防HBV免疫耐受状态的形成。本研究对于认识肝脏独特的免疫耐受特性,对于理解HBV慢性感染诱导外周免疫耐受的机理及HBV治疗都具有一定意义。
The liver is the largest internal organ in body and plays an important role in maintaining normal metabolism and detoxifying the body. Also, the liver has been recognized as a unique immune organ which favours the induction of immune tolerance rather than immunity, such as oral tolerance, liver transplant tolerance. Some liver pathogens (HBV, HCV, and malaria) can establish persistent/chronic infections in the liver that lead to inflammatory liver disease.
HBV infects the liver as its primary target. The immune system of HBV infected patient has become tolerant to HBV and shows no response to periphery HBV vaccine. Up to now, most in vivo studies on the mechanisms of HBV tolerance have been performed by using HBV transgenic mice; however, HBV transgenic mice are inherently tolerant to HBV virus and are not suitable for studying the mechanisms of HBV tolerance in HBV infected patient who is infected after birth and have limitations in addressing the factors at the onset of infection that influence the final outcomes of chronic HBV infection. Hydrodynamic injection of pAAV/HBV1.2leads to a persistent HBV gene expression in mice, which mimics human chronic HBV infections in the immune tolerant stage. So in the current study, we used this model to study the mechanism of HBV induced immune tolerance and examine the effects of IL-15on immune response to HBV.
In this study, a mouse model for HBV tolerance was established by hydrodynamical injection of pAAV/HBV1.2plasmid into C57BL/6mice. The serum levels of HBsAg、HBeAg and Anti-HBs were measured by radioimmunoassay. Intrahepatic HBcAg expression was determined by immunohistochemistry. Serum HBV DNA was measured by quantitative PCR. In experiments of cell depletion, cell purification and cell transfer, we examined the exact role of specific cell population in HBV immune tolerance. With the aim to investigate the immunomodulatory effects of IL-15in vivo, we constructed a gene transfer vector to endogenously overexpress IL-15in mice. The status of lymphocyte subsets was analyzed with flow cytometer. Serum levels of cytokines were measured by ELISA. Our major findings are shown as follows:
Involvement of Kupffer cells in HBV-induced immuntolerance
Hydrodynamic delivery of the plasmid pAAV/HBV1.2into mouse liver allowed persistent HBV viremia and antigenemia in C57BL/6mice. Secretion of HBsAg and HBeAg into the serum remained high6weeks post pAAV/HBV1.2administration. Both cytoplasmic and nucleic HBcAg were detected in the livers of HBV-carrier mice at6weeks after injection. There were no detectable anti-HBs antibodies in the sera of these animals. The animal model mimics human chronic HBV infections in the immune tolerant stage. If mice were immunized with HBsAg vaccine ahead of tail vein hydrodynamic injection, all HBsAg-vaccinated mice could eliminated HBV virus by decreasing HBsAg and HBeAg in their sera and HBcAg in liver tissues. However, if HBV-carrier mice were immunized with HBsAg vaccine, serum anti-HBs can not be detected in HBV carrier mice and HBsAg vaccine can not cure HBV persistence in HBV carrier mice. Thus, HBV persistence in liver could induce peripheral immune tolerance. Meanwhile, the HBV-carrier mice preserved a strong immune response to other antigen such as OVA, so that peripheral tolerance toward HBsAg was antigen-specifically induced in HBV-carrier mice.
Splenocytes from naive or HBV carrier mice were transferred to ragl-/-mice. After being challenged with HBV vaccine, ragl-/-mice with the immune system of naive mice developed protective levels of anti-HBs, whereas anti-HBs levels were nearly undetectable in ragl-/-mice with the immune system of HBV carrier mice. If we replaced CD4+T cells of splenocytes from HBV carrier mice with CD4+T cells from naive mice and transferred the reconstructive splenocytes to ragl-/-mice and vaccined with HBsAg, we found the reconstructive immune system could response to HBsAg, indicating that the immune tolerant status of HBV carrier mice was associated with the dysfunction of CD4+T cells.
The inherent tolerogenicity of the liver are mediated by tolerogenic antigen-presenting cells. Although phenotype of kupffer cells has no obvious change after pAAV/HBV1.2injection, the mice received NPCs or only KCs from HBV carrier mice secreted obvious low anti-HBs levels after HBsAg immunization, suggesting that kupffer cells are critical in induction of immune tolerance.
Prevention of hepatitis B virus-induced immunotolerance by liver over-expression of interleukin-15via promoting IFN-beta production
With the aim to investigate the immunomodulatory effects of IL-15in vivo, we constructed a gene transfer vector to endogenously overexpress IL-15in mice. We found that hydrodynamic injection of the plasmid pLIVE-IL-15resulted in a sustained concentration of IL-15in serum. Liver IL-15over-expression resulted in great suppression of HBsAg and HBeAg expression early after pAAV/HBV1.2injection and even eliminated HBV virus at five weeks post injection. So, IL-15liver gene transfer induced enhanced immune responses to HBV.
IL-15is a pleiotropic cytokine known to modulate both innate and adaptive immune cells. Over-expression of IL-15similarly decreased HBsAg and HBeAg levels in Ragl-/-mice, suggesting that IL-15exerted anti-HBV activity in a T-cell and B-cell independent manner. Interestingly, despite an increase in NK cell numbers in both spleen and liver of IL-15-expression mice, the anti-HBV effect of IL-15was neither dependent on presence of NK cells in mAb depletion experiment and by using NK-deficient mice (IL-2Rγc-/-).
Type Ⅰ IFNs (IFN-α/β) and IFN-y are known to inhibit HBV gene expression noncytopathically. IL-15inhibits HBV gene expression in IFN-γ-/-mice, suggesting that IFN-y did not play a critical role in IL-15-mediated anti-HBV activity. IL-15treatment increased intrahepatic IFN-β mRNA expression as well as circulating serum IFN-β levels, whereas IFN-a mRNA and protein levels were unchanged. Blockade of IFN-β function led to a significant increase in expression of HBsAg and HBeAg in IL-15treated mice, indicating the anti-HBV activity of IL-15was probably mediated by IFN-β. Depletion of macrophages with clodronate lyposomes did not block the ability of IL-15to inhibit HBV expression in our study, suggesting that IFN-β was not produced by macrophages.
Conclusion:The characteristics of the mouse model for HBV-induced immuntolerance are analogous to those of human chronic HBV infections. The status of HBV induced immuntolerance is associated with dysfunction of CD4+T cells. Kupffer cells play an important role in inducing periphery immune tolerance. Liver over-expression of IL-15prevents HBV-induced immune tolerance in an IFN-β-dependent manner. So, the study on the mechanism of HBV-induced immuntolerance and a novel function of IL-15in anti-HBV immunity might provide an implication in clinical practice.
引文
Ajuwon K M, Jacobi S K, Kuske J L, et al.,2004. Interleukin-6 and interleukin-15 are selectively regulated by lipopolysaccharide and interferon-gamma in primary pig adipocytes. Am J Physiol Regul Integr Comp Physiol.286, R547-53.
Alpdogan O, Eng J M, Muriglan S J, et al.,2005. Interleukin-15 enhances immune reconstitution after allogeneic bone marrow transplantation. Blood.105,865-73.
Alpdogan O, van den Brink M R,2005a. IL-7 and IL-15:therapeutic cytokines for immunodeficiency. Trends Immunol.26,56-64.
Alpdogan O, van den Brink M R,2005b. IL-7 and IL-15:therapeutic cytokines for immunodeficiency. Trends in immunology.26,56-64.
Alves N L, Hooibrink B, Arosa F A, et al.,2003. IL-15 induces antigen-independent expansion and differentiation of human naive CD8+ T cells in vitro. Blood.102,2541-6.
Amicosante M, Poccia F, Gioia C, et al.,2003. Levels of interleukin-15 in plasma may predict a favorable outcome of structured treatment interruption in patients with chronic human immunodeficiency virus infection. J Infect Dis.188,661-5.
Arina A, Murillo O, Dubrot J, et al.,2008. Interleukin-15 liver gene transfer increases the number and function of IKDCs and NK cells. Gene therapy.15,473-83.
Armitage R J, Macduff B M, Eisenman J, et al.,1995a. IL-15 has stimulatory activity for the induction of B cell proliferation and differentiation. J Immunol.154,483-90.
Armitage R J, Macduff B M, Eisenman J, et al.,1995b. IL-15 has stimulatory activity for the induction of B cell proliferation and differentiation. Journal of immunology.154,483-90.
Asabe S, Wieland S F, Chattopadhyay P K, et al.,2009. The size of the viral inoculum contributes to the outcome of hepatitis B virus infection. Journal of virology.83,9652-62.
Bamford R N, Battiata A P, Burton J D, et al.,1996. Interleukin (IL) 15/IL-T production by the adult T-cell leukemia cell line HuT-102 is associated with a human T-cell lymphotrophic virus type Ⅰ region/IL-15 fusion message that lacks many upstream AUGs that normally attenuates IL-15 mRNA translation. Proc Natl Acad Sci U S A.93,2897-902.
Bamford R N, DeFilippis A P, Azimi N, et al.,1998. The 5'untranslated region, signal peptide, and the coding sequence of the carboxyl terminus of IL-15 participate in its multifaceted translational control. J Immunol.160,4418-26.
Becker T C, Wherry E J, Boone D, et al.,2002. Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T cells. J Exp Med.195,1541-8.
Berard M, Brandt K. Bulfone-Paus S, et al.,2003. IL-15 promotes the survival of naive and memory phenotype CD8+T cells. J Immunol.170,5018-26.
Bertolino P, Trescol-Biemont M C, Rabourdin-Combe C,1998. Hepatocytes induce functional activation of naive CD8+ T lymphocytes but fail to promote survival. European Journal of Immunology.28,221-36.
Bertolino P, Bowen D G, McCaughan G W, et al.,2001. Antigen-specific primary activation of CD8+ T cells within the liver. Journal of immunology.166,5430-8.
Bertolino P, McCaughan G W, Bowen D G,2002. Role of primary intrahepatic T-cell activation in the 'liver tolerance effect'. Immunology and cell biology.80,84-92.
Bowen D G, Zen M, Holz L, et al.,2004. The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity. The Journal of clinical investigation. 114,701-12.
Bowen D G, McCaughan G W, Bertolino P,2005. Intrahepatic immunity:a tale of two sites? Trends in immunology.26,512-7.
Brandt K, Bulfone-Paus S, Foster D C, et al.,2003. Interleukin-21 inhibits dendritic cell activation and maturation. Blood.102,4090-8.
Breous E, Somanathan S, Vandenberghe L H, et al.,2009. Hepatic regulatory T cells and Kupffer cells are crucial mediators of systemic T cell tolerance to antigens targeting murine liver. Hepatology.50,612-21.
Budagian V, Bulanova E, Paus R, et al.,2006a. IL-15/IL-15 receptor biology:a guided tour through an expanding universe. Cytokine & Growth Factor Reviews.17,259-80.
Budagian V, Bulanova E, Paus R, et al.,2006b. IL-15/IL-15 receptor biology:a guided tour through an expanding universe. Cytokine Growth Factor Rev.17,259-80.
Bulfone-Paus S, Bulanova E, Pohl T, et al.,1999. Death deflected:IL-15 inhibits TNF-alpha-mediated apoptosis in fibroblasts by TRAF2 recruitment to the IL-15Ralpha chain. FASEB J.13,1575-85.
Burton J D, Bam ford R N, Peters C, et al.,1994. A lymphokine, provisionally designated interleukin T and produced by a human adult T-cell leukemia line, stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. Proceedings of the National Academy of Sciences of the United States of America.91,4935-9.
Callcry M P, Kamei T, Flye M W,1989. Kupffer cell blockade inhibits induction of tolerance by the portal venous route. Transplantation.47,1092-4.
Gallery M P, Mangino M J, Flye M W,1991. Arginine-specific suppression of mixed lymphocyte culture reactivity by Kupffer cells--a basis of portal venous tolerance. Transplantation.51, 1076-80.
Calne R Y, Sells R A, Pena J R, et al.,1969. Induction of immunological tolerance by porcine liver allografts. Nature.223,472-6.
Cantor H M, Dumont A E,1967. Hepatic suppression of sensitization to antigen absorbed into the portal system. Nature.215,744-5.
Cao O, Furlan-Freguia C, Arruda V R, et al.,2007. Emerging role of regulatory T cells in gene transfer. Current gene therapy.7,381-90.
Carson W E, Fehniger T A, Haldar S, et al.,1997. A potential role for interleukin-15 in the regulation of human natural killer cell survival. J Clin Invest.99,937-43.
Cavanaugh V J, Guidotti L G, Chisari F V,1997. Interleukin-12 inhibits hepatitis B virus replication in transgenic mice. Journal of virology.71,3236-43.
Cavanaugh V J, Guidotti L G, Chisari F V,1998. Inhibition of hepatitis B virus replication during adenovirus and cytomegalovirus infections in transgenic mice. Journal of virology.72,2630-7.
Chitnis V, Pahwa R, Pahwa S,2003. Determinants of HIV-specific CD8 T-cell responses in HIV-infected pediatric patients and enhancement of HIV-gag-specific responses with exogenous IL-15. Clin Immunol.107,36-45.
Crispe I N, Dao T, Klugewitz K, et al.,2000. The liver as a site of T-cell apoptosis:graveyard, or killing field? Immunological reviews.174,47-62.
Crispe IN,2003. Hepatic T cells and liver tolerance. Nature reviews. Immunology.3,51-62.
Crispe I N,2009. The liver as a lymphoid organ. Annual review of immunology.27,147-63.
Davies E, Reid S, Medina M F, et al.,2010. IL-15 has innate anti-tumor activity independent of NK and CD8 T cells. Journal of Leukocyte Biology.88,529-36.
De Creus A, Abe M, Lau A H, et al.,2005. Low TLR4 expression by liver dendritic cells correlates with reduced capacity to activate allogeneic T cells in response to endotoxin. Journal of immunology.174,2037-45.
Diehl L, Schurich A, Grochtmann R, et al.,2008. Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance. Hepatology.47, 296-305.
Dobrzynski E, Mingozzi F, Liu Y L, et al.,2004. Induction of antigen-specific CD4+T-cell anergy and deletion by in vivo viral gene transfer. Blood.104,969-77.
Dubois B, Joubert G, Gomez de Aguero M, et al.,2009. Sequential role of plasmacytoid dendritic cells and regulatory T cells in oral tolerance. Gastroenterology.137,1019-28.
Dubois S, Mariner J, Waldmann T A, et al.,2002. IL-15Ralpha recycles and presents IL-15 In trans to neighboring cells. Immunity.17,537-47.
Dubois S P, Waldmann T A, Muller J R,2005. Survival adjustment of mature dendritic cells by IL-15. Proc Natl Acad Sci U S A.102,8662-7.
Fawaz L M, Sharif-Askari E, Menezes J,1999. Up-regulation of NK cytotoxic activity via IL-15 induction by different viruses:a comparative study. Journal of immunology.163,4473-80.
Fehniger T A, Caligiuri M A,2001. Interleukin 15:biology and relevance to human disease. Blood. 97,14-32.
Gill N, Rosenthal K L, Ashkar A A,2005. NK and NKT cell-independent contribution of interleukin-15 to innate protection against mucosal viral infection. Journal of virology.79, 4470-8.
Giri J G, Ahdieh M, Eisenman J, et al.,1994. Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J.13,2822-30.
Giri J G, Kumaki S, Ahdieh M, et al.,1995. Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor. EMBO J.14,3654-63.
Goddard S, Youster J, Morgan E, et al.,2004. Interleukin-10 secretion differentiates dendritic cells from human liver and skin. The American journal of pathology.164,511-9.
Golden-Mason L, Kelly A M, Doherty D Q et al.,2004. Hepatic interleuklin 15 (IL-15) expression:implications for local NK/NKT cell homeostasis and development. Clinical and experimental immunology.138,94-101.
Gorczynski R M, Chan Z, Chung S, et al.,1994. Prolongation of rat small bowel or renal allograft survival by pretransplant transfusion and/or by varying the route of allograft venous drainage. Transplantation.58,816-20.
Gosselin J, TomoIu A, Gallo R C, et al.,1999. Interleukin-15 as an activator of natural killer cell-mediated antiviral response. Blood.94,4210-9.
Goubier A, Dubois B, Gheit H, et al.,2008. Plasmacytoid dendritic cells mediate oral tolerance. Immunity.29,464-75.
Grabstein K H, Eisenman J, Shanebeck K, et al.,1994. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science.264,965-8.
Guidotti L G, Matzke B, Schaller H, et al.,1995. High-level hepatitis B virus replication in transgenic mice. Journal of virology.69,6158-69.
Guidotti L G, Chisari F V,2006. Immunobiology and pathogenesis of viral hepatitis. Annual review of pathology.Ⅰ,23-61.
Herkel J, Jagemann B, Wiegard C, et al.,2003. MHC class II-expressing hepatocytes function as antigen-presenting cells and activate specific CD4 T lymphocyutes. Hepatology.37,1079-85.
Huang L, Sye K, Crispe I N,1994. Proliferation and apoptosis of B220+CD4-CD8-TCR alpha beta intermediate T cells in the liver of normal adult mice:implication for lpr pathogenesis. International immunology.6,533-40.
Huang L R, Wu H L, Chen P J, et al.,2006. An immunocompetent mouse model for the tolerance of human chronic hepatitis B virus infection. Proceedings of the National Academy of Sciences of the United States of America.103,17862-7.
Isogawa M, Furuichi Y, Chisari F V,2005a. Oscillating CD8(+) T cell effector functions after antigen recognition in the liver. Immunity.23,53-63.
Isogawa M, Robek M D, Furuichi Y, et al.,2005b. Toll-like receptor signaling inhibits hepatitis B virus replication in vivo. Journal of virology.79,7269-72.
Jalah R, Rosati M, Kulkarni V, et al.,2007. Efficient systemic expression of bioactive IL-15 in mice upon delivery of optimized DNA expression plasmids. DNA and cell biology.26,827-40.
Jewell S D, Gienapp I E, Cox K L, et al.,1998. Oral tolerance as therapy for experimental autoimmune encephalomyelitis and multiple sclerosis:demonstration of T cell anergy. Immunology and cell biology.76,74-82.
Jinushi M, Takehara T, Tatsumi T, et al.,2003. Autocrine/paracrine IL-15 that is required for type I IFN-mediated dendritic cell expression of MHC class I-related chain A and B is impaired in hepatitis C virus infection. J Immunol.171,5423-9.
Ju C, McCoy J P, Chung C J, et al.,2003. Tolerogenic role of Kupffer cells in allergic reactions. Chemical research in toxicology.16,1514-9.
Kacani L, Sprinzl G M, Erdei A, et al.,1999. Interleukin-15 enhances HIV-1-driven polyclonal B-cell response in vitro. Exp Clin Immunogenet.16,162-72.
Kakimi K, Guidotti L G, Koezuka Y, et al.,2000. Natural killer T cell activation inhibits hepatitis B virus replication in vivo. The Journal of experimental medicine.192,921-30.
Katsanis E, Xu Z, Panoskaltsis-Mortari A, et al.,1996. IL-15 administration following syngeneic bone marrow transplantation prolongs survival of lymphoma bearing mice. Transplantation.62, 872-5.
Kennedy M K, Glaccum M, Brown S N, et al.,2000. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J Exp Med.191,771-80.
Kimura K, Kakimi K, Wieland S, et al.,2002. Interleukin-18 inhibits hepatitis B virus replication in the livers of transgenic mice. Journal of virology.76,10702-7.
Kingham T P, Chaudhry U I, Plitas G, et al.,2007. Murine liver plasmacytoid dendritic cells become potent immunostimulatory cells after Flt-3 ligand expansion. Hepatology.45,445-54.
Klebanoff C A, Finkelstein S E, Surman D R, et al.,2004. IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+T cells. Proc Natl Acad Sci U S A.101,1969-74.
Knolle P, Schlaak J, Uhrig A, et al.,1995. Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge. Journal of hepatology.22,226-9.
Knolle P A, Uhrig A, Hegenbarth S, et al.,1998. IL-10 down-regulates T cell activation by antigen-presenting liver sinusoidal endothelial cells through decreased antigen uptake via the mannose receptor and lowered surface expression of accessory molecules. Clinical and experimental immunology.114,427-33.
Knolle P A, Limmer A,2001. Neighborhood politics:the immunoregulatory function of organ-resident liver endothelial cells. Trends in immunology.22,432-7.
Kumar M, Jung S Y, Hodgson A J, et al.,2011. Hepatitis B virus regulatory HBx protein binds to adaptor protein IPS-1 and inhibits the activation of beta interferon. Journal of virology.85, 987-95.
Larkin J, Clayton M, Sun B, et al.,1999. Hepatitis B virus transgenic mouse model of chronic liver disease. Nature medicine.5,907-12.
Li W, Carper K, Liang Y, et al.,2006. Anti-CD25 mAb administration prevents spontaneous liver transplant tolerance. Transplantation Proceedings.38,3207-8.
Limmer A, Ohl J, Kurts C, et al.,2000. Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance. Nature medicine.6, 1348-54.
Limmer A, Ohl J, Wingendcr G, et al.,2005. Cross-presentation of oral antigens by liver sinusoidal endothelial cells leads to CD8 T cell tolerance. European Journal of Immunology.35, 2970-81.
Liu G, Zhai Q, Schaffner D, et al.,2004. IL-15 induces IFN-beta and iNOS gene expression, and antiviral activity of murine macrophage RAW 264.7 cells. Immunology Letters.91,171-8.
Lodolce J P, Boone D L, Chai S, et al.,1998. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity.9,669-76.
Lodolce J P, Burkett P R, Boone D L, et al.,2001. T cell-independent interleukin 15Ralpha signals are required for bystander proliferation. J Exp Med.194,1187-94.
Ma A, Koka R, Burkett P,2006. Diverse functions of IL-2, IL-15, and IL-7 in lymphoid homeostasis. Annual review of immunology.24,657-79.
Mackay C R, Marston W L, Dudler L,1990. Naive and memory T cells show distinct pathways of lymphocyte recirculation. The Journal of experimental medicine.171,801-17.
Marks-Konczalik J, Dubois S, Losi J M, et al.,2000. IL-2-induced activation-induced cell death is inhibited in IL-15 transgenic mice. Proc Natl Acad Sci U S A.97,11445-50.
Mastroianni C M, d'Ettorre G, Forcina G, et al.,2004. Teaching tired T cells to fight HIV:time to test IL-15 for immunotherapy? Trends Immunol.25,121-5.
Matsuda J L, Gapin L, Sidobre S, et al.,2002. Homeostasis of V alpha 14i NKT cells. Nat Immunol.3,966-74.
Mattei F, Schiavoni G, Belardelli F, et al.,2001. IL-15 is expressed by dendritic cells in response to type I IFN, double-stranded RNA, or lipopolysaccharide and promotes dendritic cell activation. J Immunol.167,1179-87.
McClary H, Koch R, Chisari F V, et al.,2000. Inhibition of hepatitis B virus replication during schistosoma mansoni infection in transgenic mice. The Journal of experimental medicine.192, 289-94.
Mehal W Z, Juedes A E, Crispe I N,1999. Selective retention of activated CD8+T cells by the normal liver. Journal of immunology.163,3202-10.
Michel M L, Deng Q, Mancini-Bourgine M,2011. Therapeutic vaccines and immune-based therapies for the treatment of chronic hepatitis B:perspectives and challenges. Journal of hepatology.54,1286-96.
Mingozzi F, Liu Y L, Dobrzynski E, et al.,2003. Induction of immune tolerance to coagulation factor IX antigen by in vivo hepatic gene transfer. The Journal of clinical investigation. 111, 1347-56.
Miyagawa-Hayashino A, Tsuruyama T, Egawa H, et al.,2007. FasL expression in hepatic antigen-presenting cells and phagocytosis of apoptotic T cells by FasL+Kupffer cells are indicators of rejection activity in human liver allografts. The American journal of pathology.171, 1499-508.
Monbaliu D, van Pelt J, De Vos R, et al.,2007. Primary graft nonfunction and Kupffer cell activation after liver transplantation from non-heart-beating donors in pigs. Liver transplantation:official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.13,239-47.
Mueller Y M, Bojczuk P M, Halstead E S, et al.,2003. IL-15 enhances survival and function of HIV-specific CD8+T cells. Blood.101,1024-9.
Munger W, DeJoy S Q, Jeyaseelan R, Sr., et al.,1995. Studies evaluating the antitumor activity and toxicity of interleukin-15, a new T cell growth factor:comparison with interleukin-2. Cell Immunol.165,289-93.
Nilsen E M, Johansen F E, Jahnsen F L, et al.,1998. Cytokine profiles of cultured microvascular endothelial cells from the human intestine. Gut.42,635-42.
Ohteki T, Suzue K, Maki C, et al.,2001. Critical role of IL-15-IL-15R for antigen-presenting cell functions in the innate immune response. Nat Immunol.2,1138-43.
Onu A, Pohl T, Krause H, et al.,1997. Regulation of IL-15 secretion via the leader peptide of two IL-15 isoforms. J Immunol.158,255-62.
Ortaldo J R, Winkler-Pickett R T, Bere E W, Jr., et al.,2005. In vivo hydrodynamic delivery of cDNA encoding IL-2:rapid, sustained redistribution, activation of mouse NK cells, and therapeutic potential in the absence of NKT cells. Journal of immunology.175,693-9.
Paik Y H, Lee K S, Lee H J, et al.,2006. Hepatic stellate cells primed with cytokines upregulate inflammation in response to peptidoglycan or lipoteichoic acid. Laboratory investigation; a journal of technical methods and pathology.86,676-86.
Park C S, Yoon S O, Armitage R J, et al.,2004. Follicular dendritic cells produce IL-15 that enhances germinal center B cell proliferation in membrane-bound form. J Immunol.173, 6676-83.
Pasquetto V, Guidotti L G, Kakimi K, et al.,2000. Host-virus interactions during malaria infection in hepatitis B virus transgenic mice. The Journal of experimental medicine.192,529-36.
Peppa D, Micco L, Javaid A, et al.,2010. Blockade of immunosuppressive cytokines restores NK cell antiviral function in chronic hepatitis B virus infection. PLoS pathogens.6, e1001227.
Pereno R, Giron-Michel J, Gaggero A, et al.,2000. IL-15/IL-15Ralpha intracellular trafficking in human melanoma cells and signal transduction through the IL-15Ralpha. Oncogene.19, 5153-62.
Pillarisetty V G, Katz S C, Bleier J I, et al.,2005. Natural killer dendritic cells have both antigen presenting and lytic function and in response to CpG produce IFN-gamma via autocrine IL-12. Journal of immunology.174,2612-8.
Prlic M, Blazar B R, Farrar M A, et al.,2003. In vivo survival and homeostatic proliferation of natural killer cells. J Exp Med.197,967-76.
Pulendran B, Dillon S, Joseph C, et al.,2004. Dendritic cells generated in the presence of GM-CSF plus IL-15 prime potent CD8+Tcl responses in vivo. Eur J Immunol.34,66-73.
Rehermann B, Nascimbeni M,2005. Immunology of hepatitis B virus and hepatitis C virus infection. Nature reviews. Immunology.5,215-29.
Rodrigues L, Bonorino C,2009. Role of IL-15 and IL-21 in viral immunity:applications for vaccines and therapies. Expert review of vaccines.8,167-77.
Rubinstein M P, Kadima A N, Salem M L, et al.,2002. Systemic administration of IL-15 augments the antigen-specific primary CD8+T cell response following vaccination with peptide-pulsed dendritic cells. J Immunol.169,4928-35.
Sato K, Yabuki K, Haba T, et al.,1996. Role of Kupffer cells in the induction of tolerance after liver transplantation. The Journal of surgical research.63,433-8.
Schluns K S, Williams K, Ma A, et al.,2002. Cutting edge:requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J Immunol.168,4827-31.
Shortman K, Villadangos J A,2006. Is it a DC, is it an NK? No, it's an IKDC. Nature medicine.12, 167-8.
Silva W A, Jr., Covas D T, Panepucci R A, et al.,2003. The profile of gene expression of human marrow mesenchymal stem cells. Stem Cells.21,661-9.
Stevens A C, Matthews J, Andres P, et al.,1997. Interleukin-15 signals T84 colonic epithelial cells in the absence of the interleukin-2 receptor beta-chain. Am J Physiol.272, G1201-8.
Sun J, Dirden-Kramer B, Ito K, et al.,1999. Antigen-specific T cell activation and proliferation during oral tolerance induction. Journal of immunology.162,5868-75.
Suzuki A, McCall S, Choi S S, et al.,2006. Interleukin-15 increases hepatic regenerative activity. Journal of hepatology.45,410-8.
Thatte A, Dewitte-Orr S J, Lichty B, et al.,2011. A critical role for IL-15 in TLR-mediated innate antiviral immunity against genital HSV-2 infection. Immunology and cell biology.89,663-9.
Thomson A W, Lu L,1999. Are dendritic cells the key to liver transplant tolerance? Immunology today.20,27-32.
Thomson A W, Knolle P A,2010. Antigen-presenting cell function in the tolerogenic liver environment. Nature reviews. Immunology.10,753-66.
Tinhofer I, Marschitz I, Henn T, et al.,2000. Expression of functional interleukin-15 receptor and autocrine production of interleukin-15 as mechanisms of tumor propagation in multiple myeloma. Blood.95,610-8.
Tjwa E T, van Oord G W, Hegmans J P, et al.,2011. Viral load reduction improves activation and function of natural killer cells in patients with chronic hepatitis B. Journal of hepatology.54, 209-18.
Tokita D, Sumpter T L, Raimondi G, et al.,2008. Poor allostimulatory function of liver plasmacytoid DC is associated with pro-apoptotic activity, dependent on regulatory T cells. Journal of hepatology.49,1008-18.
van Oosten M, van de Bilt E, de Vries H E, et al.,1995. Vascular adhesion molecule-1 and intercellular adhesion molecule-1 expression on rat liver cells after lipopolysaccharide administration in vivo. Hepatology.22,1538-46.
Vergani D, Mieli-Vergani G,2004. Autoimmune hepatitis. Minerva gastroenterologica e dietologica.50,113-23.
Vinas O, Bataller R, Sancho-Bru P, et al.,2003. Human hepatic stellate cells show features of antigen-presenting cells and stimulate lymphocyte proliferation. Hepatology.38,919-29.
Waldmann T A,2006a. The biology of interleukin-2 and interleukin-15:implications for cancer therapy and vaccine design. Nature reviews. Immunology.6,595-601.
Waldmann T A,2006b. The biology of interleukin-2 and interleukin-15:implications for cancer therapy and vaccine design. Nat Rev Immunol.6,595-601.
Wang H, Ryu W S,2010. Hepatitis B virus polymerase blocks pattern recognition receptor signaling via interaction with DDX3:implications for immune evasion. PLoS pathogens.6, e1000986.
Warren A, Le Couteur D G, Fraser R, et al.,2006. T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells. Hepatology.44,1182-90.
Wei C, Ni C, Song T, et al.,2010. The hepatitis B virus X protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein. Journal of immunology.185,1158-68.
Wieland S, Thimme R, Purcell R H, et al.,2004. Genomic analysis of the host response to hepatitis B virus infection. Proceedings of the National Academy of Sciences of the United States of America.101,6669-74.
Wieland S F, Guidotti L G, Chisari F V,2000. Intrahepatic induction of alpha/beta interferon eliminates viral RNA-containing capsids in hepatitis B virus transgenic mice. Journal of virology.74,4165-73.
Wieland S F, Eustaquio A, Whitten-Bauer C, et al.,2005. Interferon prevents formation of replication-competent hepatitis B virus RNA-containing nucleocapsids. Proceedings of the National Academy of Sciences of the United States of America.102,9913-7.
Willerford D M, Chen J, Ferry J A, et al.,1995. Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity.3,521-30.
Winau F, Hegasy G, Weiskirchen R, et al.,2007. Ito cells are liver-resident antigen-presenting cells for activating T cell responses. Immunity.26,117-29.
Wuensch S A, Pierce R H, Crispe I N,2006. Local intrahepatic CD8+ T cell activation by a non-self-antigen results in full functional differentiation. Journal of immunology.177,1689-97.
Yajima T, Nishimura H, Wajjwalku W, et al.,2002. Overexpression of interleukin-15 in vivo enhances antitumor activity against MHC class I-negative and -positive malignant melanoma through augmented NK activity and cytotoxic T-cell response. Int J Cancer.99,573-8.
You Q, Cheng L, Kedl R M, et al.,2008. Mechanism of T cell tolerance induction by murine hepatic Kupffer cells. Hepatology.48,978-90.
Zhang X, Sun S, Hwang I, et al.,1998. Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15. Immunity.8,591-9.
Alpdogan O, Eng J M, Muriglan S J, et al.,2005. Interleukin-15 enhances immune reconstitution after allogeneic bone marrow transplantation. Blood.105,865-73.
Alpdogan O, van den Brink M R,2005a. IL-7 and IL-15:therapeutic cytokines for immunodeficiency. Trends Immunol.26,56-64.
Alpdogan O, van den Brink M R,2005b. IL-7 and IL-15:therapeutic cytokines for immunodeficiency. Trends in immunology.26,56-64.
Alves N L, Hooibrink B, Arosa F A, et al.,2003. IL-15 induces antigen-independent expansion and differentiation of human naive CD8+ T cells in vitro. Blood.102,2541-6.
Amicosante M, Poccia F, Gioia C, et al.,2003. Levels of interleukin-15 in plasma may predict a favorable outcome of structured treatment interruption in patients with chronic human immunodeficiency virus infection. J Infect Dis.188,661-5.
Arina A, Murillo O, Dubrot J, et al.,2008. Interleukin-15 liver gene transfer increases the number and function of IKDCs and NK cells. Gene therapy.15,473-83.
Armitage R J, Macduff B M, Eisenman J, et al.,1995a. IL-15 has stimulatory activity for the induction of B cell proliferation and differentiation. J Immunol.154,483-90.
Armitage R J, Macduff B M, Eisenman J, et al.,1995b. IL-15 has stimulatory activity for the induction of B cell proliferation and differentiation. Journal of immunology.154,483-90.
Asabe S, Wieland S F, Chattopadhyay P K, et al.,2009. The size of the viral inoculum contributes to the outcome of hepatitis B virus infection. Journal of virology.83,9652-62.
Bamford R N, Battiata A P, Burton J D, et al.,1996. Interleukin (IL) 15/IL-T production by the adult T-cell leukemia cell line HuT-102 is associated with a human T-cell lymphotrophic virus type Ⅰ region/IL-15 fusion message that lacks many upstream AUGs that normally attenuates IL-15 mRNA translation. Proc Natl Acad Sci U S A.93,2897-902.
Bamford R N, DeFilippis A P, Azimi N, et al.,1998. The 5'untranslated region, signal peptide, and the coding sequence of the carboxyl terminus of IL-15 participate in its multifaceted translational control. J Immunol.160,4418-26.
Becker T C, Wherry E J, Boone D, et al.,2002. Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T cells. J Exp Med.195,1541-8.
Berard M, Brandt K. Bulfone-Paus S, et al.,2003. IL-15 promotes the survival of naive and memory phenotype CD8+T cells. J Immunol.170,5018-26.
Bertolino P, Trescol-Biemont M C, Rabourdin-Combe C,1998. Hepatocytes induce functional activation of naive CD8+ T lymphocytes but fail to promote survival. European Journal of Immunology.28,221-36.
Bertolino P, Bowen D G, McCaughan G W, et al.,2001. Antigen-specific primary activation of CD8+ T cells within the liver. Journal of immunology.166,5430-8.
Bertolino P, McCaughan G W, Bowen D G,2002. Role of primary intrahepatic T-cell activation in the 'liver tolerance effect'. Immunology and cell biology.80,84-92.
Bowen D G, Zen M, Holz L, et al.,2004. The site of primary T cell activation is a determinant of the balance between intrahepatic tolerance and immunity. The Journal of clinical investigation. 114,701-12.
Bowen D G, McCaughan G W, Bertolino P,2005. Intrahepatic immunity:a tale of two sites? Trends in immunology.26,512-7.
Brandt K, Bulfone-Paus S, Foster D C, et al.,2003. Interleukin-21 inhibits dendritic cell activation and maturation. Blood.102,4090-8.
Breous E, Somanathan S, Vandenberghe L H, et al.,2009. Hepatic regulatory T cells and Kupffer cells are crucial mediators of systemic T cell tolerance to antigens targeting murine liver. Hepatology.50,612-21.
Budagian V, Bulanova E, Paus R, et al.,2006a. IL-15/IL-15 receptor biology:a guided tour through an expanding universe. Cytokine & Growth Factor Reviews.17,259-80.
Budagian V, Bulanova E, Paus R, et al.,2006b. IL-15/IL-15 receptor biology:a guided tour through an expanding universe. Cytokine Growth Factor Rev.17,259-80.
Bulfone-Paus S, Bulanova E, Pohl T, et al.,1999. Death deflected:IL-15 inhibits TNF-alpha-mediated apoptosis in fibroblasts by TRAF2 recruitment to the IL-15Ralpha chain. FASEB J.13,1575-85.
Burton J D, Bam ford R N, Peters C, et al.,1994. A lymphokine, provisionally designated interleukin T and produced by a human adult T-cell leukemia line, stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. Proceedings of the National Academy of Sciences of the United States of America.91,4935-9.
Callcry M P, Kamei T, Flye M W,1989. Kupffer cell blockade inhibits induction of tolerance by the portal venous route. Transplantation.47,1092-4.
Gallery M P, Mangino M J, Flye M W,1991. Arginine-specific suppression of mixed lymphocyte culture reactivity by Kupffer cells--a basis of portal venous tolerance. Transplantation.51, 1076-80.
Calne R Y, Sells R A, Pena J R, et al.,1969. Induction of immunological tolerance by porcine liver allografts. Nature.223,472-6.
Cantor H M, Dumont A E,1967. Hepatic suppression of sensitization to antigen absorbed into the portal system. Nature.215,744-5.
Cao O, Furlan-Freguia C, Arruda V R, et al.,2007. Emerging role of regulatory T cells in gene transfer. Current gene therapy.7,381-90.
Carson W E, Fehniger T A, Haldar S, et al.,1997. A potential role for interleukin-15 in the regulation of human natural killer cell survival. J Clin Invest.99,937-43.
Cavanaugh V J, Guidotti L G, Chisari F V,1997. Interleukin-12 inhibits hepatitis B virus replication in transgenic mice. Journal of virology.71,3236-43.
Cavanaugh V J, Guidotti L G, Chisari F V,1998. Inhibition of hepatitis B virus replication during adenovirus and cytomegalovirus infections in transgenic mice. Journal of virology.72,2630-7.
Chitnis V, Pahwa R, Pahwa S,2003. Determinants of HIV-specific CD8 T-cell responses in HIV-infected pediatric patients and enhancement of HIV-gag-specific responses with exogenous IL-15. Clin Immunol.107,36-45.
Crispe I N, Dao T, Klugewitz K, et al.,2000. The liver as a site of T-cell apoptosis:graveyard, or killing field? Immunological reviews.174,47-62.
Crispe IN,2003. Hepatic T cells and liver tolerance. Nature reviews. Immunology.3,51-62.
Crispe I N,2009. The liver as a lymphoid organ. Annual review of immunology.27,147-63.
Davies E, Reid S, Medina M F, et al.,2010. IL-15 has innate anti-tumor activity independent of NK and CD8 T cells. Journal of Leukocyte Biology.88,529-36.
De Creus A, Abe M, Lau A H, et al.,2005. Low TLR4 expression by liver dendritic cells correlates with reduced capacity to activate allogeneic T cells in response to endotoxin. Journal of immunology.174,2037-45.
Diehl L, Schurich A, Grochtmann R, et al.,2008. Tolerogenic maturation of liver sinusoidal endothelial cells promotes B7-homolog 1-dependent CD8+ T cell tolerance. Hepatology.47, 296-305.
Dobrzynski E, Mingozzi F, Liu Y L, et al.,2004. Induction of antigen-specific CD4+T-cell anergy and deletion by in vivo viral gene transfer. Blood.104,969-77.
Dubois B, Joubert G, Gomez de Aguero M, et al.,2009. Sequential role of plasmacytoid dendritic cells and regulatory T cells in oral tolerance. Gastroenterology.137,1019-28.
Dubois S, Mariner J, Waldmann T A, et al.,2002. IL-15Ralpha recycles and presents IL-15 In trans to neighboring cells. Immunity.17,537-47.
Dubois S P, Waldmann T A, Muller J R,2005. Survival adjustment of mature dendritic cells by IL-15. Proc Natl Acad Sci U S A.102,8662-7.
Fawaz L M, Sharif-Askari E, Menezes J,1999. Up-regulation of NK cytotoxic activity via IL-15 induction by different viruses:a comparative study. Journal of immunology.163,4473-80.
Fehniger T A, Caligiuri M A,2001. Interleukin 15:biology and relevance to human disease. Blood. 97,14-32.
Gill N, Rosenthal K L, Ashkar A A,2005. NK and NKT cell-independent contribution of interleukin-15 to innate protection against mucosal viral infection. Journal of virology.79, 4470-8.
Giri J G, Ahdieh M, Eisenman J, et al.,1994. Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J.13,2822-30.
Giri J G, Kumaki S, Ahdieh M, et al.,1995. Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor. EMBO J.14,3654-63.
Goddard S, Youster J, Morgan E, et al.,2004. Interleukin-10 secretion differentiates dendritic cells from human liver and skin. The American journal of pathology.164,511-9.
Golden-Mason L, Kelly A M, Doherty D Q et al.,2004. Hepatic interleuklin 15 (IL-15) expression:implications for local NK/NKT cell homeostasis and development. Clinical and experimental immunology.138,94-101.
Gorczynski R M, Chan Z, Chung S, et al.,1994. Prolongation of rat small bowel or renal allograft survival by pretransplant transfusion and/or by varying the route of allograft venous drainage. Transplantation.58,816-20.
Gosselin J, TomoIu A, Gallo R C, et al.,1999. Interleukin-15 as an activator of natural killer cell-mediated antiviral response. Blood.94,4210-9.
Goubier A, Dubois B, Gheit H, et al.,2008. Plasmacytoid dendritic cells mediate oral tolerance. Immunity.29,464-75.
Grabstein K H, Eisenman J, Shanebeck K, et al.,1994. Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science.264,965-8.
Guidotti L G, Matzke B, Schaller H, et al.,1995. High-level hepatitis B virus replication in transgenic mice. Journal of virology.69,6158-69.
Guidotti L G, Chisari F V,2006. Immunobiology and pathogenesis of viral hepatitis. Annual review of pathology.Ⅰ,23-61.
Herkel J, Jagemann B, Wiegard C, et al.,2003. MHC class II-expressing hepatocytes function as antigen-presenting cells and activate specific CD4 T lymphocyutes. Hepatology.37,1079-85.
Huang L, Sye K, Crispe I N,1994. Proliferation and apoptosis of B220+CD4-CD8-TCR alpha beta intermediate T cells in the liver of normal adult mice:implication for lpr pathogenesis. International immunology.6,533-40.
Huang L R, Wu H L, Chen P J, et al.,2006. An immunocompetent mouse model for the tolerance of human chronic hepatitis B virus infection. Proceedings of the National Academy of Sciences of the United States of America.103,17862-7.
Isogawa M, Furuichi Y, Chisari F V,2005a. Oscillating CD8(+) T cell effector functions after antigen recognition in the liver. Immunity.23,53-63.
Isogawa M, Robek M D, Furuichi Y, et al.,2005b. Toll-like receptor signaling inhibits hepatitis B virus replication in vivo. Journal of virology.79,7269-72.
Jalah R, Rosati M, Kulkarni V, et al.,2007. Efficient systemic expression of bioactive IL-15 in mice upon delivery of optimized DNA expression plasmids. DNA and cell biology.26,827-40.
Jewell S D, Gienapp I E, Cox K L, et al.,1998. Oral tolerance as therapy for experimental autoimmune encephalomyelitis and multiple sclerosis:demonstration of T cell anergy. Immunology and cell biology.76,74-82.
Jinushi M, Takehara T, Tatsumi T, et al.,2003. Autocrine/paracrine IL-15 that is required for type I IFN-mediated dendritic cell expression of MHC class I-related chain A and B is impaired in hepatitis C virus infection. J Immunol.171,5423-9.
Ju C, McCoy J P, Chung C J, et al.,2003. Tolerogenic role of Kupffer cells in allergic reactions. Chemical research in toxicology.16,1514-9.
Kacani L, Sprinzl G M, Erdei A, et al.,1999. Interleukin-15 enhances HIV-1-driven polyclonal B-cell response in vitro. Exp Clin Immunogenet.16,162-72.
Kakimi K, Guidotti L G, Koezuka Y, et al.,2000. Natural killer T cell activation inhibits hepatitis B virus replication in vivo. The Journal of experimental medicine.192,921-30.
Katsanis E, Xu Z, Panoskaltsis-Mortari A, et al.,1996. IL-15 administration following syngeneic bone marrow transplantation prolongs survival of lymphoma bearing mice. Transplantation.62, 872-5.
Kennedy M K, Glaccum M, Brown S N, et al.,2000. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J Exp Med.191,771-80.
Kimura K, Kakimi K, Wieland S, et al.,2002. Interleukin-18 inhibits hepatitis B virus replication in the livers of transgenic mice. Journal of virology.76,10702-7.
Kingham T P, Chaudhry U I, Plitas G, et al.,2007. Murine liver plasmacytoid dendritic cells become potent immunostimulatory cells after Flt-3 ligand expansion. Hepatology.45,445-54.
Klebanoff C A, Finkelstein S E, Surman D R, et al.,2004. IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+T cells. Proc Natl Acad Sci U S A.101,1969-74.
Knolle P, Schlaak J, Uhrig A, et al.,1995. Human Kupffer cells secrete IL-10 in response to lipopolysaccharide (LPS) challenge. Journal of hepatology.22,226-9.
Knolle P A, Uhrig A, Hegenbarth S, et al.,1998. IL-10 down-regulates T cell activation by antigen-presenting liver sinusoidal endothelial cells through decreased antigen uptake via the mannose receptor and lowered surface expression of accessory molecules. Clinical and experimental immunology.114,427-33.
Knolle P A, Limmer A,2001. Neighborhood politics:the immunoregulatory function of organ-resident liver endothelial cells. Trends in immunology.22,432-7.
Kumar M, Jung S Y, Hodgson A J, et al.,2011. Hepatitis B virus regulatory HBx protein binds to adaptor protein IPS-1 and inhibits the activation of beta interferon. Journal of virology.85, 987-95.
Larkin J, Clayton M, Sun B, et al.,1999. Hepatitis B virus transgenic mouse model of chronic liver disease. Nature medicine.5,907-12.
Li W, Carper K, Liang Y, et al.,2006. Anti-CD25 mAb administration prevents spontaneous liver transplant tolerance. Transplantation Proceedings.38,3207-8.
Limmer A, Ohl J, Kurts C, et al.,2000. Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance. Nature medicine.6, 1348-54.
Limmer A, Ohl J, Wingendcr G, et al.,2005. Cross-presentation of oral antigens by liver sinusoidal endothelial cells leads to CD8 T cell tolerance. European Journal of Immunology.35, 2970-81.
Liu G, Zhai Q, Schaffner D, et al.,2004. IL-15 induces IFN-beta and iNOS gene expression, and antiviral activity of murine macrophage RAW 264.7 cells. Immunology Letters.91,171-8.
Lodolce J P, Boone D L, Chai S, et al.,1998. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity.9,669-76.
Lodolce J P, Burkett P R, Boone D L, et al.,2001. T cell-independent interleukin 15Ralpha signals are required for bystander proliferation. J Exp Med.194,1187-94.
Ma A, Koka R, Burkett P,2006. Diverse functions of IL-2, IL-15, and IL-7 in lymphoid homeostasis. Annual review of immunology.24,657-79.
Mackay C R, Marston W L, Dudler L,1990. Naive and memory T cells show distinct pathways of lymphocyte recirculation. The Journal of experimental medicine.171,801-17.
Marks-Konczalik J, Dubois S, Losi J M, et al.,2000. IL-2-induced activation-induced cell death is inhibited in IL-15 transgenic mice. Proc Natl Acad Sci U S A.97,11445-50.
Mastroianni C M, d'Ettorre G, Forcina G, et al.,2004. Teaching tired T cells to fight HIV:time to test IL-15 for immunotherapy? Trends Immunol.25,121-5.
Matsuda J L, Gapin L, Sidobre S, et al.,2002. Homeostasis of V alpha 14i NKT cells. Nat Immunol.3,966-74.
Mattei F, Schiavoni G, Belardelli F, et al.,2001. IL-15 is expressed by dendritic cells in response to type I IFN, double-stranded RNA, or lipopolysaccharide and promotes dendritic cell activation. J Immunol.167,1179-87.
McClary H, Koch R, Chisari F V, et al.,2000. Inhibition of hepatitis B virus replication during schistosoma mansoni infection in transgenic mice. The Journal of experimental medicine.192, 289-94.
Mehal W Z, Juedes A E, Crispe I N,1999. Selective retention of activated CD8+T cells by the normal liver. Journal of immunology.163,3202-10.
Michel M L, Deng Q, Mancini-Bourgine M,2011. Therapeutic vaccines and immune-based therapies for the treatment of chronic hepatitis B:perspectives and challenges. Journal of hepatology.54,1286-96.
Mingozzi F, Liu Y L, Dobrzynski E, et al.,2003. Induction of immune tolerance to coagulation factor IX antigen by in vivo hepatic gene transfer. The Journal of clinical investigation. 111, 1347-56.
Miyagawa-Hayashino A, Tsuruyama T, Egawa H, et al.,2007. FasL expression in hepatic antigen-presenting cells and phagocytosis of apoptotic T cells by FasL+Kupffer cells are indicators of rejection activity in human liver allografts. The American journal of pathology.171, 1499-508.
Monbaliu D, van Pelt J, De Vos R, et al.,2007. Primary graft nonfunction and Kupffer cell activation after liver transplantation from non-heart-beating donors in pigs. Liver transplantation:official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.13,239-47.
Mueller Y M, Bojczuk P M, Halstead E S, et al.,2003. IL-15 enhances survival and function of HIV-specific CD8+T cells. Blood.101,1024-9.
Munger W, DeJoy S Q, Jeyaseelan R, Sr., et al.,1995. Studies evaluating the antitumor activity and toxicity of interleukin-15, a new T cell growth factor:comparison with interleukin-2. Cell Immunol.165,289-93.
Nilsen E M, Johansen F E, Jahnsen F L, et al.,1998. Cytokine profiles of cultured microvascular endothelial cells from the human intestine. Gut.42,635-42.
Ohteki T, Suzue K, Maki C, et al.,2001. Critical role of IL-15-IL-15R for antigen-presenting cell functions in the innate immune response. Nat Immunol.2,1138-43.
Onu A, Pohl T, Krause H, et al.,1997. Regulation of IL-15 secretion via the leader peptide of two IL-15 isoforms. J Immunol.158,255-62.
Ortaldo J R, Winkler-Pickett R T, Bere E W, Jr., et al.,2005. In vivo hydrodynamic delivery of cDNA encoding IL-2:rapid, sustained redistribution, activation of mouse NK cells, and therapeutic potential in the absence of NKT cells. Journal of immunology.175,693-9.
Paik Y H, Lee K S, Lee H J, et al.,2006. Hepatic stellate cells primed with cytokines upregulate inflammation in response to peptidoglycan or lipoteichoic acid. Laboratory investigation; a journal of technical methods and pathology.86,676-86.
Park C S, Yoon S O, Armitage R J, et al.,2004. Follicular dendritic cells produce IL-15 that enhances germinal center B cell proliferation in membrane-bound form. J Immunol.173, 6676-83.
Pasquetto V, Guidotti L G, Kakimi K, et al.,2000. Host-virus interactions during malaria infection in hepatitis B virus transgenic mice. The Journal of experimental medicine.192,529-36.
Peppa D, Micco L, Javaid A, et al.,2010. Blockade of immunosuppressive cytokines restores NK cell antiviral function in chronic hepatitis B virus infection. PLoS pathogens.6, e1001227.
Pereno R, Giron-Michel J, Gaggero A, et al.,2000. IL-15/IL-15Ralpha intracellular trafficking in human melanoma cells and signal transduction through the IL-15Ralpha. Oncogene.19, 5153-62.
Pillarisetty V G, Katz S C, Bleier J I, et al.,2005. Natural killer dendritic cells have both antigen presenting and lytic function and in response to CpG produce IFN-gamma via autocrine IL-12. Journal of immunology.174,2612-8.
Prlic M, Blazar B R, Farrar M A, et al.,2003. In vivo survival and homeostatic proliferation of natural killer cells. J Exp Med.197,967-76.
Pulendran B, Dillon S, Joseph C, et al.,2004. Dendritic cells generated in the presence of GM-CSF plus IL-15 prime potent CD8+Tcl responses in vivo. Eur J Immunol.34,66-73.
Rehermann B, Nascimbeni M,2005. Immunology of hepatitis B virus and hepatitis C virus infection. Nature reviews. Immunology.5,215-29.
Rodrigues L, Bonorino C,2009. Role of IL-15 and IL-21 in viral immunity:applications for vaccines and therapies. Expert review of vaccines.8,167-77.
Rubinstein M P, Kadima A N, Salem M L, et al.,2002. Systemic administration of IL-15 augments the antigen-specific primary CD8+T cell response following vaccination with peptide-pulsed dendritic cells. J Immunol.169,4928-35.
Sato K, Yabuki K, Haba T, et al.,1996. Role of Kupffer cells in the induction of tolerance after liver transplantation. The Journal of surgical research.63,433-8.
Schluns K S, Williams K, Ma A, et al.,2002. Cutting edge:requirement for IL-15 in the generation of primary and memory antigen-specific CD8 T cells. J Immunol.168,4827-31.
Shortman K, Villadangos J A,2006. Is it a DC, is it an NK? No, it's an IKDC. Nature medicine.12, 167-8.
Silva W A, Jr., Covas D T, Panepucci R A, et al.,2003. The profile of gene expression of human marrow mesenchymal stem cells. Stem Cells.21,661-9.
Stevens A C, Matthews J, Andres P, et al.,1997. Interleukin-15 signals T84 colonic epithelial cells in the absence of the interleukin-2 receptor beta-chain. Am J Physiol.272, G1201-8.
Sun J, Dirden-Kramer B, Ito K, et al.,1999. Antigen-specific T cell activation and proliferation during oral tolerance induction. Journal of immunology.162,5868-75.
Suzuki A, McCall S, Choi S S, et al.,2006. Interleukin-15 increases hepatic regenerative activity. Journal of hepatology.45,410-8.
Thatte A, Dewitte-Orr S J, Lichty B, et al.,2011. A critical role for IL-15 in TLR-mediated innate antiviral immunity against genital HSV-2 infection. Immunology and cell biology.89,663-9.
Thomson A W, Lu L,1999. Are dendritic cells the key to liver transplant tolerance? Immunology today.20,27-32.
Thomson A W, Knolle P A,2010. Antigen-presenting cell function in the tolerogenic liver environment. Nature reviews. Immunology.10,753-66.
Tinhofer I, Marschitz I, Henn T, et al.,2000. Expression of functional interleukin-15 receptor and autocrine production of interleukin-15 as mechanisms of tumor propagation in multiple myeloma. Blood.95,610-8.
Tjwa E T, van Oord G W, Hegmans J P, et al.,2011. Viral load reduction improves activation and function of natural killer cells in patients with chronic hepatitis B. Journal of hepatology.54, 209-18.
Tokita D, Sumpter T L, Raimondi G, et al.,2008. Poor allostimulatory function of liver plasmacytoid DC is associated with pro-apoptotic activity, dependent on regulatory T cells. Journal of hepatology.49,1008-18.
van Oosten M, van de Bilt E, de Vries H E, et al.,1995. Vascular adhesion molecule-1 and intercellular adhesion molecule-1 expression on rat liver cells after lipopolysaccharide administration in vivo. Hepatology.22,1538-46.
Vergani D, Mieli-Vergani G,2004. Autoimmune hepatitis. Minerva gastroenterologica e dietologica.50,113-23.
Vinas O, Bataller R, Sancho-Bru P, et al.,2003. Human hepatic stellate cells show features of antigen-presenting cells and stimulate lymphocyte proliferation. Hepatology.38,919-29.
Waldmann T A,2006a. The biology of interleukin-2 and interleukin-15:implications for cancer therapy and vaccine design. Nature reviews. Immunology.6,595-601.
Waldmann T A,2006b. The biology of interleukin-2 and interleukin-15:implications for cancer therapy and vaccine design. Nat Rev Immunol.6,595-601.
Wang H, Ryu W S,2010. Hepatitis B virus polymerase blocks pattern recognition receptor signaling via interaction with DDX3:implications for immune evasion. PLoS pathogens.6, e1000986.
Warren A, Le Couteur D G, Fraser R, et al.,2006. T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells. Hepatology.44,1182-90.
Wei C, Ni C, Song T, et al.,2010. The hepatitis B virus X protein disrupts innate immunity by downregulating mitochondrial antiviral signaling protein. Journal of immunology.185,1158-68.
Wieland S, Thimme R, Purcell R H, et al.,2004. Genomic analysis of the host response to hepatitis B virus infection. Proceedings of the National Academy of Sciences of the United States of America.101,6669-74.
Wieland S F, Guidotti L G, Chisari F V,2000. Intrahepatic induction of alpha/beta interferon eliminates viral RNA-containing capsids in hepatitis B virus transgenic mice. Journal of virology.74,4165-73.
Wieland S F, Eustaquio A, Whitten-Bauer C, et al.,2005. Interferon prevents formation of replication-competent hepatitis B virus RNA-containing nucleocapsids. Proceedings of the National Academy of Sciences of the United States of America.102,9913-7.
Willerford D M, Chen J, Ferry J A, et al.,1995. Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity.3,521-30.
Winau F, Hegasy G, Weiskirchen R, et al.,2007. Ito cells are liver-resident antigen-presenting cells for activating T cell responses. Immunity.26,117-29.
Wuensch S A, Pierce R H, Crispe I N,2006. Local intrahepatic CD8+ T cell activation by a non-self-antigen results in full functional differentiation. Journal of immunology.177,1689-97.
Yajima T, Nishimura H, Wajjwalku W, et al.,2002. Overexpression of interleukin-15 in vivo enhances antitumor activity against MHC class I-negative and -positive malignant melanoma through augmented NK activity and cytotoxic T-cell response. Int J Cancer.99,573-8.
You Q, Cheng L, Kedl R M, et al.,2008. Mechanism of T cell tolerance induction by murine hepatic Kupffer cells. Hepatology.48,978-90.
Zhang X, Sun S, Hwang I, et al.,1998. Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15. Immunity.8,591-9.