上海肝病在线 Shanghai Liver Diseases' Online

LAK(+APC)治疗病毒感染和肿瘤成功的原理

（天然免疫与获得性免疫相维系）

病毒感染人体后最先遇到的阻碍和最先激发的反应是天然免疫（innate immunity），参与天然免疫反应的免疫活性细胞有单核巨噬细胞、NK细胞和NK-T细胞及产生I型IFN的树突细胞（natural interferon (IFN)-alpha/beta-producing cells ，IPCs ），其通过产生IFN-alpha/beta等和其他胞毒与非胞毒机制发挥抗病毒作用，而IFN-alpha/beta又通过自分泌机制激活 IPC分化成熟为功能健全的抗原提呈细胞，诱导处女型/幼稚型CD4阳性T淋巴细胞产生抗原特异性IFN-gamma 和interleukin (IL)-10，进而并辅助B淋巴细胞产生抗原特异性抗体和辅助CD8阳性T淋巴细胞通过胞毒与非胞毒机制产生抗原特异性抗病毒作用（获得性免疫），将天然免疫与获得性免疫相联系，有效地完成人体的抗病毒效应。

肿瘤免疫机制与病毒免疫相类似，但胞毒性机制更具明显的有抗肿瘤作用。

LAK（+APC）中的LAK细胞通过增养产生大量有抗病毒和抗肿瘤活性的NK型和T型的LAK细胞（NK-T），有效恢复和重建机体的天然免疫，而LAK（+APC）中的APC细胞又直接通过促进APC功能而诱导处女型/幼稚型CD4阳性T淋巴细胞产生抗原特异性IFN-gamma 和interleukin (IL)-10，进而并辅助B淋巴细胞产生抗原特异性抗体和辅助CD8阳性T淋巴细胞通过胞毒与非胞毒机制产生抗原特异性抗病毒作用，有效恢复和重建机体的抗原特异性获得性免疫。因此LAK（+APC）疗法有机地强化机体的天然免疫与获得性免疫，故临床效果很佳，而进一步采用HBV抗原脉冲APC将更加增加其抗病毒和抗肿瘤的疗效。

J Exp Med 2000 Jul 17;192(2):219-26

Natural interferon alpha/beta-producing cells link innate and adaptive immunity.

Kadowaki N, Antonenko S, Lau JY, Liu YJ.

Department of Immunobiology, DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, California 94304, USA.

Innate immune responses to pathogens critically impact the development of adaptive immune responses. However, it is not completely understood how innate immunity controls the initiation of adaptive immunities or how it determines which type of adaptive immunity will be induced to eliminate a given pathogen. Here we show that viral stimulation not only triggers natural interferon (IFN)-alpha/beta-producing cells (IPCs) to produce vast amounts of antiviral IFN-alpha/beta but also induces these cells to differentiate into dendritic cells (DCs). IFN-alpha/beta and tumor necrosis factor alpha produced by virus-activated IPCs act as autocrine survival and DC differentiation factors, respectively. The virus-induced DCs stimulate naive CD4(+) T cells to produce IFN-gamma and interleukin (IL)-10, in contrast to IL-3-induced DCs, which stimulate naive CD4(+) T cells to produce T helper type 2 cytokines IL-4, IL-5, and IL-10. Thus, IPCs may play two master roles in antiviral immune responses: directly inhibiting viral replication by producing large amounts of IFN-alpha/beta, and subsequently triggering adaptive T cell-mediated immunity by differentiating into DCs. IPCs constitute a critical link between innate and adaptive immunity.

PMID: 10899908 [PubMed - indexed for MEDLINE]

J Immunol 2000 Apr 15;164(8):4220-8

Type I IFN modulates innate and specific antiviral immunity.

Durbin JE, Fernandez-Sesma A, Lee CK, Rao TD, Frey AB, Moran TM, Vukmanovic S, Garcia-Sastre A, Levy DE.

Departments of Pathology and Kaplan Comprehensive Cancer Center, Cell Biology, and Pathology and Heidelberger Division of Immunology, New York University School of Medicine, New York, NY 10016, USA.

IFNs protect from virus infection by inducing an antiviral state and by modulating the immune response. Using mice deficient in multiple aspects of IFN signaling, we found that type I and type II IFN play distinct although complementing roles in the resolution of influenza viral disease. Both types of IFN influenced the profile of cytokines produced by T lymphocytes, with a significant bias toward Th2 differentiation occurring in the absence of responsiveness to either IFN. However, although a Th1 bias produced through inhibition of Th2 differentiation by IFN-gamma was not required to resolve infection, loss of type I IFN responsiveness led to exacerbated disease pathology characterized by granulocytic pulmonary inflammatory infiltrates. Responsiveness to type I IFN did not influence the generation of virus-specific cytotoxic lymphocytes or the rate of viral clearance, but induction of IL-10 and IL-15 in infected lungs through a type I IFN-dependent pathway correlated with a protective response to virus. Combined loss of both IFN pathways led to a severely polarized proinflammatory immune response and exacerbated disease. These results reveal an unexpected role for type I IFN in coordinating the host response to viral infection and controlling inflammation in the absence of a direct effect on virus replication.

PMID: 10754318 [PubMed - indexed for MEDLINE]

J Exp Med 2000 Dec 18;192(12):1785-96

Comment in: J Exp Med. 2000 Dec 18;192(12):F39-44

Generation of interferon alpha-producing predendritic cell (Pre-DC)2 from human CD34(+) hematopoietic stem cells.

Blom B, Ho S, Antonenko S, Liu YJ.

Department of Immunobiology, DNAX Research Institute of Molecular and Cellular Biology, Palo Alto, California 94304, USA.

Upon viral stimulation, the natural interferon (IFN)-alpha/beta-producing cells (IPCs; also known as pre-dendritic cells (DCs 2) in human blood and peripheral lymphoid tissues rapidly produce huge amounts of IFN-alpha/beta. After performing this innate antiviral immune response, IPCs can differentiate into DCs and strongly stimulate T cell-mediated adaptive immune responses. Using four-color immunofluorescence flow cytometry, we have mapped the developmental pathway of pre-DC2/IPCs from CD34(+) hematopoietic stem cells in human fetal liver, bone marrow, and cord blood. At least four developmental stages were identified, including CD34(++)CD45RA(-) early progenitor cells, CD34(++)CD45RA(+) late progenitor cells, CD34(+)CD45RA(++)CD4(+)interleukin (IL)-3Ralpha(++) pro-DC2, and CD34(-)CD45RA(++) CD4(+)IL-3Ralpha(++) pre-DC2/IPCs. Pro-DC2s have already acquired the capacity to produce large amounts of IFN-alpha/beta upon viral stimulation and to differentiate into DCs in culture with IL-3 and CD40 ligand. CD34(++)CD45RA(-) early progenitor cells did not have the capacity to produce large amounts of IFN-alpha/beta in response to viral stimulation; however, they can be induced to undergo proliferation and differentiation into IPCs/pre-DC2 in culture with FLT3 ligand.

PMID: 11120775 [PubMed - indexed for MEDLINE]

Rev Immunogenet 2000;2(3):374-86

Interferon activation and innate immunity.

Le Page C, Genin P, Baines MG, Hiscott J.

Terry Fox Molecular Oncology Group, Lady Davis Institute for Medical Research, Montreal, Canada.

The interferons are a family of cytokine mediators critically involved in alerting the cellular immune system to viral infection of host cells. Interferons not only exhibit important antiviral effects but also exert a key influence on the quality of the cellular immune responses and amplify antigen presentation to specific T cells. Type I interferon (IFN-alpha and IFN-beta) is secreted by virus-infected cells while type II, immune or gamma interferon (IFN-gamma) is mainly secreted by T cells, natural killer (NK) cells and macrophages. Interferons interact with specific cellular receptors, which promote production of second messengers ultimately leading to expression of antiviral and immune modulatory genes. The IFN genes themselves are regulated by transcriptional and posttranscriptional mechanisms including modulation by a family of interferon regulatory factors (IRFs) synthesised by host cells. IFNs activate macrophages, induce B cells to switch immunoglobulin type, alter T helper response, inhibit cell growth, promote apoptosis and induce an antiviral state in uninfected cells. The therapeutic potential of the IFNs is currently the focus of intense attention in a number of virus-associated diseases, tumours and autoimmune disorders. Publication Types: Review Review, Tutorial

PMID: 11256746 [PubMed - indexed for MEDLINE]