Transfer of a functional human immune system to mice with severe combined immunodeficiency

The pressing need for a better experimental system for AIDS research has brought into sharp focus the shortcomings of available animal models and the practical and ethical limitations of studies of immune responses and viral pathogenesis in humans. Current studies of the human immune responses are limited to relatively restrictive in vivo experiments and several in vitro systems that, although useful, allow only short-term studies and support responses to a few antigens. Neither model is particularly amenable to studies of the pathogenesis of diseases of the immune system. We report here that injection of human peripheral blood leukocytes (PBL) can result in the stable long-term reconstitution of a functional human immune system in mice with severe combined immunodeficiency (SCID). Human PBL transplanted to SCID mice increase in number and survive for at least six months; reconstituted mice show spontaneous secretion of human immunoglobulin and a specific human antibody response is induced following immunization with tetanus toxoid. All of the major cell populations present in PBL are found in the lymphoid tissue and blood of SCID recipients, although the relative proportions of B cells, T-cell subsets and monocytes/macrophages in long-term recipients differ from those found in normal PBL and, in mice transplanted with 50 x 10(6) or more PBL from Epstein-Barr virus (EBV)-seropositive donors, EBV-positive B-cell lymphomas often develop. Our results suggest that xenogeneic transplantation of human lymphoid cells into SCID mice may provide a useful model for the study of normal human immune function, the response of the immune system to pathogenic agents and early events in lymphomagensis.     

Memory B-cell persistence is independent of persisting immunizing antigen

Immunological memory in the antibody system is generated in T-cell-dependent responses and carried by long-lived memory B cells that recognize antigen by high-affinity antibodies. But it remains controversial whether these B cells represent true 'memory' cells (that is, their maintenance is independent of the immunizing antigen), or whether they are a product of a chronic immune response driven by the immunizing antigen, which can be retained in the organism for extended time periods on the surface of specialized antigen-presenting cells (follicular dendritic cells). Cell transfer experiments provided evidence in favour of a role of the immunizing antigen; however, analysis of memory cells in intact animals, which showed that these cells are mostly resting and can persist in the absence of detectable T-cell help or follicular dendritic cells, argued against it. Here we show, by using a genetic switch mediated by Cre recombinase, that memory B cells switching their antibody specificity away from the immunizing antigen are indeed maintained in the animal over long periods of time, similar to cells retaining their original antigen-binding specificity.     

Sharing of an idiotypic marker by monoclonal antibodies specific for distinct regions of hen lysozyme

Idiotypes have been defined serologically as variable-region markers present on unique subsets of antibody molecules. Most studies involving myeloma proteins and antibody responses in inbred mice have indicated that idiotypy is closely related to antigenic specificity. However, indirect evidence suggests that idiotypy can sometimes be dissociated from specificity. In the response to the small monomeric protein, hen egg-white lysozyme (HEL), previous results demonstrated that 70--95% of the anti-HEL antibody found in sera of primed and boosted mice is specific for a particular region of HEL and bears a predominant idiotype (IdX-HEL). In this report, hybridoma anti-HEL antibodies tested with well-characterized peptide fragments of HEL show that the IdX-HEL marker can be found on antibodies of completely distinct antigen specificities. Thus, a mode of recognition other than antigenic recognition probably plays a major role in the immune response to HEL.     

免疫优化在QoS组播路由中的应用

提出了一种时延约束的最小代价组播源路由免疫算法．该算法的主要思想是：利用自然免疫系统中抗体和抗原的交互关系来模拟QoS组播路由中可行解（满足QOS约束的解）和不可行解（不满足QoS约束的解）之问协同演化过程,避免了传统的处理约束的方法——罚函数方法的局限性．算法的实现借鉴了前人提出的高效的克隆选择算子,可有效地提高算法的搜索性能．仿真实验证明：算法性能要好于被测试的著名路由算法．     

Immunology: Toll-like receptors and antibody responses

Microbial components, such as lipopolysaccharides, augment immune responses by activating Toll-like receptors (TLRs). Some have interpreted this to mean that TLR signalling might not only help to initiate the adaptive immune response, but may also be required for it. The expanded view is shared by Pasare and Medzhitov, who conclude from an analysis of mice deficient in MyD88 (a TLR-signalling adaptor protein) that the generation of T-dependent antigen-specific antibody responses requires activation of TLRs in B cells. However, we show here that robust antibody responses can be elicited even in the absence of TLR signals. This appreciable TLR-independence of immune responses should be taken into account in the rational design of immunogenic and toleragenic vaccines.     

Immunization to a syngeneic sarcoma by a monoclonal auto-anti-idiotypic antibody

Idiotypic networks regulate the immune response to a variety of antigens. Antibodies generated against other antibodies, called anti-idiotypic antibodies, can themselves mimic antigen and elicit a specific immune response. They have been shown to induce delayed-type hypersensitivity (DTH) to model antigens in the mouse. As anti-idiotypic antibodies are thought to be involved in the response to tumour-associated antigens we tested whether injection of monoclonal antibodies derived from mice hyperimmunized to a syngeneic, chemically induced sarcoma could mimic antigen and induce DTH to the sarcoma in naive mice. One of the monoclonal antibodies, 4.72, primed BALB/c mice for DTH to the sarcoma but not for DTH to another sarcoma or to sheep erythrocytes. Antibody 4.72 did not induce DTH in mice of immunoglobulin allotype congeneic strains nor did it bind to the sarcoma cells. As antibodies specific for this sarcoma have not been detected, we do not know whether idiotype on immunoglobulin molecules is recognized by antibody 4.72. However, as the response induced by antibody 4.72 was both antigen-specific and allotype-restricted, analogous to those induced by anti-idiotypic antibodies in other systems, we propose that antibody 4.72 is an anti-idiotypic antibody.     

基于生物免疫系统克隆选择机理和免疫网络理论的免疫算法

提出一种基于生物免疫系统克隆选择机理和免疫网络理论的免疫算法.该算法通过抗体的克隆选择和变异过程,完成对入侵抗原的清除,实现免疫防御的功能;利用免疫网络调节的思想选择抗体记忆细胞,完成知识的学习和积累,实现免疫自稳的功能;利用所建立的抗体记忆矩阵实现对类似入侵抗原的快速应答,行使免疫监视识别功能.该算法利用生物变异机制实现抗体的自适应调节,使系统具有自适应、自学习能力.在加热炉状态识别的应用研究表明,本文所提出的算法在解决数据识别方面具有较好的效果.     

Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens

Under physiological conditions the gut-associated lymphoid tissues not only prevent the induction of a local inflammatory immune response, but also induce systemic tolerance to fed antigens. A notable exception is coeliac disease, where genetically susceptible individuals expressing human leukocyte antigen (HLA) HLA-DQ2 or HLA-DQ8 molecules develop inflammatory T-cell and antibody responses against dietary gluten, a protein present in wheat. The mechanisms underlying this dysregulated mucosal immune response to a soluble antigen have not been identified. Retinoic acid, a metabolite of vitamin A, has been shown to have a critical role in the induction of intestinal regulatory responses. Here we find in mice that in conjunction with IL-15, a cytokine greatly upregulated in the gut of coeliac disease patients, retinoic acid rapidly activates dendritic cells to induce JNK (also known as MAPK8) phosphorylation and release the proinflammatory cytokines IL-12p70 and IL-23. As a result, in a stressed intestinal environment, retinoic acid acted as an adjuvant that promoted rather than prevented inflammatory cellular and humoral responses to fed antigen. Altogether, these findings reveal an unexpected role for retinoic acid and IL-15 in the abrogation of tolerance to dietary antigens.     

硬骨鱼IgM结构和功能及其体液免疫应答

经典免疫学理论有2个基本模式阐述抗体免疫反应的发展和功能:（1）亲和力成熟依赖于机体本身的和通过突变形成的高亲和力抗体的抗原驱动选择过程；（2）抗体的生物效应功能是由抗体的类型所决定的.最近研究发现硬骨鱼的免疫系统通过调控结合抗原的亲和力大小来改变分泌的IgM抗体同质异构体结构的比例，从而影响其抗体在血清中的半衰期.这种独特性质的发现是对经典免疫学理论的补充和扩展.文章概述了硬骨鱼IgM抗体结构和功能的亲和力驱动调节，并介绍维持体液免疫记忆的长寿命浆细胞和记忆性B细胞的性质以及抗体分泌细胞（如原浆细胞、浆细胞）在体液免疫应答中的作用.了解硬骨鱼IgM结构和功能的关系，以及不同分化阶段B细胞维持体液免疫反应的机制，将有利于探索构建硬骨鱼免疫评价体系，并为高效的渔用疫苗开发和疫苗效果精确性评价奠定理论基础.     

基于免疫的图形识别算法

本文提出了一种新型的基于免疫的图形识别模型并给出了相应的算法设计,定量的刻画了抗原、最佳抗体、成熟抗体、记忆抗体、免疫周期之间的演化情况,阐明了抗原提取、抗体特征库、成熟抗体、记忆抗体的产生方法,以及如何在解空间引入竞争机制.文章最后分析了此算法的时间复杂度.     

Maintenance of B-cell memory by long-lived cells generated from proliferating precursors

A basic feature of T-cell dependent antibody responses is the generation of memory: on a second contact with an antigen a secondary response is produced in which somatically mutated antibodies with increased affinity are synthesized. Memory can persist for long periods of time. This has classically been ascribed to the generation of long-lived memory B cells. However, it is also possible that persisting antigen, on which memory may depend, maintains a population of cycling memory cells under continuous selection or continuously recruits newly generated B cells into the memory B-cell compartment. To discriminate between these mechanisms we have now directly analysed the proliferative activity in the memory B-cell compartment of the mouse by measuring bromodeoxyuridine incorporation in vivo. We show that after an initial phase of extensive proliferation after primary immunization, memory cells can persist in the organism for extended periods of time in the absence of cell division.     

Antigenic peptides recognized by T lymphocytes from AIDS viral envelope-immune humans

T-lymphocyte immunity is likely to be an important component of the immune defence against the AIDS virus, because helper T cells are necessary for the antibody response as well as the cytotoxic response. We have previously predicted two antigenic sites of the viral envelope protein gp120 likely to be recognized by T lymphocytes, based on their ability to fold as amphipathic helices, and have demonstrated that these are recognized by T cells of mice immunized with gp120 (ref. 1). A peptide corresponding to one of these sites can also be induce immunity in mice to the whole gp120 protein. Because many clinically healthy seropositive blood donors have already lost their T-cell proliferative response to specific antigen, we tested the response to these synthetic peptides of lymphocytes from 14 healthy human volunteers who had been immunized with a recombinant vaccinia virus containing the AIDS viral envelope gene and boosted with a recombinant fragment. Eight of the 14 responded to one peptide, and four to the other peptide, not included in the boost. These antigenic sites recognized by human T cells may be useful components of a vaccine against AIDS. We also found a correlation between boosting with antigen-antibody complexes (compared to free antigen) and higher stimulation indices, suggesting a more effective method of immunization.     

Recognition of bacterial glycosphingolipids by natural killer T cells

Natural killer T (NKT) cells constitute a highly conserved T lymphocyte subpopulation that has the potential to regulate many types of immune responses through the rapid secretion of cytokines. NKT cells recognize glycolipids presented by CD1d, a class I-like antigen-presenting molecule. They have an invariant T-cell antigen receptor (TCR) alpha-chain, but whether this invariant TCR recognizes microbial antigens is still controversial. Here we show that most mouse and human NKT cells recognize glycosphingolipids from Sphingomonas, Gram-negative bacteria that do not contain lipopolysaccharide. NKT cells are activated in vivo after exposure to these bacterial antigens or bacteria, and mice that lack NKT cells have a marked defect in the clearance of Sphingomonas from the liver. These data suggest that NKT cells are T lymphocytes that provide an innate-type immune response to certain microorganisms through recognition by their antigen receptor, and that they might be useful in providing protection from bacteria that cannot be detected by pattern recognition receptors such as Toll-like receptor 4.     

Abrogation of oral tolerance by contrasuppressor T cells suggests the presence of regulatory T-cell networks in the mucosal immune system

Continuous ingestion of a thymus-dependent (TD) antigen differentially affects two compartments of the immune system. A secretory IgA antibody response is induced in mucosal tissues, concurrent with a state of antigen-specific systemic unresponsiveness to parenteral challenge, termed oral tolerance. The precise mechanisms whereby gut antigenic exposure induces oral tolerance are unknown, although T-suppressor cells, anti-idiotypic networks and immune complex formation have all been proposed. Here we show that the systemic unresponsiveness of mice made orally tolerant to the TD antigen sheep red blood cells (SRBC) is reversed by the adoptive transfer of Lyt-1+,2-, Vicia villosa lectin-adherent and I-J+ T cells derived from mice which are genetically resistant to the induction of oral tolerance to SRBC. This T-cell subpopulation has the characteristics of contrasuppressor effector T cells (Tcs). Small numbers of these Tcs cells reverse SRBC-specific tolerance both in vivo and in vitro. This finding offers new insight into the mechanisms of oral tolerance induction and maintenance, and suggests that a network of T cells are involved in the regulation of host responses to ingested antigens.     

Neuronal cell killing by the envelope protein of HIV and its prevention by vasoactive intestinal peptide

The clinical manifestations of AIDS (acquired immune deficiency syndrome) often include neuropsychiatric and neurological deficits, including early memory loss and progressive dementia. HIV (human immunodeficiency virus), the aetiological agent of AIDS, is probably carried by infected macrophages in the central nervous system. The virus enters cells by binding its envelope glycoprotein gp120 to the CD4 antigen present on brain and immune cells. From the data reported in this paper, we now suggest that the neuronal deficits associated with HIV may not be entirely a result of infectivity, but that gp120 shed from HIV could directly produce the neuropathology as a result of its interference with endogenous neurotrophic substances. It is known that an analogue of a sequence contained in vasoactive intestinal peptide (VIP) occurs in all known sequenced gp120 isolates and that VIP is important for neuronal survival in cell culture. Here we show that purified gp120 from two diverse HIV isolates and a recombinant gp120 from a third isolate were all potent in specifically producing significant neuronal cell death in dissociated hippocampal cultures derived from fetal mice, and that this could be reduced by monoclonal antibodies against the murine CD4 antigen and completely antagonized by VIP.     

Specific in vitro antibody response to influenza virus by human blood lymphocytes.

Advances in understanding of human immune responses depend, for obvious reasons, on the use of in vitro techniques for culture of peripheral blood lymphocytes (PBL). We report here that specific antibody responses to influenza virus can readily be obtained using simple, reproducible methods. The system will be useful for the analysis of the cellular requirements for antibody production, the genetics of immune responsiveness and in clinical studies of immunosuppressed and immunodeficient patients.     

Killing of antigen-reactive B cells by class II-restricted, soluble antigen-specific CD8+ cytolytic T lymphocytes

Cytolytic T lymphocytes (CTLs) are generally thought to recognize cellular antigens presented by class I MHC molecules. A number of studies, however, have revealed responses of considerable magnitude involving both CD8+ and CD4+ CTLs with class II restriction, suggesting that class II-restricted CTLs recognizing exogeneous protein antigens may exist. As class II antigens are normally expressed on limited types of cells such as B cells and macrophages, such CTLs might be expected to exert a suppressive effect on antibody responses. Here we report that stimulation of mouse lymphocytes with a soluble antigen induced CD8+ and CD4+ CTLs specific for the antigen with class II restriction. The specific lysis was far more efficient when target B cells specifically recognized the antigen than when they did not, indicating that the primary targets for these CTLs are probably B cells expressing immunoglobulin receptors reactive for the same antigen molecule. These results suggest that the natural occurrence of such CTLs during immune responses may explain antigen-specific suppression on antibody responses by T cells.     

T cells with receptors for IgD

The role of IgD in the immune response has been elusive, although its predominance on the cell surface suggests a receptor function. We have shown previously that euthymic but not athymic BALB/c mice, injected with IgD before antigen, exhibit enhanced antibody responses which can be transferred by T cells. Isotype-specific T cells have been reported to have both upward and downward immunoregulatory effects. Here we demonstrate the existence of T cells with receptors for IgD, and show that exposure to IgD in vivo or in vitro significantly increases the number of T delta cells in the spleen and lymph nodes but not in the thymus. The kinetics of T delta-cell appearance in vivo parallels that of the immunoenhancing effect which occurs after injection of IgD. These T delta cells are of the Lyt 1+2- T-cell phenotype.     

Functional analysis of schistosomes EF-hand domain-containing tegument proteins

Schistosomes cause schistosomiasis disease which severely threatens human health. Little is known about the functions of EF-hand domain containing schistosomes tegument proteins other than as an-tigens. More possible functions of these tegument proteins were investigated with in silico analyses including protein-protein functional interaction,site-specific variation and glycosylation modification. The analysis results suggested that schistosomes could actively modulate host immune responses for its own favor through functional interactions with host proteins with immunomodulatory function,and passively regulate host immune responses through sequence variation under positive selection and glycosylating the recognition sites of host immune attack. In addition,the analysis of the C-terminal domain of these tegument proteins indicated that they could assist schistosomes in escaping host immune attacks through inhibiting chemotaxis and non-complement fixing antibody (IgG4) responses. In summary,our results suggested that these tegument antigen proteins could assist schistosomes in escaping and modulating host immune responses for self-protection during the process of host-para-site interaction.     

免疫遗传算法在MATLAB环境中的实现

阐述了免疫遗传算法的基本原理,探讨了在MATLAB环境下实现免疫遗传算法中抗原记忆、抗体促进与抑制、抗体多样性保持等功能的方法,并以智能交流接触器优化设计问题为例,说明免疫遗传算法与标准遗传算法相比的优越性及其在MATLAB环境中实现的可行性.