Abrogation of resistance to bone marrow transplantation by induction of specific tolerance in natural killer cells?

Hybrid resistance describes the capacity of first generation (F1) hybrids between certain mouse strains to inhibit the growth of tumour or haematopoietic cells of parental origin. The cells that appear to mediate this phenomenon differ from classical T and B lymphocytes in several respects. For example, they are unusually radioresistant, show no immunological memory, are present in thymectomized or congenitally athymic mice, are not functional until about 3 weeks after birth. These characteristics suggest that the effectors are natural killer (NK) cells. Although most of the evidence implicating NK cells in hybrid resistance is circumstantial, the experiments of Warner and Dennert are more direct in that they show that resistance can be restored to mice with a congenital or induced defect in NK activity by the infusion of cells belonging to an NK clone. Conversely, treatment of mice with an antibody to NK cells abrogated hybrid resistance to parental bone marrow grafts. Both NK cells and the effectors of hybrid resistance are generally considered to be nonspecific. We have now investigated this assumption by attempting to prevent hybrid resistance by neonatal tolerance induction with parental strain antigens. Our data indicate that hybrid resistance can be abrogated by this means and that the tolerance is specific and transferable with Thy-1+ spleen cells.     

Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells

Although immune mechanisms can suppress tumour growth, tumours establish potent, overlapping mechanisms that mediate immune evasion. Emerging evidence suggests a link between angiogenesis and the tolerance of tumours to immune mechanisms. Hypoxia, a condition that is known to drive angiogenesis in tumours, results in the release of damage-associated pattern molecules, which can trigger the rejection of tumours by the immune system. Thus, the counter-activation of tolerance mechanisms at the site of tumour hypoxia would be a crucial condition for maintaining the immunological escape of tumours. However, a direct link between tumour hypoxia and tolerance through the recruitment of regulatory cells has not been established. We proposed that tumour hypoxia induces the expression of chemotactic factors that promote tolerance. Here we show that tumour hypoxia promotes the recruitment of regulatory T (T(reg)) cells through induction of expression of the chemokine CC-chemokine ligand 28 (CCL28), which, in turn, promotes tumour tolerance and angiogenesis. Thus, peripheral immune tolerance and angiogenesis programs are closely connected and cooperate to sustain tumour growth.     

几种常见植物香料的真伪鉴别

论述几种市场上常见的植物香料如草果、八角茴香、花椒、小茴香等及其伪品和混淆品的性状特征,总结出了它们的鉴别要点,这不仅在基础理论研究方面有一定意义,而且可为市场交易提供一定的鉴别依据。     

Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition.

In a longitudinal study of HIV seropositive patients, there were fluctuations in the specificity of cytotoxic T cells for the virus. This was matched by variability in proviral gag DNA epitope sequences in the lymphocytes of these patients. Some of these viral variants are not recognized by autologous T cells. Accumulation of such mutations in T-cell antigenic targets would provide a mechanism for immune escape.     

Viral escape by selection of cytotoxic T cell-resistant virus variants in vivo.

Viruses persist in an immune population, as in the case of influenza, or in an individual, as postulated for human immunodeficiency virus, when they are able to escape existent neutralizing antibody responses by changing their antigens. It is now shown that viruses can in principle escape the immunosurveillance of virus-specific cytotoxic T cells by mutations that alter the relevant T-cell epitope.     

Essential requirement for major histocompatibility complex recognition in T-cell tolerance induction

The induction of T-cell responses involves the recognition of extrinsic antigen in association with antigens of the major histocompatibility complex (MHC), in mice and man, with different T cells recognizing antigen in association with either class I (H-2K/D, HLA-A, B, C) or class II (Ia, HLA-D/DR) MHC antigens. However, the requirement of MHC recognition in the induction of immunological tolerance remains ill defined. With human T helper clones recognizing synthetic peptides of influenza haemagglutinin (HA-1), we have investigated the nature of antigen-induced stimulation, and antigen-induced antigen-specific unresponsiveness, immunological tolerance. Tolerance is not due to cell death, as the cells remain responsive to interleukin-2 and is associated with the loss of T3 antigen from the cell surface. Using monoclonal antibodies to the non-polymorphic regions of human class II antigens to inhibit the induction of T-cell tolerance we report here that induction of tolerance requires the recognition of MHC antigens.     

水杨酸在诱导番茄抗冷性中的作用

以番茄为试验材料,探讨了叶面喷施水杨酸对于番茄幼苗抗低温能力的影响.实验结果表明番茄叶片中的SA在常温下主要以结合态形式存在.低温下SA质量分数大幅上升,而造成其上升的主要原因是游离态SA的大量积累.对番茄叶面喷施不同浓度SA,24 h后番茄叶片中游离态SA和结合态SA均大量积累,并且积累程度与喷施浓度呈显著正相关.低温下番茄叶片的抗氧化防御系统被明显激发,但并不足以减缓低温胁迫对植物所造成的氧化损伤.对番茄幼苗进行不同浓度的SA预处理,发现0.5 mmol/LSA能够显著提高其抗冷性.0.5 mmol/LSA预处理24 h后,低温下番茄叶片的相对电导率、MDA浓度较对照明显降低,而H2O2质量分数以及CAT,POD,APX,GR的活性则显著上升,叶片内c(AsA)/c(DHA)与c(GSH)/c(GSSG)维持在相对稳定的水平.因此,我们推测对番茄幼苗进行适宜浓度的SA预处理能够使其叶片中的SA质量分数上升至一定程度,从而诱导H2O2的适量积累,上调植物的抗氧化能力,使植物细胞在低温下维持相对稳定的氧化还原状态,从而缓解了低温对植物所造成的氧化损伤,提高了其抗冷性.     

Nucleoside-specific tolerance suppresses anti-nucleoside antibody forming cells

Since its original development by Jerne, the haemolytic plaque assay has increased our understanding of antibody formation to a wide variety of antigens, including proteins, lipopolysaccharides, and simple haptens. We have now developed an assay to detect plaque forming cells (PFC) making anti-nucleoside antibodies. Previously we reported the suppression of circulating antibody to DNA determinants by nucleoside-IgG conjugates. Here we show that BALB/c mice can be rendered tolerant in terms of both direct and indirect anti-nucleoside antibody forming cells and that the state of tolerance is nucleoside-specific at the cellular level.     

Normal human mammary epithelial cells spontaneously escape senescence and acquire genomic changes

Senescence and genomic integrity are thought to be important barriers in the development of malignant lesions. Human fibroblasts undergo a limited number of cell divisions before entering an irreversible arrest, called senescence. Here we show that human mammary epithelial cells (HMECs) do not conform to this paradigm of senescence. In contrast to fibroblasts, HMECs exhibit an initial growth phase that is followed by a transient growth plateau (termed selection or M0; refs 3-5), from which proliferative cells emerge to undergo further population doublings (approximately 20-70), before entering a second growth plateau (previously termed senescence or M1; refs 4-6). We find that the first growth plateau exhibits characteristics of senescence but is not an insurmountable barrier to further growth. HMECs emerge from senescence, exhibit eroding telomeric sequences and ultimately enter telomere-based crisis to generate the types of chromosomal abnormalities seen in the earliest lesions of breast cancer. Growth past senescent barriers may be a pivotal event in the earliest steps of carcinogenesis, providing many genetic changes that predicate oncogenic evolution. The differences between epithelial cells and fibroblasts provide new insights into the mechanistic basis of neoplastic transformation.     

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.     

Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes.

Potent virus-specific cytotoxic T lymphocyte (CTL) responses elicited by candidate AIDS vaccines have recently been shown to control viral replication and prevent clinical disease progression after pathogenic viral challenges in rhesus monkeys. Here we show that viral escape from CTL recognition can result in the eventual failure of this partial immune protection. Viral mutations that escape from CTL recognition have been previously described in humans infected with human immunodeficiency virus (HIV) and monkeys infected with simian immunodeficiency virus (SIV). In a cohort of rhesus monkeys that were vaccinated and subsequently infected with a pathogenic hybrid simian-human immunodeficiency virus (SHIV), the frequency of viral sequence mutations within CTL epitopes correlated with the level of viral replication. A single nucleotide mutation within an immunodominant Gag CTL epitope in an animal with undetectable plasma viral RNA resulted in viral escape from CTLs, a burst of viral replication, clinical disease progression, and death from AIDS-related complications. These data indicate that viral escape from CTL recognition may be a major limitation of the CTL-based AIDS vaccines that are likely to be administered to large human populations over the next several years.