Melatonin in relation to the antioxidative defense and immune systems: possible implications for cell and organ transplantation

Melatonin, a molecule synthesized and secreted by the mammalian (including human) pineal gland, has a variety of seemingly unrelated functions in organisms. In photoperiodically-dependent seasonal breeders, the changing melatonin signal imparts seasonal information to the species thereby regulating the annual cycle of reproduction [1]. Melatonin also is involved in a number of 24 h rhythms and is believed to be an important component of the circadian system [2, 3]. More recently, melatonin was found to relate to immune function [4] in organisms and to be an effective antioxidant [5]. As an antioxidant melatonin would appear to provide substantial protection against free radicals which are generated under a variety of experimental corrections, including ischemia/reperfusion injury [6, 7]. These latter two functions of melatonin, i.e., as an immune system modulator and as an antioxidant, both may have applicability to cell and organ transplantation [8–11].     

Modeling immune intervention strategies for HIV-1 infection of humans in the macaque model

The introduction of potent antiretroviral therapy (ART) has generated hope and prospects in the management of human immunodeficiency virus-1 (HIV-1) infection. Long-term side effects of ART, however, have also indicated the limitations of this approach alone. A decade ago, immune therapy trials in HIV-1-infected individuals were performed in the absence of ART with a gp160-based vaccine [1]. At that time, the notion that the HIV-1 env obtained from lab-adapted strains would be a poor inducer of antibodies able to neutralize primary HIV-1 isolates was in its infancy [2]. Similarly, the importance of cell-mediated immune response in the containment of HIV-1 replication both in acute and chronic infection [3], [4], [5], [6], [7] and [8], albeit predictable from other models of viral infection, was not fully appreciated. Here, attempts to model immune intervention in SIVmac251-infected macaques using vaccines able to elicit cell-mediated immune responses will be reviewed.The introduction of ART has resulted in effective suppression of viral replication and decreased morbidity and mortality of HIV-1-infected individuals [9]. The decreased morbidity appears to be associated with the reconstitution of immune responses to pathogens, such as cytomegalovirus and Epstein-Barr virus [10], [11] and [12]. However, HIV-1-specific immune responses decline during ART treatment of adults and children [13], [14], [15], [16] and [17], perhaps because of a decrease of HIV-1 replication and antigen exposure under ART. The wide use of ART has also resulted in a better appreciation of the limitations of this daily multi-drug combination treatment, such as compliance [18] and [19], due to the complexity of treatment and life-threatening side effects after long-term treatment [20], [21], [22], [23], [24], [25], [26], [27], [28], [29] and [30].     

Increased activity of caspase 3 and caspase 8 in anti-Fas-induced apoptosis in lymphocytes from ageing humans.

We have previously shown an increased susceptibility of T cell subsets to anti-Fas-induced apoptosis in human ageing [1]. In this study, we have examined the role of downstream mediators, including caspases, in Fas-mediated apoptosis in lymphocytes from ageing humans. The cleavage activity of caspase-8 and caspase-3 was compared between ageing and young subjects at different times following anti-Fas treatment, using colorimetric detection analysis. The expression of Fas-associated death domain (FADD), caspase-8, and caspase-3 in lymphocytes was compared at the protein level using Western blotting, and at the mRNA level by Northern blot analysis. In lymphocytes from ageing subjects, there was an early increase in the cleavage activity of caspase-8 and caspase-3 compared with young controls. Furthermore, increased protein expression of FADD, caspase-8 and caspase-3 at the basal level was observed in lymphocytes from ageing humans. Our results suggest that the altered expression and activity of molecules in the Fas/FasL signalling pathway may play a role in increased Fas-induced apoptosis and T cell deficiency in ageing humans.     

多肽修饰聚合物PLGA-[ASP-PEG]对骨髓基质细胞黏附特性的影响

探讨在PLGA-[ASP-PEG]表面进行多肽改性后,对骨髓基质细胞在其表面黏附力的影响。在骨支架材料PLGA-[ASP-PEG]表面固定多肽GRGDSPC,用微吸管吸吮法测定骨髓基质细胞不同的时间段在骨支架材料表面的黏附力,并进行扫描电镜观察。结果表明:骨髓基质细胞接种在二种支架材料上4 h时,PLGA-[ASP-PEG]表面黏附力为172.78±15.23 N,多肽改性的PLGA-[SP-PEG]细胞黏附力209.47±92.59 N,二者无明显差异;在12h,多肽改性的PLGA-[ASP-PEG]黏附力576.23±165.74 N,PLGA-[ASP-PEG]黏附力为261.84±100.09 N,前者表面细胞黏附力明显强于后者(P<0.01);在24 h时,二种材料表面的细胞黏附力无明显差异(P>0.05)。扫描电镜观察结果为多肽改性支架材料上表面黏附的细胞数明显多于未改性材料表面黏附的细胞数。在生物材料表面结合多肽可以增强细胞在材料表面的黏附力,从而改善生物材料生物相容性。     

Homeostatic migration and distribution of innate immune cells in primary and secondary lymphoid organs with ageing

Ageing of the innate and adaptive immune system, collectively termed immune senescence, is a complex process. One method to understand the components of ageing involves dissociating the effects of ageing on the cells of the immune system, on the microenvironment in lymphoid organs and tissues where immune cells reside and on the circulating factors that interact with both immune cells and their microenvironment. Heterochronic parabiosis, a surgical union of two organisms of disparate ages, is ideal for this type of study, as it has the power to dissociate the age of the cell and the age of the microenvironment into which the cell resides or is migrating. So far, however, it has been used sparingly to study immune ageing. Here we review the limited literature on homeostatic innate immune cell trafficking in ageing in the absence of chronic inflammation. We also review our own recent data on trafficking of innate immune subsets between primary and secondary lymphoid organs in heterochronic parabiosis. We found no systemic bias in retention or acceptance of neutrophils, macrophages, dendritic cells or natural killer cells with ageing in primary and secondary lymphoid organs. We conclude that these four innate immune cell types migrate to and populate lymphoid organs (peripheral lymph nodes, spleen and bone marrow), regardless of their own age and of the age of lymphoid organs.     

In Vivo Effects of Antibodies to Immune Response Gene Products. II. Suppression of Humoral Immune Responses with Monoclonal Anti-I-A Is Due to Suppressor Cells

The I region of the murine major histocompatibility complex (H-2) encodes two cell surface glycoprotein complexes (A_α:A_β and E_α:E_β) which exert profound control over many immunologic reactions including humoral and cellular responses to a variety of antigens, i.e., Ir gene effects, stimulation in mixed lymphocyte reaction, graft versus host disease, antigen presentation to T cells by macrophages, collaboration between T and B cells and determination of T cell help or suppression [1-13]. In the past few years, several laboratories have reported that antibodies directed against I region gene products (anti-la) are effective in modulating immune responses both in vitro and in vivo [14-32, 48-51]. The ability of anti-la antibodies to alter immune responsiveness was attributed to their interaction with macrophage la antigens, thus masking or sterically hindering la epitopes involved in antigen presentation [16,17, 33-35]. However, other reports have suggested that additional mechanisms may be involved [28, 36-39, 49-51]. Experiments with anti-DR (human equivalent of mouse la) and anti-la reagents indicate that these antibodies can induce depression of humoral and cellular responses via active suppression [28, 36-39]. Both T suppressor cells and macrophages have been implicated [28, 36-39]. Additionally, anti-la reagents may deplete antigen specific B cell and helper T cells [48, 50, 51].     

Premature ageing of the immune system underlies immunodeficiency in ataxia telangiectasia

ATM kinase modulates pathways implicated in premature ageing and ATM genotype predicts survival, yet immunodeficiency in ataxia telangiectasia is regarded as mild and unrelated to age. We address this paradox in a molecularly characterised sequential adult cohort with classical and mild variant ataxia telangiectasia. Immunodeficiency has the characteristics of premature ageing across multiple cellular and molecular immune parameters. This immune ageing occurs without previous CMV infection. Age predicts immunodeficiency in genetically homogeneous ataxia telangiectasia, and in comparison with controls, calendar age is exceeded by immunological age defined by thymic naïve CD4+ T cell levels. Applying ataxia telangiectasia as a model of immune ageing, pneumococcal vaccine responses, characteristically deficient in physiological ageing, are predicted by thymic naïve CD4+ T cell levels. These data suggest inherited defects of DNA repair may provide valuable insight into physiological ageing. Thymic naïve CD4+ T cells may provide a biomarker for vaccine responsiveness in elderly cohorts.     

Zinc,infections and immunosenescence

Infections may cause mortality in old age due to damaged immune responses. As zinc is required as a catalyst, structural (zinc fingers) and regulatory ion, it is involved in many biological functions, including immune responses. Low zinc ion bioavailability and impaired cell-mediated immunity are common in ageing and may be restored by physiological supplementation with zinc for 1–2 months, impacting upon morbidity and survival. This article reviews the role of zinc in immune efficacy during ageing, and also describes the main biochemical pathways involved in the role of zinc in resistance to infections in ageing in order to better understand the possible causes of immunosenescence.     

Zinc, infections and immunosenescence

Infections may cause mortality in old age due to damaged immune responses. As zinc is required as a catalyst, structural (zinc fingers) and regulatory ion, it is involved in many biological functions, including immune responses. Low zinc ion bioavailability and impaired cell-mediated immunity are common in ageing and may be restored by physiological supplementation with zinc for 1-2 months, impacting upon morbidity and survival. This article reviews the role of zinc in immune efficacy during ageing, and also describes the main biochemical pathways involved in the role of zinc in resistance to infections in ageing in order to better understand the possible causes of immunosenescence.     

MHC Recombinant Mice: Genetic Tools for Study of Resistance to Viral Disease

Immunology has existed as a recognized scientific field for more than 50 years. Initially, the immune response was thought of mainly in terms of a reaction to infectious disease in live animals. In many immune response models the genes of the major histocompatibility complex (MHC) have played an important role, no doubt because of the importance of MHC gene products in regulating the complex interactions of cells of the immune system. It is now obvious that the rapid progress made nearly 20 years ago in understanding some of the functions of these gene products was in very large measure do to the ability to study and compare inbred mouse populations differing genetically only at certain regions of the MHC. Often these early functional observations could be assigned to particular MHC subregions merely by testing a panel of congenic MHC recombinant mice [1, 2]. This was particularly true in the case of MHC genes involved in resistance to retroviral diseases [3-5].     

Cytokine receptor signalling and aging

With ageing the immune system is deregulated and this leads to the development of immunosenescence mainly affecting the adaptive immune response. There is much knowledge accumulated concerning various receptor functions and signalling with ageing such as TCR, FcRs, TLRs. Cytokines are playing a major role in haematopoietic cell functions and in the harmonious and integrated coordination of the innate and adaptive immune response. There exists a large amount of data on cytokine production changes with ageing, as IL-2 production is decreasing, while IL-6 production is increasing. In contrast, there is only scarce knowledge concerning the cytokine receptors and their signalling in ageing. However, there is some evidence that the signalling of IL-2 receptors is altered in T cells and macrophages, mainly in relation to the JAK/STAT pathway. We present here evidence that the IL-6 induced signalling is also altered in T cells with ageing. An alteration in the JAKs and STATs activations in T cells and macrophages was demonstrated. The exact cause of these altered activations is not known and future studies are needed to elucidate them. In this review we summarise our present knowledge on cytokine signalling with ageing, mainly focusing on IL-2 and IL-6 receptors signalling.     

The role of contrasuppressor T cells in the adoptive transfer of contact sensitivity responses to picryl chloride

It is clear that the regulation of the immune response to contact-sensitizing agents is very complex. At least three functionally distinct cell types are involved in the initial response to antigen. These cells can be regulated by the activity of suppressor T cells directed at either the PCl-F-producing cell [17, 18], the Tinf cell [17, 18], or the natural contrasuppressor cell [27]. Within at least one of these populations are two subpopulations of suppressor cells, the Ts-afferent cells and the Ts-efferent cells [4, 13]. It is likely that not all of these regulatory cells are unique, but rather mediate different immunologic activities based on the circumstances of their surroundings. As an example, it has been found that unique functional activities can be ascribed to certain domains of regulatory molecules secreted by Ts cells [30–32], and it is possible that each Ts cell subset mediates multiple functions depending on its partner or target cell [33–35]. The similarities in functional activity between Ts and Tcs suggest that Tcs cells may also have a heterogeneity of functional activity. What is clear is that wherever there is suppression there is likely to be contrasuppression, and we have described at least two levels of contrasuppression active in the regulation of contact sensitivity. The challenge to all of us is to discover how the immune system activates and utilizes these diametrically opposed activities to function normally.     

Ageing of the gut microbiome: Potential influences on immune senescence and inflammageing

Advancing age is accompanied by changes in the gut microbiota characterised by a loss of beneficial commensal microbes that is driven by intrinsic and extrinsic factors such as diet, medications, sedentary behaviour and chronic health conditions. Concurrently, ageing is accompanied by an impaired ability to mount a robust immune response, termed immunesenescence, and age-associated inflammation, termed inflammaging. The microbiome has been proposed to impact the immune system and is a potential determinant of healthy aging. In this review we summarise the knowledge on the impact of ageing on microbial dysbiosis, intestinal permeability, inflammaging, and the immune system and investigate whether dysbiosis of the gut microbiota could be a potential mechanism underlying the decline in immune function, overall health and longevity with advancing age. Furthermore, we examine the potential of altering the gut microbiome composition as a novel intervention strategy to reverse the immune ageing clock and possibly support overall good health during old age.     

Immunosenescence: ageing of the immune system

Suboptimal function of an aged immune system may contribute significantly to morbidity and mortality in the elderly. At present, little is known of the biochemistry and molecular genetics of immunosenescence in humans. A recent meeting¹ brought together an interdisciplinary group to discuss whether current understanding of the molecular basis of ageing in other cells might be relevant to ageing of the immune system.     

Is cell death and replacement a factor in aging?

The central theme of the 3rd International Conference on Functional Genomics of Ageing was tissue regeneration as a remedial strategy to address age-related cellular damage and the pathology that ensues. The conference included sessions on maintaining genome integrity and the potential of stem cells to restore function to damaged tissues. In addition to several human syndromes that appear to reflect accelerated ageing, there are now a number of mouse models that prematurely display phenotypes associated with ageing. The intent of this summary presented at the end of the conference was to: (1) discuss various human syndromes and mouse models of accelerated ageing; (2) evaluate whether the phenotypes displayed might result from an elevated rate of cell death coupled with an inability to adequately maintain cell number in various tissues with increasing age; and (3) discuss whether similar events may be occurring during normal ageing, albeit much more slowly.     

Apoptotic capability in ageing T cells

The ageing immune system shows a gradual decline in responsiveness to antigens and tumours due to the emergence of immunosenescence. The main functions of T cells are activation, anergy and apoptosis and these are all affected during ageing. Apoptosis is vital in controlling cell numbers, deleting self-reactive T cells and maintaining immune surveillance. One of the principle instigators of death involves the CD95:CD95-ligand interaction and as T cells age both receptor and ligand levels increase. This view will describe the current knowledge of the apoptotic susceptibility of ageing T cells and evaluate the factors that may affect the apoptotic capability of immunosenescent T cells.     

Apoptotic capability in ageing T cells

The ageing immune system shows a gradual decline in responsiveness to antigens and tumours due to the emergence of immunosenescence. The main functions of T cells are activation, anergy and apoptosis and these are all affected during ageing. Apoptosis is vital in controlling cell numbers, deleting self-reactive T cells and maintaining immune surveillance. One of the principle instigators of death involves the CD95:CD95-ligand interaction and as T cells age both receptor and ligand levels increase. This view will describe the current knowledge of the apoptotic susceptibility of ageing T cells and evaluate the factors that may affect the apoptotic capability of immunosenescent T cells.     

The earlier age of onset of malignancy in developing world is related to overall infection burden and could be due to the effect on telomere length

It is a common observation that many common cancers occur at a younger age in developing countries, like India. The cancer registry data provide incidence rate of different cancers, which suggest the same. Telomere shortening is involved in ageing of cells. Inflammation and infection result in telomere shortening in immune cells. The higher infection burden in developing countries might mean an earlier ageing of immune cells, resulting in decreased efficiency of immune surveillance and thus predisposing to cancer at an earlier age than seen in developed countries with lesser infection burden.