Oral tolerance revisited: prior oral tolerization abrogates cholera toxin-induced mucosal IgA responses

Oral delivery of a large dose or prolonged feeding of protein Ags induce systemic unresponsiveness most often characterized as reduced IgG and IgE Ab- and Ag-specific CD4(+) T cell responses. It remains controversial whether oral tolerance extends to diminished mucosal IgA responses in the gastrointestinal tract. To address this issue, mice were given a high oral dose of OVA or PBS and then orally immunized with OVA and cholera toxin as mucosal adjuvant, and both systemic and mucosal immune responses were assessed. OVA-specific serum IgG and IgA and mucosal IgA Ab levels were markedly reduced in mice given OVA orally compared with mice fed PBS. Furthermore, when OVA-specific Ab-forming cells (AFCs) in both systemic and mucosa-associated tissues were examined, IgG AFCs in the spleen and IgA AFCs in the gastrointestinal tract lamina propria of mice given OVA orally were dramatically decreased. Furthermore, marked reductions in OVA-specific CD4(+) T cell proliferative and cytokine responses in spleen and Peyer's patches were seen in mice given oral OVA but were unaffected in PBS-fed mice. We conclude that high oral doses of protein induce both mucosal and systemic unresponsiveness and that use of mucosal adjuvants that induce both parenteral and mucosal immunity may be a better way to assess oral tolerance.     

Mechanisms underlying insect freeze tolerance

Freeze tolerance – the ability to survive internal ice formation – has evolved repeatedly in insects, facilitating survival in environments with low temperatures and/or high risk of freezing. Surviving internal ice formation poses several challenges because freezing can cause cellular dehydration and mechanical damage, and restricts the opportunity to metabolise and respond to environmental challenges. While freeze‐tolerant insects accumulate many potentially protective molecules, there is no apparent ‘magic bullet’ – a molecule or class of molecules that appears to be necessary or sufficient to support this cold‐tolerance strategy. In addition, the mechanisms underlying freeze tolerance have been minimally explored. Herein, we frame freeze tolerance as the ability to survive a process: freeze‐tolerant insects must withstand the challenges associated with cooling (low temperatures), freezing (internal ice formation), and thawing. To do so, we hypothesise that freeze‐tolerant insects control the quality and quantity of ice, prevent or repair damage to cells and macromolecules, manage biochemical processes while frozen/thawing, and restore physiological processes post‐thaw. Many of the molecules that can facilitate freeze tolerance are also accumulated by other cold‐ and desiccation‐tolerant insects. We suggest that, when freezing offered a physiological advantage, freeze tolerance evolved in insects that were already adapted to low temperatures or desiccation, or in insects that could withstand small amounts of internal ice formation. Although freeze tolerance is a complex cold‐tolerance strategy that has evolved multiple times, we suggest that a process‐focused approach (in combination with appropriate techniques and model organisms) will facilitate hypothesis‐driven research to understand better how insects survive internal ice formation.     

Mechanisms of plant desiccation tolerance.

Anhydrobiosis ("life without water") is the remarkable ability of certain organisms to survive almost total dehydration. It requires a coordinated series of events during dehydration that are associated with preventing oxidative damage and maintaining the native structure of macromolecules and membranes. The preferential hydration of macromolecules is essential when there is still bulk water present, but replacement by sugars becomes important upon further drying. Recent advances in our understanding of the mechanism of anhydrobiosis include the downregulation of metabolism, dehydration-induced partitioning of amphiphilic compounds into membranes and immobilization of the cytoplasm in a stable multicomponent glassy matrix.     

Mechanisms of salinity tolerance in plants

The mechanisms of salt stress response and tolerance have eluded definition despite reasonable success in defining their physiological manifestations. In this review, we consider the integrated salt metabolism of plants, essentially as a problem in meganutrient physiology. Two critical aspects of cellular and organismal metabolism are given particular attention—those involved in the control and integration of Na⁺ acquisition and allocation in plants and those involved in readjustment of other aspects of metabolism, especially those involving carbon as a resource.     

Kinetic analysis of oral tolerance: memory lymphocytes are refractory to oral tolerance.

Oral administration of soluble Ag before immunization induces peripheral tolerance and is effective in suppressing animal models of autoimmune diseases. Although tolerance induction in primed animals is more clinically relevant, it is not well studied. Therefore, this study was designed to examine the feeding effects on different phases of the immune response. We observed that feeding a single high dose (250 mg) of OVA to OVA-primed BALB/c mice could induce OVA-specific suppression in the Ab production and T cell proliferation only at the naive and the activation phases of the immune response, whereas multiple high doses (100 mg/feed for 10 days) were effective at the effector phase. OVA-specific IL-4 production in culture supernatant was also suppressed in the tolerized groups. However, when the mice had resting memory lymphocytes, even multiple feeding regimens were not effective in tolerance induction, although multiple low doses (1 mg/feed for 10 days) partially suppressed Ab production. This phenomenon was confirmed by adoptive transfer study. Nevertheless, the reactivated memory response was suppressed partially by multiple high doses. Our findings have an important implication for understanding the mechanism of oral tolerance and for the therapeutic applications of oral tolerance to autoimmune diseases.     

Desiccation tolerance of Sphagnum revisited: a puzzle resolved

As ecosystem engineers, Sphagnum mosses control their surroundings through water retention, acidification and peat accumulation. Because water retention avoids desiccation, sphagna are generally intolerant to drought; however, the literature on Sphagnum desiccation tolerance (DT) provides puzzling results, indicating the inducible nature of their DT. To test this, various Sphagnum species and other mesic bryophytes were hardened to drought by (i) slow drying; (ii) ABA application and (iii) chilling or frost. DT tolerance was assessed as recovery of chlorophyll fluorescence parameters after severe desiccation. We monitored the seasonal course of DT in bog bryophytes. Under laboratory conditions, following initial de‐hardening, untreated Sphagnum shoots lacked DT; however, DT was induced by all hardening treatments except chilling, notably by slow drying, and in Sphagnum species of the section Cuspidata. In the field, sphagna in hollows and lawns developed DT several times during the growing season, responding to reduced precipitation and a lowered water table. Hummock and aquatic species developed DT only in late autumn, probably as a response to frost. Sphagnum protonemata failed to develop DT; hence, desiccation may limit Sphagnum establishment in drier habitats with suitable substrate chemistry. Desiccation avoiders among sphagna form compact hummocks or live submerged; thus, they do not develop DT in the field, lacking the initial desiccation experience, which is frequent in hollow and lawn habitats. We confirmed the morpho‐physiological trade‐off: in contrast to typical hollow sphagna, hummock species invest more resources in water retention (desiccation avoidance), while they have a lower ability to develop physiological DT.     

Mechanisms of starvation tolerance in pearl millet

The response of pearl millet (Pennisetum glaucum [L.]) seedlings to prolonged starvation was investigated at the biochemical and ultrastructural level. After 2 days of darkness the bulk of the seedling carbohydrate reserves were depleted. After 8 days in the dark the respiratory rate had declined to less than 50% of its initial value and the plants had lost half of their total protein content. Unlike the situation with carbohydrate depletion, protein loss was restricted to specific organs. The secondary leaf and stem (including the apical meristem) showed little or no protein loss during this period. In the primary leaf, seed, and roots, protein loss was substantial. In spite of the high rate of protein degradation in the primary leaf and roots, these organs showed no ultrastructural changes suggestive of tissue, cellular, or subcellular degradation. In addition, ribulose bisphosphate carboxylase was not preferentially degraded during starvation and only a small decline in chlorophyll content was observed after 8 days in the dark. During the period from 8 to 14 days, cell death started at the tip of the primary leaf and gradually spread downward. Both shoot and root meristems remained alive up to 14 days. Consequently, the eventual death of the plant was due to the loss of the carbohydrate-producing regions rather than the meristems. We suggest that these results provide an explanation for the high degree of starvation tolerance exhibited by pearl millet.     

Protein hydrolysates for oral tolerance

To induce oral tolerance in multiple sclerosis treatment, we proposed to use the predigested protein of pig spinal cord. The most biologically active composition was obtained from the hydrolysis of an undenaturated homogenate of proteins digested with pepsin. Feeding the rats with our preparation, before or after immunization with MS antigens, strongly reduced development of the experimental autoimmune encephalomyelitis (EAE). The biological results obtained in animals suggest that the developed method of induction of the oral tolerance should be effective in human treatment, at least as a support mechanism in combination with other treatment methods.     

Mechanisms of tolerance induction: blockade of co-stimulation

Induction of tolerance to transplantation antigens is believed to be a promising way to achieve long-term allograft survival without a deleterious immunosuppressive regimen. T-cell activation, which is an essential feature of graft rejection, requires a first signal provided by T-cell receptor (TCR) ligation and a second signal provided by engagement of co-stimulatory molecules with their respective ligands on antigen-presenting cells. The coordinated triggering of these two independent signalling systems ensures the full T-cell activation, including proliferation and acquisition of effector function. TCR occupancy in the absence of co-stimulatory signals leads to a sustained loss of antigen responsiveness called clonal anergy, which could be of major importance in transplantation. In vivo, co-stimulation blockade was indeed shown to allow for long-term allograft survival in several transplantation models. However, the current continuous identification of new co-stimulatory molecules suggests that a functional redundancy of the system exists and that tolerance to transplantation antigens might be achieved more easily through the combined blockade of two or several co-stimulatory signals. In this review, we analyse the biological effects of the disruption of some co-stimulation pathways in vitro and in vivo and discuss their potential interest for tolerance induction.     

Mechanisms and evolution of hypoxia tolerance in fish

The ability of an organism to acquire O(2) from its environment is key to survival and can play an important role in dictating a species' ecological distribution. This study is the first, to our knowledge, to show a tight, phylogenetically independent correlation between hypoxia tolerance, traits involved in dictating O(2) extraction capacity and the distribution of a group of closely related fish species, sculpins from the family Cottidae, along the nearshore marine environment. Sculpins with higher hypoxia tolerance, measured as low critical O(2) tensions (P(crit)), inhabit the O2 variable intertidal zones, while species with lower hypoxia tolerance inhabit the more O(2) stable subtidal zone or freshwater. Hypoxia tolerance is phylogenetically independently associated with an enhanced O(2) extraction capacity, with three principal components accounting for 75 per cent of the variation in P(crit): routine O(2) consumption rate; mass-specific gill surface area; and whole blood haemoglobin (Hb)- O(2)-binding affinity (P(50)). Variation in whole blood Hb-O(2)P(50) is strongly correlated with the intrinsic O(2)-binding properties of the purified Hb while the differences in the concentration of the allosteric Hb modulators, ATP and GTP, provide a Hb system with substantial plasticity for survival in a highly O(2) variable environment.     

Mechanisms of hyphal tip growth: tube dwelling amebae revisited

Over 100 years ago, Reinhardt suggested that hyphal tip growth is comparable to ameboid movement inside a tube; the apical cytoplasm being protruded like a pseudopodium with the wall assembled on its surface. There are increasing data from hyphae which are explicable by this model. Fungi produce pseudopodia-like structures and their cytoplasm contains all of the major components implicated in pseudopodium production in animal cells. Most of these components are concentrated in hyphal tips and tip growth involves actin, a major component of pseudopodia. Together these data indicate that the essence of the ameboid model is still tenable. However, detailed mechanisms of tip growth remain too poorly known to provide definitive proof of the model and the behavior of the trailing cytoplasm indicates differences which are probably a response to the walled lifestyle.     

Mechanisms of polyclonal tolerance induced by lipopolysaccharide and cyclophosphamide

The treatment of recipient mice with LPS from S. marcescens followed by the injection of CY 48 h later inhibited a subsequent antibody production against unrelated antigen (SRBC) and polyclonal mitogen (LPS from Br. abortus). Such a reactivity persisted for 2-3 weeks after treatment. It was shown that the number of Ig+ cells in the spleens of treated mice was decreased, while the population of spleen Thy-1.2+ cells remained unaltered. Cell-cooperative test revealed that the function of B cells, but not T cells, was inhibited by the treatment. There were no changes in DTH response to SRBC. Thus, a subsequent treatment of mice with LPS and CY led to B-cell deficiency. The nature of this phenomenon is presumably the same as the nature of CY-induced antigen-specific immunological tolerance.