Immunologic 'ignorance' of vascularized organ transplants in the absence of secondary lymphoid tissue

Secondary lymphoid organs (the spleen, lymph nodes and mucosal lymphoid tissues) provide the proper environment for antigen-presenting cells to interact with and activate naive T and B lymphocytes. Although it is generally accepted that secondary lymphoid organs are essential for initiating immune responses to microbial antigens and to skin allografts, the prevailing view has been that the immune response to primarily vascularized organ transplants such as hearts and kidneys does not require the presence of secondary lymphoid tissue. The assumption has been that the immune response to such organs is initiated in the graft itself when recipient lymphocytes encounter foreign histocompatibility antigens presented by the graft's endothelial cells. In contrast to this view, we show here that cardiac allografts are accepted indefinitely in recipient mice that lack secondary lymphoid tissue, indicating that the alloimmune response to a vascularized organ transplant cannot be initiated in the graft itself. Moreover, we demonstrate that the permanent acceptance of these grafts is not due to tolerance but is because of immunologic 'ignorance'.     

Re-establishing peripheral tolerance in the absence of CTLA-4: complementation by wild-type T cells points to an indirect role for CTLA-4

CTLA-4 plays an important role in the down-regulation of activated T cells and in the establishment of peripheral tolerance. It has been hypothesized that CTLA-4 on the cell surface signals directly into T cells during primary immune responses, resulting in intrinsic T cell down-regulation. It is not known, however, whether CTLA-4 directly inhibits the less intense activating signals received by autoreactive T cells in the periphery. We investigated whether CTLA-4 acts intrinsically upon self-reactive cells in vivo, or whether it inhibits autoreactive cells indirectly, in a non-cell autonomous manner. The adoptive transfer of CTLA-4-deficient splenocytes or Thy 1(+) cells into recombinase-activating gene 2-deficient mice resulted in fatal inflammation and tissue destruction similar to that seen in CTLA-4-deficient mice. When an equivalent number of splenocytes or Thy 1(+) cells from wild-type animals was transferred with the CTLA-4-deficient cells, recipient mice survived indefinitely. Since CTLA-4 was absent in the T cells responsible for the inflammatory phenotype, the down-regulation of these autoreactive cells must have been facilitated indirectly by wild-type Thy 1(+) cells. In addition, a rapid reduction in the ratio of CTLA-4-deficient to wild-type cells was observed. We propose two possible indirect mechanisms by which CTLA-4 may function in the establishment and maintenance of peripheral tolerance.     

Maternal acceptance of the fetus: true human tolerance

Induction and maintenance of immunologic tolerance in humans remains a desirable but elusive goal. Therefore, understanding the physiologic mechanisms of regulation of immune responses is highly clinically relevant for immune-mediated diseases (e.g., autoimmunity and asthma/allergy) and for cell and organ transplantation. Acceptance of the fetus, which expresses paternally inherited alloantigens, by the mother during pregnancy is a unique example of how the immune system reshapes a destructive alloimmune response to a state of tolerance. Understanding the complex mechanisms of fetomaternal tolerance has important implications for developing novel strategies to induce immunologic tolerance in humans in general and for prevention of spontaneous abortion in at-risk populations in particular.     

New strategies in immune tolerance induction

Induction of tolerance in clinical organ transplantation that will obviate the use of chronic immunosuppression and preserve host immune response to other antigens remains the goal of transplant research. The thymus plays a critical role in the ability of the immune system to discriminate between self- and nonself-antigens or harmful and harmless alloantigens. We now know that multiple factors determine how the immune system responds to a self-antigen or foreign antigen. These determinants include developmental stage of the host, stage of T-cell maturity, site of antigen encounter, type and maturity of antigen-presenting cells, and presence and type of costimulatory molecules. Our understanding of the mechanisms of T-cell interactions with peptide/major histocompatibility complex in peripheral lymphoid organs has led to experiments that translate into peripheral T-cell tolerance. The induction of high-avidity peripheral alloreactive T cells in the early phase of organ transplantation makes it difficult to achieve long-term alloantigen-specific tolerance without the use of transient perioperative immunosuppression. Therefore, protocols that induce robust tolerance in rodent and nonhuman primate models involve the use of donor antigen combined with a short course of perioperative immunosuppression. These studies suggest that the underlying mechanisms of peripheral tolerance include deletion, anergy, immune deviation, and regulatory T cells. This review focuses on recent advances in tolerance induction in experimental animal models and discusses their relevance to the development of protocols for the induction and maintenance of clinical transplant tolerance.     

The selective advantage of reaction norms for environmental tolerance

A tolerance curve defines the dependence of a genotype's fitness on the state of an environmental gradient. It can be characterized by a mode (the genotype's optimal environment) and a width (the breadth of adaptation). It seems possible that one or both of these characters can be modified in an adaptive manner, at least partially, during development. Thus, we extend the theory of environmental tolerance to include reaction norms for the mode and the width of the tolerance curve. We demonstrate that the selective value of such reaction norms increases with increasing spatial heterogeneity and between-generation temporal variation in the environment and with decreasing within-generation temporal variation. Assuming that the maintenance of a high breadth of adaptation is costly, reaction, norms are shown to induce correlated selection for a reduction in this character. Nevertheless, regardless of the magnitude of the reaction norm, there is a nearly one to one relationship between the optimal breadth of adaptation and the within-generation temporal variation perceived by the organism. This suggests that empirical estimates of the breadth of adaptation may provide a useful index of this type of environmental variation from the organism's point of view.     

A critical review of the taxonomy of Gulgastrura reticulosa (Collembola: Hypogastruridae), a cave springtail from Korea

ABSTRACT. The cave collembolan Gulgastrura reticulosa was re-examined from a systematic point of view, using data obtained from scanning electron microscopy and investigation of temperature tolerances and moulting cycles. Absences of the third antennal organ, postantennal organ, pseudocellus, eyes and furca were confirmed, along with the prominent development, by contrast, of an "apical organ" at the apex of the antenna. The intermoulting period was shown to be 110 days on average at 9.5°C which is almost twice as long as the longest known intermoulting period for a collembolan. These exceptional characteristics are suggestive of drastic divergence from existing family groups of Collembola. It is suggested that the erection of a new family, separate from the Hypogastruridae to which Gulgastrura was assigned by the original author, may become appropriate some time in the future when evidence other than of morphology becomes available supporting this divergence. Gulgastrura is apparently limited to cave entrances, rendering the animal enigmatic in view of the usual occurrence of troglobites deep in caves.     

Editorial

Welcome to issue two of Organogenesis! On the following pages, you will find another selection of papers describing ground-breaking work at the interface of developmental biology and organ transplantation and regeneration.

Two of the papers concern the stability of differentiation in the gut and its appendages, and carry important implications for regeneration and tissue engineering. The review by Shen et al. [1] considers the propensity of cells of the gastrointestinal system to transdifferentiate; that is, to taken on the differentiated state characteristic of another organ or part of an organ. As well as being very interesting from the point of view of basic developmental biology, this transdifferentiation offers a great hope to regenerative medicine because it may be possible to use an undamaged organ as a source of cells to replace those in a damaged organ. Pancreas, for example, may contain cells that can be persuaded to build new liver. The original report by Lear et al. challenges the traditional view that islet cells of the pancreas develop only from endodermal precursors and suggests that, at least in culture models, islet cells can differentiate from the mesenchyme as well. Again, the message is that lineage in the gastrointestinal system is not as inflexible as was once thought: future work may uncover the signals that promote ‘unconventional’ differentiation and, therefore, open new paths to regeneration.

Stability of differentiation is also connected, tangentially, with the paper that demonstrates a negative correlation between the evolutionary age of an organ and that organ’s propensity to become cancerous in humans. This correlation may be entirely spurious, or it may indicate some deep-seated instability in the differentiated states of ‘modern’ organs, an instability we may one day be able either to use or to control.

The remaining papers address aspects of transplantation, and both point to techniques that may one day improve clinical outcomes. Rogers and Hammerman report a novel way of stimulating the development and function of transplanted foetal kidneys by treating them, just before transplantation, with vitamin D3. The mechanism by which vitamin D3 works in this system is not yet clear. Indeed, the fact vitamin D3 is more effective than its derivative, 1,25(OH)2D3, which is the active molecule in most systems, suggests that the explanation will not be simple. Nevertheless, from a technical point of view, Rogers and Hammerman’s technique can begin to be useful even before it is understood deeply. The report by Sawada et al. focuses on the largest and most accessible organ of the human body, the skin. The authors describe a transplantation technique that can be used to expand the area of epithelium by culturing it in vivo in a way that encourages it to form a cyst.

I hope you enjoy this issue, and that you will consider Organogenesis for publication of your own research in the general areas of organ development, regeneration, and tissue engineering.     

The early development of the Jacobson's organ in the cat (Felis silvestris)

The histological study of the nose of an embryo of the cat (Felis silvestris 10 mm) presents a simple cavity which caudally communicates with the oral cavity by a narrow cleft, the primitive choana. This aperture results from the former rupture of the membrana bucconasalis of which the present material still contains remnants. Compared to the simple nasal cavity, the organ of Jacobson, situated at the base of the broad fetal nasal septum, shows a progressive development. From this one might conclude, according to ontogenetical rules, an early functional importance of the accessory olfactory organ. The currently fetal nose under investigation presents the organ as a primary open groove which increases in depth from rostral to caudal. Only caudally, a short section of the organ is already formed into a tube. From the functional point of view, the epithelial lining of this organ is still undifferentiated, but its dorsal part is clearly thickened. It seems that this indicates an early arrangement of the later olfactory epithelium. Beside this it is striking that in early fetal life, the organ of Jacobson extends to a remarkable length within the nasal cavity. Obviously the organ occupies, early in ontogeny, its area inside the little developed nose. Finally, the striking resemblance of the topography of the organ of Jacobson between early embryos of mammals and those of fetal and even some adult reptiles is discussed.     

Commitment events in early G1 requirement for the synthesis of dolichol dependent glycoproteins

Dolichol functions as a carrier of oligosaccharides to polypeptide chains in the biosynthesis of N-linked glycoproteins. It is here reported that a short (4 hours) transient exposure to tunicamycin, (a specific inhibitor of dolichol dependent glycosylation) causes a cell cycle delay in post-mitotic 3T3-cells. From kinetic point of view the delay following treatment by tunicamycin resembles the delay caused by short exposures to serum deprivation or treatment by cycloheximide, indicating that the expression of N-linked glycoproteins may be involved in the cell cycle regulation. Evidence is that the availability of dolichol may be a limiting factor in this process is also presented.     

Neonatal tolerance in the absence of Stat4- and Stat6- dependent Th cell differentiation

Neonatal tolerance to specific Ag is achieved by nonimmunogenic exposure within the first day of life. The mechanism that regulates this tolerance may provide the basis for successful organ transplantation and has recently been thought to be immune deviation from the inflammatory Th1 response to a Th2 response. To test the importance of Th2 cells in the establishment of neonatal tolerance, we examined neonatal tolerance in Stat4- and Stat6-deficient mice, which have reduced Th1 and Th2 cell development, respectively. Neonatal tolerance of both the T and B cell compartments in Stat4- and Stat6-deficient mice was similar to that observed in wild-type mice. Cytokine production shifted from a Th1 to a Th2 response in wild-type mice tolerized as neonates. In contrast, tolerance was observed in Stat6-deficient mice despite maintenance of a Th1 cytokine profile. These results suggest that cells distinct from Stat6-dependent Th2 cells are required for the establishment of neonatal tolerance.     

Induction of transplantation tolerance in guinea pigs by spleen allografts. II. Responses in the mixed leukocyte reaction correlate with the tolerant state

We have developed a model for the induction of transplantation tolerance in the guinea pig by vascularized spleen allografts. Spleen allografts from strain 13 to strain 2 hosts frequently survived in healthy recipients without clinical GVHD or induced clinical GVHD. (2 x 13)F1 to strain 2 spleen allografts survived indefinitely without inducing GVHD. In contrast, strain 2 spleen allografts were rejected by strain 13 hosts. An excellent correlation was observed between the clinical course and the degree of reactivity to donor strain stimulator cells in the MLR. Animals that had rejected their grafts had normal or enhanced proliferative responses in the MLR. Strain 2 hosts with long-term surviving strain 13 or (2 x 13)F1 grafts had markedly suppressed anti-13 responses. Animals with GVHD had a suppressed MLR toward donor strain stimulator cells with simultaneous reactivity to host strain stimulator cells. Cells capable of suppressing the response of normal host strain cells to donor strain stimulators were present in some long-term surviving animals and may be responsible in part for the maintenance of the tolerant state.     

Outline of a mathematical biology of leadership

Leadership, whether executive, political or any other type, is connected with the achievement of some goal by the social group through an appropriate organization of that group. From this point of view different leadership ranks in a group would be assigned to individuals according to their ability to organize the group for the purpose of reaching a specific goal. The situation is actually complicated by the circumstance that an individual may have the necessary ability but may not like the responsibility connected with the leadership, or vice versa. Also, he may not be interested in the goal. The suggested mathematical approach is to consider that the satisfaction of an individual is a function of his leadership rank, of the goal, and of several other parameters. If each individual tends to adjust his position in society so as to maximize his own satisfaction, this condition gives us the equations which determine the leadership rank of each individual. It is found that, in general, the rank of an individual depends not only on his ability, but on the abilities of all other individuals. The method enables us to calculate the distribution function of abilities among individuals of a given rank, and leads to results which allow, in principle, experimental verification.     

Neonatal tolerance to hypoxia: a comparative-physiological approach.

Newborn mammals exhibit a number of physiological reactions which differ from normal adult physiology and are often regarded as signs of immaturity. However, when looked upon from a comparative point of view, it becomes obvious that some of these 'physiological peculiarities' bear striking similarity to adaptation mechanisms known from hypoxia-tolerant animals and may thus contribute to the well-established, yet poorly understood, phenomenon of neonatal hypoxia tolerance. As the mammalian fetus lives at oxygen partial pressures corresponding to 8000 m altitude, the first line of perinatal hypoxia defense consists of long-term adaptations to limited intrauterine oxygen supply: (1) improved O2 transport by fetal acclimatization to high altitude, (2) reduced metabolic rate by hibernation-like deviation from metabolic size allometry, (3) diminished cerebral vulnerability by functional analogies to diving turtle brain, and (4) enhanced metabolic flexibility by optional repartitioning of energy supply from growth to maintenance metabolism. In the case of birth asphyxia, these background mechanisms are complemented by short-term responses to acute oxygen lack: (1) reduction of body temperature as in natural torpor, (2) reduction of heart rate and redistribution of circulation as in diving mammals, (3) reduction of respiration rate typical of 'hypoxic hypometabolism', and (4) reduction of blood pH according to the concept of 'acidotic torpidity'. Although anaerobic metabolism is improved in neonatal mammals by increased glycogen stores, reduced metabolic demands, and sustained wash-out of acid metabolites, neonatal hypoxia tolerance seems to be primarily based on the ability to maintain tissue aerobiosis as long as possible. This is even reflected by isoenzyme patterns which do not consistently favour anaerobic glycolysis and, thus, are reminiscent of the 'lactate paradox' found in high altitude adaptation. Altogether, from a biological point of view, the perinatal period appears as a source of adaptive mechanisms that can be refound, in varying combinations, in many survival strategies. From a clinical point of view, the interplay of long- and short-term mechanisms offers a novel approach to estimation of the newborn's ability to withstand temporary oxygen lack. However, most of these mechanisms are not unambiguous and, above all, not unlimited in their protective effect so that they do not release obstetricians or neonatologists from their obligation to counteract fetal or neonatal hypoxia without delay.     

Bone As An Endocrine Organ

ObjectiveTo review the recent evidence that has emerged supporting the role of bone as an endocrine organ.MethodsThis review will detail how bone has emerged as a bona fide endocrine “gland,” and with that, the potential therapeutic implications that could be realized for this hormone-secreting tissue by detailing the evidence in the literature supporting this view.ResultsThe recent advances point to the skeleton as an endocrine organ that modulates glucose tolerance and testosterone production by secretion of the bone-specific protein osteocalcin.ConclusionsBone has classically been viewed as an inert structure that is necessary for mobility, calcium homeostasis, and maintenance of the hematopoietic niche. Recent advances in bone biology using complex genetic manipulations in mice have highlighted the importance of bone not only as a structural scaffold to support the human body, but also as a regulator of a number of metabolic processes that are independent of mineral metabolism. (Endocr Pract. 2012;18:758-762)     

Rapamycin in combination with donor-specific CD4CD25Treg cells amplified in vitro might be realize the immune tolerance in clinical organ transplantation

It is an urgent need to induce and keep the donor-specific immune tolerance without affecting the function of normal immune defense and immune surveillance in clinical organ transplantation. Large number of studies showed that both the establishment of donor-recipient chimerism and the application of antibodies or drugs could obtain the donor-specific immune tolerance in animal transplantation model. However, the former as treatment of clinical practice has a poor feasibility, the latter has a very low success rate in clinical organ transplantation. There is a group of naturally occurring CD4⁺CD25⁺ regulatory T cells (Tregs) that mediate immune tolerance by suppressing alloreactive T cells in vivo. These cells are unable to curb the occurrence of allograft rejection owing their low content. And donor-specific Tregs amplified in vitro alone can not induce donor-specific immune tolerance for recipient. Rapamycin (RPM) as a proliferation signal inhibitor, studies have shown it can effectively inhibit allograft rejection and maybe contribute to induction of immune tolerance. But there exist still many dose-dependent adverse reactions which could prevent the establishment of immune tolerance and reduce the life quality of recipients in the clinical application of RPM. Therefore, we speculate a small amount of RPM combined with donor-specific Tregs amplified in vitro may be not only induce the achievement of donor-specific tolerance, but also reduce or eliminate the side effects of RPM in clinical organ transplantation.     

Natural selection, infectious transfer and the existence conditions for bacterial plasmids

Despite the near-ubiquity of plasmids in bacterial populations and the profound contribution of infectious gene transfer to the adaptation and evolution of bacteria, the mechanisms responsible for the maintenance of plasmids in bacterial populations are poorly understood. In this article, we address the question of how plasmids manage to persist over evolutionary time. Empirical studies suggest that plasmids are not infectiously transmitted at a rate high enough to be maintained as genetic parasites. In part i, we present a general mathematical proof that if this is the case, then plasmids will not be able to persist indefinitely solely by carrying genes that are beneficial or sometimes beneficial to their host bacteria. Instead, such genes should, in the long run, be incorporated into the bacterial chromosome. If the mobility of host-adaptive genes imposes a cost, that mobility will eventually be lost. In part ii, we illustrate a pair of mechanisms by which plasmids can be maintained indefinitely even when their rates of transmission are too low for them to be genetic parasites. First, plasmids may persist because they can transfer locally adapted genes to newly arriving strains bearing evolutionary innovations, and thereby preserve the local adaptations in the face of background selective sweeps. Second, plasmids may persist because of their ability to shuttle intermittently favored genes back and forth between various (noncompeting) bacterial strains, ecotypes, or even species.     

Maintenance of segment and appendage primordia by the Tribolium gene knödel

For homeotic and segment-polarity genes in Drosophila, a switch in gene regulation has been described that distinguishes patterning and maintenance phases. Maintenance of segment and organ primordia involves secondary patterning and differentiation steps, as well as survival factors regulating proliferation and organ size. In a screen for embryonic lethal mutations in the flour beetle Tribolium castaneum, we have recovered two alleles of the kn?del gene, which result in short, bag-like embryos. These embryos have severely reduced appendages and differentiate a cuticle that lacks most overt signs of segmentation. In addition, they lack bristles and display defects in the nervous system. Early patterning in kn?del mutant embryos is normal up to the extended germ band stage, as indicated by the formation of regular even-skipped (Tc'eve) and wingless (Tc'wg) stripes. Afterwards, however, these patterns degenerate. Similarly, proximo-distal growth and patterning of limbs are nearly normal initially, but limb primordia shrink, and proximo-distal patterns degenerate, during subsequent stages. kn?del could be a segment polarity gene required for segment border maintenance in both trunk and appendages. Alternatively, it may have a more general role in tissue or organ maintenance.     

Stay wet or else: three ways in which plants can adjust hydraulically to their environment

The literature on whole-plant acclimation to drought is reviewed and it is proposed that leaf-level homeostasis in water status is attained during ontogeny largely thanks to whole-plant changes in physical resistance to liquid water flow caused by morphological and anatomical adjustments. It is shown that, in response to water deficits, plant resistance changes at different levels (tissue, organ, individual), levels that are correlated with the time scale of the response. It was found that such adjustments apparently tend to increase resistance to flow in the short term and to reduce it in the long term. A critical view of those findings is provided based on the principle that drought-induced changes cannot be analysed separately from the allometric changes that take place through ontogeny, as for example proposed by the widely cited hydraulic limitation hypothesis. A graphic synthetic model is presented according to which developmental responses to water deficits operate largely through reductions in whole-plant water transport capacity, combined with more or less strong reductions in leaf area (different "hydraulic allometries"), depending on the intrinsic tolerance of leaf tissues to partial desiccation. The model is used to show that, as the result of such adjustments, the water transport capacity per unit leaf area can decrease, remain constant, or increase, and it is argued that the expected leaf-level response would be different in each case, respectively involving a decreased, constant, or increased potential for transpiration. The article ends with a plea to collect the evidence needed to evaluate the occurrence of these three different response types across taxa and their association with different environments, including the reanalysis of existing data.     

Insulin secretion, carbohydrate tolerance, fat metabolism and body weight in maturity onset diabetics requiring various methods of therapy.

Maturity onset diabetes (MOD) is characterized by the fact that the response of insulin secretion to glucose loading is either completely missing or is reduced if compared with that of persons whose metabolism is intact. But insulin secretion can be provoked by other specific stimuli. However, the quantitative IRI response can provide no information as to which of the MO diabetics must be treated by dietetic measures only and which of them are liable to treatment with sulfonylurea. It was, therefore, investigated whether in 109 patients suffering from recently developed overt MOD a differentiation from a therapeutical point of view can be attained by joint evaluation of stimulated IRI secretion, of glucose tolerance, of the dynamics of free fatty acids, of the fasting values of triglycerides and cholesterol and of the body weight. The findings suggest that no better differentiation for the two methods of treatment of MOD stated above is possible by simultaneous evaluation of the parameters of fat metabolism, glucose level and IRI secretion than by IRI secretion and carbohydrate tolerance alone.