Tolerance and immunity in a mathematical model of T-cell mediated suppression

Regulatory CD4+CD25+ T cells play a major role in natural tolerance to body components and therefore are relevant to understand the self-non-self discrimination by the immune system. The most pressing theoretical question, regarding the fact that these regulatory cells perform their function through linked recognition of the APCs, is how this "non-specific" mechanism permits a proper balance between tolerance and immunity that is compatible with an effective self-non-self discrimination. To tackle this issue, we develop a numerical simulation, which extends a previous mathematical model of T-cell-mediated suppression to include the thymic generation and the peripheral dynamics of many T cell clones. This simulation can mimic the capacity of the immune system to establish natural tolerance to self-antigens and reliably mount immune responses to foreign antigens. Natural tolerance is based on ubiquitous and constitutive self-antigens, which select and sustain clones of specific regulatory cells. Immune responses to foreign antigens are only achieved if they displace the self-antigens from the APCs, leading to a loss of the regulatory cells, and/or if the foreign antigen introduction entails a sharp increase in the total number of APCs. Meaningful behavior is obtained even if differentiation of regulatory cells in the thymus is antigen non-specific, but requires that a minimum number of new T cells enter the periphery per unit of time, and that the repertoire is selected so that anti-self-affinities are within a proper interval. We conclude that positive selection is required to generate a sufficiently high frequency of self-antigen specific regulatory cells that reliably mediate natural tolerance. Negative selection is required to avoid the emergence at the periphery of very high affinity anti-self-regulatory cells that will make the tolerant state so robust that it could no be broken by the introduction of a foreign antigen. This result highlights the importance of repertoire selection in dominant tolerance proposing a novel role for the processes of positive and negative selection within this framework.     

The cell-mediated immune reaction in the cutaneous lesion of Chromoblastomycosis and their correlation with different clinical forms of the disease

Chromoblastomycosis is a fungal infection caused by dematiaceous fungi inducing skin lesions of difficult treatment and of frequent recurrence. The objective of the present investigation was to characterize cell-mediated tissue reactions in the skin in cases of Chromoblastomycosis using histopathology and immunocytochemistry methods and to correlate them with different clinical forms of Chromoblastomycosis. Biopsies from 19 patients were stained with HE and Giemsa, and serial sections were immunohistochemically stained using CD45RO, CD20, CD4, CD8, CD68, CD1a, CD34, IL4, IL10, TNF- and IFN- antibodies. A quantitative and semi quantitative analysis of the cell subsets and cytokines in the inflammatory infiltrates was performed by counting ten high-power fields (400×). The cutaneous lesion presented as verrucous plaque (n = 15) or erythematous atrophic plaque (n = 4). We observed two types of tissue reaction: A) a granulomatous reaction with a suppurative granuloma with several fungi cells in the cutaneous lesion presenting as verrucous plaque; B) a granulomatous reaction with a tuberculoid granuloma with few fungi cells in the cutaneous lesion presenting as atrophic plaque. The data obtained suggest that patients with lesion presented as verrucous plaque have a type Th2 immunological response, while patients with lesion presented as erythematous atrophic plaque have a type Th1 response.This revised version was published online in October 2005 with corrections to the Cover Date.     

Examinations of cell mediated immunity in diffuse peritonitis]

Phagocytic index and rosette test E have been determined in 50 patients, including 15 with diffuse peritonitis and the noncomplicated diffuse peritonitis, 20 patients with septic complications, and 15 patients who underwent abdominal surgery. It was found, that phagocytic index is decreased in all patients after abdominal surgery. The most marked decrease of this index was found in patients with complicated peritonitis. It still decreases in the course of peritonitis and increases in the reference group. The marked decrease in the number of T-cells was observed in complicated peritonitis during the whole period of follow-up while it normalizes in case of noncomplicated peritonitis as in the reference group. Using the tests under study it was possible to assess cell-mediated immunity which is depressed in peritonitis. The tests enable also the prediction of septic complications of peritonitis.     

Glucose supplement reverses the fasting-induced suppression of cellular immunity in Mongolian gerbils (Meriones unguiculatus)

Glucose plays an important role in immunity. Three day fasting will decrease cellular immunity and blood glucose levels in Mongolian gerbils (Meriones unguiculatus). In the present study, we tested the hypothesis that glucose supplement can reverse the fasting-induced suppression in cellular immunity in gerbils. Twenty-eight male gerbils were selected and randomly divided into fed and fasting groups. Half of the gerbils in each group were then provided with either 10% glucose water or pure water. After 66 h, each gerbil was injected with phytohaemagglutinin (PHA) solution to challenge cellular immunity. Results showed that glucose supplement restored blood glucose levels in fasted gerbils to those of the fed controls. It also recovered cellular immunity, body fat mass and serum leptin levels in fasted gerbils to the values of the fed controls. Blood glucose levels were positively correlated with body fat mass, leptin levels and cellular immune responses. Thymus and spleen masses, and white blood cells in fasted gerbils were not affected by glucose supplement. In general, our data demonstrate that glucose supplement could reverse fasting-induced suppression of cellular immunity in Mongolian gerbils.     

幽门螺杆菌相关性胃炎的细胞免疫功能的研究

目的:探讨细胞免疫在Helicobacter pylori(Hp)相关性胃炎的损伤中的作用.方法:检测外周血T淋巴细胞亚群及IL-2、sIL-2R、IL-6、IL-8水平.结果:病例组与对照组比较,CD3 、CD 4和CD 4/CD 8比值及血清IL-2水平均显著降低(P＜0.01),而sIL-2R、IL-6和IL-8水平均显著升高(P＜0.01).结论:细胞免疫在Hp相关性胃炎的损伤中作用明显,检测细胞免疫功能对Hp相关性胃炎的病情监测、疗效观察及预后判定有一定价值.     

Photoperiod and cell mediated immunity of clinically normal dogs

Abstract

Previously, the authors have reported seasonal variations in cell mediated immunity in the dog during the period July, 1977 ‐ October 1978 as measured by whole blood lectin‐induced lymphocyte transformation. Peak activity occurred in the summer, suggesting association with photoperiodicity. Here the authors report on immune response of dogs kept indoors ‐ under controlled physical environment ‐ with a natural (outdoor) photoperiod or under a 12:12 h (LD) regime, and a control group kept in outdoor kennels. Peak immune activity in 1979 occurred in the winter, in both indoor groups as well as the outdoor groups subject to natural photoperiod. Since the indoor dogs were kept at a constant temperature and humidity in clean (filtered) air, photoperiod, temperature, and particulate air contaminants probably are not associated with seasonal variations in immunity. The underlying cause for either the seasonal variations or the shift from peak activity in the summer of 1978 to winter of 1979 is unknown. Dogs under LD = 12:12 light regime had a significantly lowered immunity relative to the dogs with the natural photoperiod.     

Infradian rhythm in hematology,cell mediated immunity and serum micronutrient concentration around peripartum periods in high yielding crossbred cows before and after micronutrient supplementation

Alteration in hematology and cell-mediated immunity around peripartum periods before and after micronutrient supplementation was studied in this investigation. Twelve (12) high-yielding cross-bred cows in advanced pregnancy were selected for the experiment and divided into two equal groups viz. supplemented (n = 6) and unsupplemented (n = 6). Supplemented animals were provided with a micronutrient mixture (@ 25 g per cow) as per the recommendation of NRC over the normal feeding. Unsupplemented group of cows were kept as control with standard farm feeding management. Blood samples (15 ml/cow) were collected from all the animals during days 30th, 15th, and 7th before calving, on the day of calving, and during days 7th, 15th, and 30th after calving and analyzed for hematology viz. hemoglobin (Hb), total erythrocyte counts (TEC), total leukocyte counts, and differential leukocyte counts. In vitro phagocytic index (PI) of neutrophils and lymphocyte proliferation response (LPR) were also evaluated. Copper (Cu), zinc (Zn), manganese, and selenium (Se) concentrations in serum were estimated by atomic absorption spectrophotometer. The Hb concentration was found to be significantly (p < 0.01) higher in supplemented group compared to the unsupplemented group of cows. There were no significant differences in Hb concentration during different days of peripartum in both the group of cows. There was a significantly (p < 0.001) higher TEC in supplemented group compared to unsupplemented group of cows, though it did not vary significantly between different days of peripartum in both the group of cows. There was a significantly (p < 0.001) higher PI in supplemented group compared to the unsupplemented group of cows. In both the groups, the PI of blood neutrophils was significantly (p < 0.001) lower during calving. The LPR did not differ significantly between the groups, but it differed significantly (p < 0.01) between different days of peripartum and was lowest on the day of calving in both the groups. The Cu, Zn, and SE concentration was found to be significantly (p < 0.01) higher in supplemented group compared to the unsupplemented group of cows, but remained unaltered throughout the peripartum period. The study indicated that there was a marked immune depression around peripartum (15 days precalving to 15 days postcalving) in terms of in vitro phagocytic activity of blood neutrophils and in vitro LPR. Supplementation of micronutrients improves the hematological status as well as immune status, so it was recommended to supplement these micronutrients for better productivity and disease resistance in high-yielding cross-bred cows around peripartum.     

Recent advances in crayfish hematopoietic stem cell culture: a model for studies of hemocyte differentiation and immunity

Hematopoiesis is the process by which blood cells (hemocytes) mature and subsequently enter the circulation and we have developed a new technique to culture the hematopoietic progenitor cells in vitro. The reason for the successful culture was the isolation of a plasma protein that turned out to be a novel cytokine, astakine 1 (Ast1) containing a domain present in several vertebrates, so-called prokineticins. Now we have detected several astakines from other invertebrate species. Depending on our discovery of the cytokine Ast1 we have an opportunity to study in detail the differentiation of cells in the hematopoietic tissue of a crustacean, a tissue of evolutionary interest for studies of the connection between the vascular system and the nervous system. We have been able to isolate the entire hematopoietic tissue and for the first time detected a link between this tissue and the brain. We have further localized a proliferation center in the tissue and characterized its different parts. We have also used this system to isolate a new hematopoietic factor CHF that is important in the crossroad between apoptosis and hemocyte differentiation. Our technique for culture of crayfish hematopoietic stem cells provides a simple tool for studying the mechanism of hematopoiesis, but also enables detailed studies of immune defense reactions. Further, the culture system has been used for studies of viral defense and the system is suitable for gene silencing which allows functional characterization of different molecules involved in host defense as well as in hemocyte differentiation.     

Effect of pregnancy plasma upon in vitro parameters of cell mediated immunity

Abstract Pregnant women were classified according to their serological status for cytomegalovirus, herpes simplex virus or rubella virus. Lymphocytes taken from non-pregnant women were shown to be able to recognise viral antigens and the mitogen phytohaemagglutinin by the measurement of proliferative responses and by the production of gamma interferon.
Proliferative responses or gamma interferon production were greatly reduced in the presence of plasma taken during the first, second or third trimester and immediately post-partum. The responses then gradually returned to normal after delivery. The availability of serial sera taken before pregnancy as well as during and after pregnancy in individual women showed that this effect was maintained even when sera had been stored frozen for more than one year.
Mixing experiments were performed to vary the proportion of pregnancy serum in any particular assay but this did not prove that pregnancy sera were actively suppressive. Instead, the data suggest that pregnancy sera are deficient in some factor or factors which are required to support lymphocyte proliferation. The effect was not attributable to the physiological haemodilution of pregnancy leading to a reduced concentration of putative factors nor could transferrin levels or the iron binding capacity of this protein be implicated.     

The role of Pimpla hypochondriaca venom in the suppression of pupal Noctuid host immunity

When pupae of the Tomato moth (Lacanobia oleracea L.) (Lepidoptera: Noctuidae) are injected with venom from the endoparasitoid wasp Pimpla hypochondriaca Retzius (Hymenoptera: Ichneumonidae), they show an increased susceptibility to the fungal entomopathogen Metarhizium anisopliae Sorokin (Fungi Imperfecti: Deuteromycotina). This observation, coupled with the fact that wasp eggs are comparatively unlikely to be encapsulated when implanted into envenomated pupae, suggests that venom of P. hypochondriaca suppresses the cellular immune defense mechanisms of L. oleracea. Injection of host pupae with the venom of P. hypochondriaca has a rapid, adverse effect on the normal respiration pattern of L. oleracea. It is possible that severe disruption to host-metabolism may contribute to a general failure in the hosts' normal immune response repertoire.     

Effect of pregnancy plasma upon in vitro parameters of cell mediated immunity

Pregnant women were classified according to their serological status for cytomegalovirus, herpes simplex virus or rubella virus. Lymphocytes taken from non-pregnant women were shown to be able to recognise viral antigens and the mitogen phytohaemagglutinin by the measurement of proliferative responses and by the production of gamma interferon. Proliferative responses or gamma interferon production were greatly reduced in the presence of plasma taken during the first, second or third trimester and immediately post-partum. The responses then gradually returned to normal after delivery. The availability of serial sera taken before pregnancy as well as during and after pregnancy in individual women showed that this effect was maintained even when sera had been stored frozen for more than one year. Mixing experiments were performed to vary the proportion of pregnancy serum in any particular assay but this did not prove that pregnancy sera were actively suppressive. Instead, the data suggest that pregnancy sera are deficient in some factor or factors which are required to support lymphocyte proliferation. The effect was not attributable to the physiological haemodilution of pregnancy leading to a reduced concentration of putative factors nor could transferrin levels or the iron binding capacity of this protein be implicated.     

Changes of cell mediated immunity in malignant ovarian tumor patients after operation

OBJECTIVES: The authors discuss upon the changes in the two cell types involved in cell mediated immunity (Killer and Natural Killer) as a result of operation in malignant ovarian tumor atients. METHODS: They study the preoperative and postoperative cell mediated immunity of 28 malignant cystadenocarcinoma cases (FIGO stage I/a-III/c). To determine the maximum K and NK cell activity they used the kinetic model of cytotoxicity enzyme. RESULTS AND CONCLUSIONS: They conclude that operation of malignant ovarian tumors had no significant influence on K and NK cell activity. They hypothesize that unchanged cell mediated immunity seems to be independent of malignant tumors, especially in these conditions. We need further information about this change of cell mediated immunity.     

A novel immunoregulatory axis of NKT cell subsets regulating tumor immunity

There are many mechanisms that regulate and dampen the immune response to cancers, including several types of regulatory T cells. Besides the T reg cell, we have identified another immunoregulatory circuit initiated by NKT cells that produce IL-13 in response to tumor growth and this IL-13 then induces myeloid cells to make TGF-beta that inhibits cytotoxic T cell-mediated tumor immunosurveillance in several mouse tumor models. This finding created a paradox in the role of NKT cells in tumor immunity, in that they can also contribute to protection. We resolve this paradox by the finding that the suppressive NKT cell is a type II NKT cell that lacks the canonical invariant T cell receptor, whereas the protective cell is a type I NKT cell that expresses the invariant receptor. Further, we see that these two subsets of NKT cells counter-regulate each other, defining a new immunoregulatory axis. The balance along this axis may determine the outcome of tumor immunosurveillance as well as influence the efficacy of anti-cancer vaccines and immunotherapy.     

Antigen-specific mediated suppression of beta cell autoimmunity by plasmid DNA vaccination

In this study, we have investigated the use of plasmid DNA (pDNA) vaccination to elicit Th2 effector cell function in an Ag-specific manner and in turn prevent insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice. pDNA recombinants were engineered encoding a secreted fusion protein consisting of a fragment of glutamic acid decarboxylase 65 (GAD65) linked to IgGFc, and IL-4. Intramuscular injection of pDNA encoding GAD65-IgGFc and IL-4 effectively prevented diabetes in NOD mice treated at early or late preclinical stages of IDDM. This protection was GAD65-specific since NOD mice immunized with pDNA encoding hen egg lysozyme-IgGFc and IL-4 continued to develop diabetes. Furthermore, disease prevention correlated with suppression of insulitis and induction of GAD65-specific regulatory Th2 cells. Importantly, GAD65-specific immune deviation was dependent on pDNA-encoded IL-4. In fact, GAD65-specific Th1 cell reactivity was significantly enhanced in animals immunized with pDNA encoding only GAD65-IgGFc. Finally, NOD.IL4(null) mice treated with pDNA encoding GAD65-IgGFc and IL-4 continued to develop diabetes, indicating that endogenous IL-4 was also required for disease prevention. These results demonstrate that pDNA vaccination is an effective strategy to elicit beta cell-specific Th2 regulatory cell function for the purpose of preventing IDDM even at a late stage of disease development.     

Pharmacologic suppression of neuronal oxidative damage and dendritic degeneration following direct activation of glial innate immunity in mouse cerebrum

Activation of glial innate immunity is widely proposed to contribute to a number of degenerative and destructive diseases of brain. However, the precise role of activated innate immunity has been difficult to define in vivo because of multiple simultaneous pathogenic processes and responses to injury that confound interpretation of results from complex models of disease. Here, we used the model of intracerebroventricular (ICV) injection of lipopolysaccharide (LPS) to test the hypothesis that directly activated glial innate immunity leads to neurodegeneration in cerebrum and to establish the molecular determinants of and neuroprotectants from such innate immunity-mediated neuronal damage. Our results showed that ICV LPS induced delayed, reversible oxidative damage to cerebral neuronal membranes as measured by F4-neuroprostanes that was coincident with degeneration of the hippocampal pyramidal neuron dendritic system, but not neuron death, in adult mice. Both neuronal oxidative damage and dendritic degeneration were NF-kappaB and iNOS dependent and were completely suppressed by ibuprofen and alpha-tocopherol, but not naproxen or gamma-tocopherol. These results prove that activation of glial innate immunity can lead to neurodegeneration independent of other pathologic processes, closely associate oxidative damage to neuronal membranes with degeneration of the dendritic system, and provide a possible explanation for the varying efficacy of neuroprotectants that have been suggested in observational studies of dementia.     

Polydnavirus-mediated suppression of insect immunity

Polydnaviruses are symbiotic proviruses of some ichneumonid and braconid wasps that modify the physiology, growth and development of host lepidopteran larvae. Polydnavirus infection targets neuroendocrine and immune systems, altering behavior, stunting growth, and immobilizing immune responses to wasp eggs and larvae. Polydnavirus-mediated disruption of cellular and humoral immunity renders parasitized lepidopteran larvae suitable for development of wasp larvae as well as more susceptible to opportunistic infections. Evidence from the Campoletis sonorensis polydnavirus system indicates that the unique genomic organization of polydnaviruses may have evolved to amplify the synthesis of immunosuppressive viral proteins. Immunosuppressive viruses have been essential to elucidating vertebrate immunity. Polydnaviruses have similar potential to clarify insect immune responses and may also provide novel insights into the role of insect immunity in shaping polydnavirus genomes.     

Social immunity and the evolution of group living in insects

The evolution of group living requires that individuals limit the inherent risks of parasite infection. To this end, group living insects have developed a unique capability of mounting collective anti-parasite defences, such as allogrooming and corpse removal from the nest. Over the last 20 years, this phenomenon (called social immunity) was mostly studied in eusocial insects, with results emphasizing its importance in derived social systems. However, the role of social immunity in the early evolution of group living remains unclear. Here, I investigate this topic by first presenting the definitions of social immunity and discussing their applications across social systems. I then provide an up-to-date appraisal of the collective and individual mechanisms of social immunity described in eusocial insects and show that they have counterparts in non-eusocial species and even solitary species. Finally, I review evidence demonstrating that the increased risks of parasite infection in group living species may both decrease and increase the level of personal immunity, and discuss how the expression of social immunity could drive these opposite effects. By highlighting similarities and differences of social immunity across social systems, this review emphasizes the potential importance of this phenomenon in the early evolution of the multiple forms of group living in insects.     

Role of gamma-secretase in human umbilical-cord derived mesenchymal stem cell mediated suppression of NK cell cytotoxicity

Background

Mesenchymal stem cells (MSCs) are increasingly considered to be used as biological immunosuppressants in hematopoietic stem cell transplantation (HSCT). In the early reconstitution phase following HSCT, natural killer (NK) cells represent the major lymphocyte population in peripheral blood and display graft-vs-leukemia (GvL) effects. The functional interactions between NK cells and MSCs have the potential to influence the leukemia relapse rate after HSCT. Until date, MSC-NK cell interaction studies are largely focussed on bone marrow derived (BM)-MSCs. Umbilical cord derived (UC)-MSCs might be an alternative source of therapeutic MSCs. Thus, we studied the interaction of UC-MSCs with unstimulated allogeneic NK cells.

Results

UC-MSCs could potently suppress NK cell cytotoxicity in overnight cultures via soluble factors. The main soluble immunosuppressant was identified as prostaglandin (PG)-E2. Maximal PGE2 release involved IL-1β priming of MSCs after close contact between the NK cells and UC-MSCs. Interestingly, blocking gamma-secretase activation alleviated the immunosuppression by controlling PGE2 production. IL-1 receptor activation and subsequent downstream signalling events were found to require gamma-secretase activity.

Conclusion

Although the role of PGE2 in NK cell-MSC has been reported, the requirement of cell-cell contact for PGE2 induced immunosuppression remained unexplained. Our findings shed light on this puzzling observation and identify new players in the NK cell-MSC crosstalk.

     

Autophagy in immunity

Autophagy is now emerging as a spotlight in trafficking events that activate innate and adaptive immunity. It facilitates innate pathogen detection and antigen presentation, as well as pathogen clearance and lymphocyte homeostasis. In this review, we first summarize new insights into its functions in immunity, which underlie its associations with autoimmunity. As some lines of evidence are emerging to support its role in autoimmune and autoinflammatory diseases, we further discuss whether and how it affects autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, diabetes mellitus and multiple sclerosis, as well as autoinflammatory diseases, such as Crohn disease and vitiligo.