A role for fatty acid composition of complex cellular lipids in the susceptibility of tumor cells to humoral immune killing.
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Animals↗
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Regulation of cell-mediated immunity in mice immunised with Salmonella enteritidis.
The effects of diverse factors, such as route of immunisation, composition of immunogen and administration of interferon inducer, on the expression of cell-mediated immune responses against Salmonella enteritidis were investigated in BALB/c and Swiss white mice. Immunisation with live cells of S. enteritidis by the intraperitoneal route (ip) generated both delayed type hypersensitivity (DTH) and protective cell-mediated immunity (CMI). However, the two responses showed diametrically opposite time kinetics. The decline and disappearance by 9 weeks after ip immunisation of DTH and the rise of protective immunity in the same period suggested the possibility that the two responses were mediated by different subsets of T cells. Immunisation by the intradermal (id) route with a sonicate of S. enteritidis generated only DTH; id immunisation also suppressed the development of the protective response following ip immunisation with live S. enteritidis. Both responses were not seen when T cells were eliminated with anti-T cell serum. Oral immunisation with live cells of S. enteritidis induced excellent CMI expressing both DTH and protective responses. On the other hand, oral immunisation with the sonicate of S. enteritidis not only did not induce CMI, but also prevented the development of the DTH and protective response to ip immunisation with live S. enteritidis. Induction of interferon by the administration of poly I: poly C for four consecutive days after id immunisation with killed S. enteritidis suppressed the generation of DTH.
Animals↗
Peripheral blood mononuclear cell fatty acid composition and inflammatory mediator production in adult Crohn's disease.
BACKGROUND & AIMS: Crohn's disease (CD) is associated with nutritional deficiencies, altered plasma concentrations of polyunsaturated fatty acids (PUFA) and an anti-inflammatory response to fish oil that contains n-3 PUFA. This suggests that, in CD, immune cells may have altered n-3 PUFA composition with functional consequences. The aim of this study is to investigate n-3 and n-6 PUFA composition and synthetic function of peripheral blood mononuclear cells (PBMC) in the basal state. METHODS: A case control study of 52 adult CD patients and healthy, age- and sex-matched controls. Composition of PBMC and plasma phospholipids were measured by gas chromatography and production of tumour necrosis factor-alpha, prostaglandin E2 (PGE2) and interferon-gamma (IFN-gamma) by PBMC were measured by ELISA. RESULTS: CD was associated with higher concentrations of eicosapentaenoic acid and other n-3 PUFA, and lower arachidonic acid (AA) (n-6 PUFA) in PBMC. This was not explained by differences in dietary fat intake. Lower rates of production of PGE2 and IFN-gamma by PBMC were noted in quiescent and active CD, respectively, compared to controls. CONCLUSIONS: CD is associated with a greater availability, and not a deficiency, of n-3 PUFA in PBMC, but lower concentrations of AA, and lower rates of production of PGE2 and IFN-gamma, compared to healthy controls.
Adult↗
Interleukin-1alpha and interleukin-6 enhance the antibacterial properties of cultured composite keratinocyte grafts.
OBJECTIVE: To determine whether the antibacterial properties of cultured composite keratinocyte grafts can be enhanced by cytokines that stimulate the innate immune response. SUMMARY BACKGROUND DATA: Use of composite grafts of cultured keratinocytes has been limited because of their susceptibility to burn wound microorganisms as a result of their lack of a vasculature and immune cells when transplanted. Moreover, use of topical antimicrobial agents is limited with these composite grafts because of cytotoxic effects. Keratinocytes, like all epithelial cells in the body, maintain a natural defense mechanism called the innate immune system. Some components of this system can be induced by cytokines. METHODS: The innate immune response of cultured composite keratinocyte grafts treated with various cytokines was assessed indirectly by measuring the levels of mRNA encoding antimicrobial peptides (human beta defensin-1 and -2, LL-37, and antileukoprotease) and antimicrobial proteins (lysozyme, bactericidal/permeability-inducing protein, and phospholipase A2) by reverse transcription-polymerase chain reaction and directly by measuring the ability of keratinocytes to inhibit the growth of added bacteria (Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus). RESULTS: Treatment with interluekin-1alpha increased mRNA levels of antimicrobial peptides in keratinocytes on plastic dishes and in composite grafts. Interleukin-6 increased mRNA levels of antimicrobial proteins in composite grafts only. When added to composite grafts, both cytokines increased antibacterial activity against E. coli, P. aeruginosa, and S. aureus. Moreover, interleukin-1alpha and interleukin-6 did not impair the formation of a differentiated epidermis in vitro or after transplantation of the composite grafts. CONCLUSIONS: Treatment with interleukin-1alpha or interleukin-6 of cultured composite keratinocyte grafts stimulates the innate immune response of keratinocytes, enhances the antibacterial properties of these grafts, and may better prepare them to combat infections in contaminated burn wounds.
Animals↗
Effects of dietary lipid manipulation upon graft vs host and host vs graft responses in the rat.
The popliteal lymph node (PLN) assay was used to establish whether dietary lipids with differing fatty acid compositions could affect cell-mediated immunity in the rat. Weanling rats were fed for 4 weeks on a lowfat (2.5% by weight; LF) diet or on diets containing 20% (by weight) hydrogenated coconut oil (HCO), olive oil (OO), safflower oil (SO), evening primrose oil (EPO), or menhaden (fish) oil (MO). Feeding the MO diet suppressed the graft vs host response compared with feeding the LF, HCO, SO, or EPO diets, while feeding the OO diet suppressed this response compared with feeding the LF or EPO diets. Feeding the MO diet suppressed the host vs graft response compared with feeding each of the other diets. Following the graft vs host reaction, PLN lymphocytes from animals fed the MO diet had significantly lower levels of expression of LFA-1 and CD2 compared with PLN lymphocytes from animals fed the LF diet; furthermore, they had lower levels of expression of T-cell receptor (TcR), CD4, CD8, LFA-1, and CD2 compared with lymphocytes from animals fed some, and in the case of CD2 each, of the other high-fat diets. Feeding the MO diet resulted in a lower proportion of cells expressing the interleukin-2 receptor, indicating an inhibition of lymphocyte activation, and a lower proportion of CD16+/CD3- cells, indicating a decrease in the proportion of NK cells within the PLN. Following the host vs graft reaction, PLN lymphocytes from animals fed the MO diet had significantly lower levels of expression of TcR and CD8 compared with lymphocytes from animals fed each of the other diets; furthermore, they had lower levels of expression of CD4, CD2, and LFA-1 compared with lymphocytes from animals fed the LF, HCO, OO, or SO diets. These observations indicate that the smaller PLN size of animals fed the MO diet results from an inhibition of activation and subsequent proliferation of cells within the node and perhaps also a suppression of movement of cells from the bloodstream to the PLN, due to decreased level of expression of adhesion molecules. These lowered levels of expression might be due to an inhibitory effect of the n-3 polyunsaturated fatty acids found in MO upon components of the signal transduction pathways involved in lymphocyte activation or upon expression of the genes for the surface molecules or both.
Animals↗
Serious foetal growth restriction is associated with reduced proportions of natural killer cells in decidua basalis.
Extravillous trophoblasts are major participants in placental development and remodelling of spiral arteries. Trophoblast invasion is regulated by maternal immune cells, and abnormal leucocyte subpopulation composition has been reported in implantation failure. In pre-eclampsia (PE), with or without foetal growth restriction (FGR), superficial trophoblast invasion and insufficient remodelling of spiral arteries are common findings. In the present study, we have compared spiral artery remodelling and leucocyte composition in decidual tissue from 30 cases (PE=8, FGR=5, PE + FGR=17) and 31 controls. Six histological remodelling criteria were established, and each pregnancy obtained a remodelling score. Numbers of natural killer (NK) cells (CD56+), T cells (CD3+) and activated (CD25+ or CD69+) leucocytes were determined and related to total leucocyte (CD45+) numbers in serial sections. Cases demonstrated significantly impaired spiral artery remodelling, inappropriate placental growth and reduced NK cell proportions, as compared to controls (P=0.02, P<0.001 and P=0.01, respectively). Reduced NK cell proportion was primarily found in pregnancies complicated by FGR, with or without PE, and a significant positive correlation was observed between NK cell proportion, trophoblast infiltration and placental growth. Our in vivo observations support the hypothesized association between NK cells, impaired placental development and pathogenesis of PE/FGR.
Adult↗
Leukotriene release from peripheral and peritoneal leukocytes following exposure to peritoneal dialysis solutions.
During continuous ambulatory peritoneal dialysis (CAPD), peritoneal host defence mechanisms are repeatedly exposed to dialysis solutions (with unphysiological composition) which may compromise peritoneal immune cell functions. In this context, the current study focused on the capacity of peripheral and peritoneal PMN to release leukotrienes following exposure to conventional CAPD dialysates. PMN were obtained from peripheral blood of healthy volunteers and from the peritoneal effluent of CAPD patients with acute peritonitis. Following isolation, cells were incubated in fresh CAPD dialysates or control buffer, and calcium ionophore A23187-stimulated leukotriene synthesis was measured. Additional experiments included RP-HPLC analysis and radioactivity monitoring of lipoxygenase products in PMN labelled with 14C-arachidonic acid. Leukotriene B4 and leukotrienes C4/D4/E4 were determined by radioimmunoassay. Ionophore-triggered leukotriene release from cells exposed to control buffer was pronounced in inflammatory peritoneal PMN (70.4 +/- 31.3 ng/5 x 10(6) cells LTB4 and 13.4 +/- 19.8 ng/5 x 10(6) cells LTC4/D4/E4, mean +/- SD, n = 14) when compared to healthy peripheral PMN (26.6 +/- 16.9 ng/ml LTB4 and 6.3 +/- 6.6 ng/ml LTC4/D4/E4, n = 12). Incubation in fresh solutions for peritoneal dialysis severely depressed leukotriene release from both cell populations. These results indicate a severe inhibition of cellular responsiveness as a consequence of dialysate exposure which could contribute to the impairment of host defence early in the CAPD cycle.
Adult↗
[Post-stress state and communicative alterations of immunity and blood].
It is shown that intact animals caged with stressed animals or in smell contact with natural secretions of stressed animals develop alterations of the immune system and peripheral blood cell composition. The decline in the genesis of antibodies to T-dependent antigen is related to the animals' gender and occurs at the height of poststress immunodepression.
Animals↗
[Comparative study of the effect of certain nonspecific stimulators on the body's immune response].
The effect of nonspecific stimulants of different nature on the quantitative and qualitative composition of immune rosette-forming cells (RFC) and intensity of hypersensitivity of delayed type was studied and compared in BALB/c mice. The data obtained show that the living BCG vaccine, zymosan and levamisol largely affect T-cell immunity, while prodigiozan, dextran sulfate and tiloron the humoral immune response. Unlike the living vaccine, BCG exerts less stimulant effect on the immune response and increases mainly the level of B-RFC in the spleen of normal mice.
Adjuvants, Immunologic↗
[Glycosphingolipids and antitumor immunity].
Glycosphingolipids are immunogenic components of cell surface whose composition and structure change during the cell transformation. The contemporary state of the question about the influence of glycosphingolipids on specific and non-specific antitumour immunity is considered. The available information about shedding of glycosphingolipids from the tumour cell surface, about the change of the ganglioside content in blood serum of the tumour host and about the effect of glycolipids on immunocompetent cells is analyzed. The results obtained by the authors in studies of the influence of glycosphingolipids on effector cells of the body natural resistance system to tumour are discussed.
Animals↗
Malignant epithelial states drive immune dysfunction in ampulla of Vater carcinoma.
BACKGROUND: Ampulla of Vater (AoV) carcinoma is a rare malignancy arising at the junction of intestinal and pancreatobiliary epithelium. Its heterogeneous clinical behavior and histological diversity have hindered therapeutic advances, and the cellular basis of this heterogeneity remains unclear. We aimed to construct a single-cell transcriptomic atlas of AoV carcinoma, with a focus on identifying epithelial subtypes and their interactions with the tumor microenvironment (TME). METHODS: We performed single-cell RNA sequencing on eight primary AoV tumors and four matched normal tissues. Comprehensive clustering and transcriptomic analyses identified cell-type composition, epithelial heterogeneity, and tumor-immune interactions. Findings were validated using deconvolution of bulk RNA-seq data from 62 AoV carcinoma patients. Results Malignant epithelial cells were categorized into four distinct subtypes: Int-Wnt, PB-KRAS, Int-Hypoxia, and Cycling stage. PB-KRAS cells exhibited stem-like transcriptional programs and high genomic instability. Deconvolution analysis of bulk RNA-seq data from the independent AoV cohort revealed that enrichment of the PB-KRAS subtype correlated with tumor recurrence and poor survival. Our immune profiling analysis discovered a significant association between PB-KRAS subtype and GZMK+ CD8+ T cells, which are in a pre-dysfunctional state, alongside SPP1+ macrophages exhibiting immunosuppressive traits. Spatial transcriptome data further supports the immunosuppressive natures of TME around PB-KRAS subtype malignant epithelial cells in AoV carcinoma. CONCLUSIONS: Our study presents a single-cell atlas of AoV carcinoma, highlighting the molecular diversity of malignant epithelium and its association with the immune microenvironment. The PB-KRAS subtype emerges as a stem-like, immunosuppressive tumor state associated with poor prognosis, providing insights for future therapeutic targeting.
Ampulla of Vater carcinoma↗
Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting.
Interleukin-2 (IL-2) is a lymphocytotropic hormone which is thought to have a key role in the immune response of mammalian cells. It is produced by a subpopulation of activated T-lymphocytes and acts in vitro as the principal auto- and paracrine T-cell growth factor (for reviews see refs 1-3). IL-2 is, however, not the sole T-cell growth factor, nor does it act exclusively on T cells, also promoting growth of NK cells and differentiation of B cells. A role for IL-2 in T-cell development has been postulated but remains controversial. Here we test the requirement for IL-2 in vivo using IL-2-deficient mice generated by targeted recombination. We find that mice homozygous for the IL-2 gene mutation are normal with regard to thymocyte and peripheral T-cell subset composition, but that a dysregulation of the immune system is manifested by reduced polyclonal in vitro T-cell responses and by dramatic changes in the isotype levels of serum immunoglobulins.
Animals↗
Value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals.
Elderly individuals are at high risk for morbidity and mortality when infected with influenza virus. Vaccinations with inactivated virus are less effective in the elderly due to the declining competency of the aging immune system. We have explored whether immunological parameters predict poor anti-influenza virus vaccine responses and can be used as biological markers of immunosenescence. One hundred fifty-three residents of community-based retirement facilities aged 65 to 98 years received a trivalent influenza vaccine. Vaccine-induced antibody responses were determined by comparing hemagglutination inhibition titers before and 28 days after immunization. The composition of the T-cell compartment was analyzed by flow cytometry and the sizes of three T-cell subsets, CD4(+) CD45RO(+) cells, CD4(+) CD28(null) cells, and CD8(+) CD28(null) cells, were determined. Only 17% of the vaccine recipients were able to generate an increase in titers of antibody to all three vaccine components, and 46% of the immunized individuals failed to respond to any of the three hemagglutinins. The likelihood of successful vaccination declined with age and was independently correlated with the expansion of a particular T-cell subset, CD8(+) CD28(null) T cells. The sizes of the CD4(+) CD45RO(+) memory T-cell and CD4(+) CD28(null) T-cell subsets had no effect on the ability to mount anti-influenza virus antibody responses. Frequencies of CD8(+) CD28(null) T cells are useful biological markers of compromised immunocompetence, identifying individuals at risk for insufficient antibody responses.
Age Factors↗
Immune responses of teleost fish.
In fish all the pre-requisites to mount a specific immune response are present, but the main differences from the mammalian system are that the secondary response is relatively minor and IgG is not present. In teleosts mainly IgM is present, and IgD has been recently described but its function is, as yet, unknown. However, different forms of fish IgM and its observed flexibility of structure may compensate for a lack of Ig class diversity. The innate immune response of teleosts is highly developed. Multiple forms of key constitutive and inducible components, such as lysozyme, C3, alpha2-macroglobulin and C-reactive protein, are present, and may enhance immune recognition. Low ambient temperature appears to have an impact on all aspects of the immune response, particularly the T-dependent specific immune response due to the non-adaptive lipid composition of T-cell membranes. Temperature effects on the nonspecific immune system are less well characterised, but there is evidence that low temperatures are also suppressive. Knowledge of immune system function becomes essential for disease prevention strategies such as the development of vaccines, selection for increased disease resistance and identification of genes suitable for trangenesis.
Animals↗
In vitro assays for immune monitoring in transplantation.
Because immune responses to transplant allografts are the main drivers of rejection, the ability to accurately quantitate antidonor immunity is an important goal in clinical transplantation. These allow for the prediction of presensitization to the transplanted tissue and the identification of rejection without needing more invasive tests. In this chapter, we will review three methods currently used in transplantation research. Limiting dilution assays are a traditional tool. The evolution of these assays has brought about the ELISpot. Developments in flow cytometry are also contributing to the understanding of the composition of the cells involved in these immune responses. We can therefore obtain a deeper understanding of the process of rejection and tolerance and their evolution with time. This chapter reviews in vitro assays in the context of transplantation, but the scientific applications of sensitive, accurate, and specific immune-monitoring reach well beyond this field of research.
Animals↗
Human uterine leukocytes and pregnancy.
In human pregnancy, the embryo implants into the specialized mucosal wall of the uterus (decidua) and the placenta starts to form. Cells from the placenta (trophoblasts) invade into the uterine mucosa in order to open up maternal uterine arteries to ensure an adequate supply of blood to the developing fetus. The trophoblasts have a unique immunological phenotype compared to most cells especially with regard to their expression of major histocompatibility complex (MHC) antigens. On the other side of the interaction, the uterine mucosa (endometrium) differentiates in preparation for implantation. One of the changes that takes place is the appearance in the endometrium of a large number of maternal leukocytes in the final part of the menstrual cycle. If pregnancy ensues, these leukocytes continue to increase in number and are found in close contact with trophoblasts. The composition of this population of maternal immune cells is unusual compared to that seen at other mucosal sites. A lot of research has focused on whether maternal T-cell responses are suppressed or modified during pregnancy. Research has also concentrated on the specialized uterine natural killer (NK) cells, which are found in the decidua in large numbers during early pregnancy. These uterine NK cells have been shown to express receptors for trophoblast MHC antigens, but their role in pregnancy is still mysterious. The purpose of this review is to give an overview of what is known about the immunology at the implantation site and also to provide an update of some of the most recent findings in this field.
Embryonic and Fetal Development↗
Antigenic composition, not the degree of polymerization, determines the requirement for thymus-derived cells in immune responses to Salmonella flagellar proteins.
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Animals↗
Protective and memory immunity to Histoplasma capsulatum in the absence of IL-10.
We determined whether the absence of IL-10 in mice influenced protective and memory immunity to Histoplasma capsulatum. IL-10(-/-) mice cleared primary and secondary infection more rapidly than wild-type controls. Administration of mAb to TNF-alpha or IFN-gamma, but not GM-CSF, abrogated protection in naive IL-10(-/-) mice; mAb to TNF-alpha, but not IFN-gamma or GM-CSF, subverted protective immunity in secondary histoplasmosis. The inflammatory cell composition in IL-10(-/-) mice was altered in those given mAb to IFN-gamma or TNF-alpha. More Gr-1(+) and Mac-3(+) cells were present in lungs of IL-10(-/-) mice given mAb to IFN-gamma, and treatment with mAb to TNF-alpha sharply reduced the number of CD8(+) cells in lungs of IL-10(-/-) mice. We ascertained whether the lack of IL-10 modulated memory T cell generation or the protective function of cells. The percentage of CD3(+), CD44(high), CD62(low), and IFN-gamma(+) cells in IL-10(-/-) mice was higher than that of wild-type at day 7 but not day 21 or 49 after immunization. Fewer splenocytes from immunized IL-10(-/-) mice were required to mediate protection upon adoptive transfer into infected TCR alphabeta(-/-) mice. Hence, deficiency of IL-10 confers a salutary effect on the course of histoplasmosis, and the beneficial effects of IL-10 deficiency require endogenous TNF-alpha and/or IFN-gamma. Memory cell generation was transiently increased in IL-10(-/-) mice, but the protective function conferred by cells from these mice following immunization is strikingly more vigorous than that of wild-type.
Adoptive Transfer↗