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PubMed2005

Severe T-cell depletion from the PALS leads to altered spleen composition in common marmosets with experimental autoimmune encephalomyelitis (EAE).

Recent data suggest that the spleen is a crucial component of the immune system in the development of experimental autoimmune encephalomyelitis (EAE) in marmoset monkeys. Using immunohistochemistry, we investigated changes in the distribution of leukocytes in the spleen associated with clinical symptoms of EAE. Animals without EAE displayed well-developed T- and B-cell areas, germinal centers and red pulp. In contrast, a marked depletion of periarteriolar T cells with preservation of other elements was found in animals with clinical EAE. These findings suggest that immune responses within the spleen are impaired during a paralysing inflammatory process in the central nervous system.

Acid Phosphatase↗

PubMed2000

Tubulo-interstitial involvement in lupus nephritis with emphasis on pathogenesis.

Glomerular lesions in lupus nephritis have been extensively studied in recent decades, but much less attention has been paid to the tubulo-interstitial compartment. The aim of this study was to contribute to the understanding of the pathogenesis of tubulo-interstitial lesions in lupus nephritis by analysing their incidence, character, and their associations. One hundred and ninety kidney biopsies of 190 patients fulfilling American Rheumatology Association (ARA) criteria of systemic lupus erythematosus (SLE) were examined by traditional light, immunofluorescence and electron microscopy. Interstitial inflammatory infiltration and tubulo-interstitial immune deposits concurred in 72 cases (37.9%). Their frequency was the highest in WHO class IV lupus glomerulonephritis. By multivariate analysis, the intensity of interstitial inflammatory infiltration correlated best with the percentage of renal corpuscules with extracapillary crescents and the extent of interstitial fibrosis. On immunohistochemical assessment, the inflammatory infiltrate was found to be composed of CD45RO positive T lymphocytes (191.3/mm2), CD68 positive macrophages (101.7/mm2) and CD45RA positive B lymphocytes (17.2/mm2). For all cell types the median value was higher in cases with extracapillary crescents, and did not correlate with presence and intensity of tubulo-interstitial immune deposits. Infiltration showed the tendency of periglomerular distribution, especially around glomeruli showing extracapillary proliferation and destruction of the capsular basal membrane. Rare S100 positive cells were only found in the interstitium. Tubulo-interstitial lesions estimated semiquantitatively correlated with the degree of proteinuria. Our findings suggest that tubulo-interstitial deposits do not play a major role in the pathogenesis of tubulo-interstitial lesions. The formation of interstitial cell infiltrates appears to be greatly influenced by the development of extracapillary crescents, perhaps by direct transmission of the severe inflammatory process to the adjacent interstitium. The composition of the infiltrate, including antigen presenting cells may signalize an additional involvement of cell-mediated immune mechanisms acting against so far hypothetical tubular epithelial neoantigens.

Adult↗

PubMed1991

Presence of matrix-specific antibodies in affinity-purified polyclonal antibodies.

In general, antigen affinity columns made with commercially prepared activated affinity supports bind antibody specific for the coupled antigen. Nonetheless, in some cases affinity purification may yield antibodies to molecules other than the molecule of interest. In this report, we demonstrate such an occurrence: an antibody which adsorbs to an Affi-Prep 10 affinity matrix was found in the serum of sheep immunized against calmodulin. The contaminating antibody bound to cell nuclei and condensed chromosomes; the composition of the Affi-Prep 10 matrix suggests that the antibody may cross-react to the sugar-phosphate backbone of DNA. We were able to remove the contaminating antibody from the anti-calmodulin by passing the affinity-purified mixture over an antigen-free Affi-Prep 10 column.

Animals↗

PubMed2006

A comparison of eight methods for the dual-endpoint evaluation of efficacy in a proof-of-concept HIV vaccine trial.

To support the design of the world's first proof-of-concept (POC) efficacy trial of a cell-mediated immunity-based HIV vaccine, we evaluate eight methods for testing the composite null hypothesis of no-vaccine effect on either the incidence of HIV infection or the viral load set point among those infected, relative to placebo. The first two methods use a single test applied to the actual values or ranks of a burden-of-illness (BOI) outcome that combines the infection and viral load endpoints. The other six methods combine separate tests for the two endpoints using unweighted or weighted versions of the two-part z, Simes', and Fisher's methods. Based on extensive simulations that were used to design the landmark POC trial, the BOI methods are shown to have generally low power for rejecting the composite null hypothesis (and hence advancing the vaccine to a subsequent large-scale efficacy trial). The unweighted Simes' and Fisher's combination methods perform best overall. Importantly, this conclusion holds even after the test for the viral load component is adjusted for bias that can be introduced by conditioning on a postrandomization event (HIV infection). The adjustment is derived using a selection bias model based on the principal stratification framework of causal inference.

AIDS Vaccines↗

PubMed2025

Genetic and transcriptional insights into immune checkpoint blockade response and survival: lessons from melanoma and beyond.

BACKGROUND: Integration of immune checkpoint inhibitors (ICIs) with non-immune therapies relies on identifying combinatorial biomarkers, which are essential for patient stratification and personalized treatment. METHODS: We analyzed genomic and transcriptomic data from pretreatment tumor samples of 342 melanoma patients treated with ICIs to identify mutations and expression signatures associated with ICI response and survival. External validation and mechanistic exploratory analyses were conducted in two additional datasets to assess generalizability. RESULTS: Responders were more likely to have received anti-PD-1 therapy rather than anti-CTLA-4 and exhibited a higher tumor mutation burden (both P < 0.001). Mutations in the dynein axonemal heavy chain (DNAH) family genes, specifically DNAH2 (P = 0.03), DNAH6 (P < 0.001), and DNAH9 (P < 0.01), were enriched in responders. The combined mutational status of DNAH 2/6/9 effectively stratified patients by progression-free survival (hazard ratio [HR]: 0.69; 95% confidence interval [CI] 0.51-0.92; P = 0.013) and overall survival (HR: 0.58; 95% CI 0.43-0.78; P < 0.001), with consistent association observed in the validation cohort (HR: 0.28; 95% CI 0.12-0.61; P < 0.001). DNAH-altered melanomas exhibited upregulation of chemokine signaling, cytokine-cytokine receptor interaction, and cell cycle-related pathways, along with elevated expression of immune-related signatures in interferon signaling, cytolytic activity, T cell function, and immune checkpoints. Using LASSO logistic regression, we identified a 26-gene composite signature predictive of clinical response, achieving an area under the curve (AUC) of 0.880 (95% CI 0.825-0.936) in the training dataset and 0.725 (95% CI 0.595-0.856) in the testing dataset. High-risk patients, stratified by the expression levels of a 13-gene signature, demonstrated significantly shorter overall survival in both datasets (HR: 3.35; P < 0.001; HR: 2.93; P = 0.002). CONCLUSIONS: This analysis identified potential molecular determinants of response and survival to ICI treatment. Insights from melanoma biomarker research hold significant promise for translation into other malignancies, guiding individualized anti-tumor immunotherapy.

Humans↗

PubMed2001

[Tumor antigens presented to T helper lymphocytes--critical components of the cancer vaccine].

BACKGROUND: Due to acquired mutations, the protein composition of malignant tumours is distinct from that of normal cells to which the immune system is tolerant. Mobilisation of the patient's immune system against malignant cells remaining after conventional treatment is an attractive therapeutic option since lymphocytes respond with high sensitivity and specificity to non-self. MATERIAL AND METHODS: The potential of cancer vaccines targeted to T helper cells is discussed on the basis of published data including the author's studies. RESULTS: T helper cells kill cancer cells by direct cell-cell contact, stimulate other cytotoxic effector cells and respond to autologous tumour antigens like HER-2/neu (mammary and ovary cancer), tyrosinase (malignant melanoma), p21 ras (colorectal and pancreatic cancer), BCR-ABL (chronic myeloid leukaemia) and immunoglobulin (B-cell lymphoma). HER-2/neu and tyrosinase are not mutated, p21 ras and BCR-ABL represent a restricted set of mutations, and genetic variants of immunoglobulin can be characterised by hybridoma technology. INTERPRETATION: Targeted screening can, in a large number of cancer patients, identify peptide sequences potentially useful for therapeutic immunisation. Peptides can be designed to combine immunogenicity in the individual patient with proteolytic resistance, and are presently being tested as cancer vaccines.

Antigens, Neoplasm↗

PubMedDate not supplied

[Effect of fructose included in an anti-atherosclerotic diet on the course of ischemic heart disease].

The authors followed up 58 patients aged 40-56 years with coronary heart disease, who sustained myocardial infarction. Twenty-three patients received the antiatheroscleroctic diet including 140-150 g fructose (group 1), 35 subjects were given the common antiatherosclerotic diet (group 2). Fructose was included into salad, jelly, mousse, stewed fruit, cottage cheese pudding, lemon drink. A study was made on the effect of the therapeutic diets on immune responsiveness, lipid spectrum of blood serum, composition of fatty acids contained by red cell and platelet membranes, carbohydrate metabolism according to the glycemic curves after glucose intake. The data obtained demonstrate that inclusion of fructose in high doses (140-150 g) into the antiatherosclerotic diet has an untoward action on some features common to coronary heart disease.

Adult↗

PubMed1992

Intestinal changes associated with expression of immunity to challenge with Eimeria vermiformis.

To provide more information on the mechanisms involved in the immune inhibition of eimeria infections, NIH mice were adoptively immunized against infection with Eimeria vermiformis by the transfer of mesenteric lymph node cells from primed animals and homologously challenged. Subsequent changes in the architecture and cellular composition of the intestine were compared with those observed in similarly challenged susceptible control mice and correlated with the development of the parasite in the two groups. Actively immunized mice were also examined. In adoptively immunized mice, the development of E. vermiformis was inhibited within 3 days of administering the challenge inoculum. Concurrent changes in the intestine included lymphocytic infiltration, crypt hyperplasia, flattening of the crypt epithelium, and a reduction in the number of Paneth cells. Hyperplasia of goblet and pyroninophilic cells in response to challenge, although accelerated and enhanced in adoptively immunized hosts, occurred after the inhibition of the parasites, and mastocytosis was not observed in these animals, findings which suggest that the activities of goblet, pyroninophilic, and mast cells were not instrumental in reducing the numbers of parasites. The intestines of immunized mice contained fewer intraepithelial lymphocytes at the time of inhibition of the parasites than did those of the controls. The protective effects and intestinal changes described above did not differ appreciably from those seen after challenge of mice that had been immunized by infection.

Animals↗

PubMed1998

Restriction-PCR fingerprinting of the immunoglobulin VH repertoire: direct detection of an immune response and global analysis of B cell clonality.

Here we describe a method for fingerprinting the mouse immunoglobulin heavy chain variable region (VH) repertoire. Using a novel combination of existing techniques, large numbers of expressed VH genes can be simultaneously displayed as a fingerprint of VH gene fragments on a sequencing gel. This is achieved using isotype-specific reverse transcription-PCR amplification, restriction digestion and end-labeled primer run-offs. This technique (Res-PCR) allows analysis of the immune response, in this case to phenyloxazolone, in several different tissues and enables molecular cloning and sequencing of the VH genes involved in vivo. In addition, with Res-PCR, a "global" picture of expressed immunoglobulin genes is represented. This elucidates B cell clonality in different tissues and isotypes and detects a preference for shorter complementarity-determining region 3 in IgM-expressing cells. Res-PCR is a rapid and revealing method which will allow analysis of the complexity and sequence composition of the B cell immunoglobulin repertoire and so perhaps better define the B cell memory compartment and immune responses in vivo.

Amino Acid Sequence↗

PubMed1985

Immune induction by a protein antigen and by a peptide segment of the protein.

The immune induction by a protein (the tobacco mosaic virus protein-TMVP) was compared to the immune induction by the free, non-conjugated eicosa tryptic peptide fragment of the protein (tryptic peptide 8 representing residues 93-112 of the protein). The results demonstrated that like TMVP, peptide 8 was immunogenic in A/J mice. TMVP and peptide 8 do not cross react on the T cell level. However, immunization with TMVP or with peptide 8 induces antibodies which react with both TMVP and peptide 8. Characterization of the antibodies produced by both immunogens revealed that: their isotope composition is similar with IgG1 and IgG2 being the predominant isotypes; this composition indicates that both immunogens are T cell dependent antigens, the antibodies induced by TMVP and by peptide 8 are directed against the C-terminal decapeptide portion of peptide 8 (residues 103-112 of the protein), the fine specificity of these antibodies is the same. These results, and results of adoptive transfer experiments, indicate that antigen specific T cells had no effect on the expression of the fine antibody specificity. The results demonstrate the feasibility of immunizing with a portion of a protein for the purpose of inducing antibodies with the same isotype composition and specificity towards a protein epitope as those induced by immunization with the whole protein.

Amino Acid Sequence↗

PubMed1987

Induction, by adriamycin and mitomycin C, of modifications in lipid composition, size distribution, membrane fluidity and permeability of cultured RDM4 lymphoma cells.

Adriamycin and mitomycin C were previously found to modulate the sensitivity of lymphoma cells to lysis by certain effectors of immunity and this modulation was dependent on drug concentration. In the present studies, RDM4 lymphoma cells were treated with different concentrations of the two drugs for 24 h in culture. These treatments resulted in changes in the lipid composition, membrane fluidity, cell size distribution, and permeability to 51CrO4, Trypan blue, Acridine orange and trimethylaminodiphenylhexatriene (TMA-DPH) of the cells. Changes in some of these parameters, as a function of drug concentration, resulted in dose-response curves which were bell-like shaped, hence paradoxical similarities between non-drug-treated cells and cells treated with higher drug concentrations were observed.

Animals↗

PubMed2002

Visualization of signaling pathways and cortical cytoskeleton in cytolytic and noncytolytic natural killer cell immune synapses.

Recent applications of imaging approaches and other methods of cell biology have provided high-resolution visualization of the location of fluorescent proteins in living and fixed cells during cell-cell interactions between lymphocytes, antigen presenting cells and target cells. We review the composition and dynamics of molecular and cytoskeletal events occurring during natural killer cell interactions with susceptible and nonsusceptible target cells. The natural killer cell immune synapse and the concomitant changes in cytoskeletal components and cytoplasmic organelles are described. The findings are compared with the observations made in T helper cells and cytotoxic T cells. It is concluded that the cytolytic immune synapses display spatial-temporal dynamics that are accelerated as compared with T helper cells. In addition, the cytolytic conjugates have unique characteristics relating to their effector function. Furthermore, the natural killer cell immune synapses in cytolytic and noncytolytic interactions are distinctly different and display patterns consistent with characteristic signaling pathways identified in biochemical studies of disrupted cells. The precise relationship between different stages of the natural killer cell immune synapse formation and progression in signal transduction pathways is yet to be established.

Actins↗

PubMed2004

Interaction of dendritic cells with antigen-containing liposomes: effect of bilayer composition.

Vaccine efficacy might be improved by exploiting the potent antigen presenting properties of dendrite cells (DCs), since their ability to stimulate specific major histocompatibility complex-restricted immune responses has been well documented during the recent years. In that light, we investigated how the interaction of antigen-containing liposomes with DCs was affected by the bilayer composition. Monocyte-derived human DCs and murine bone marrow-derived DCs were analysed and compared upon in vitro incubation with liposomes by flow cytometry and confocal microscopy. Anionic liposomes with a bilayer composition of phosphatidylcholine, cholesterol and phosphatidylglycerol or phosphatidylserine interacted with a limited fraction of the total DC population in case of both DC types. Inclusion of mannosylated phosphatidylethanolamine (Man-PE) for targeting to the mannose receptor (MR) increased the interaction of negatively charged liposomes with both human and murine DCs. This increase could be blocked in human DCs by addition of the polysaccharide mannan indicating that uptake might be mediated by the mannose receptor. Cationic liposomes containing trimethyl ammonium propane interacted with a very high percentage of both DC types and could be detected in high amounts intracellularly. In conclusion, liposome bilayer composition has an important effect on interaction with DCs and might be critical for the vaccination outcome.

Animals↗

PubMedDate not supplied

[Immune complexes and effector cell activation (author's transl)].

The study of antibody-dependent cellular cytoxicity mechanisms in human and experimental schistosomiasis has revealed the particular role of immune complexes in triggering phagocytic cell activation. IgE complexes or aggregates were demonstrated to bind to specific receptors on rat macrophages as well as on human or baboon macrophages, leading to the killing of the parasite target. In the eosinophil-dependent cytotoxicity mechanisms, IgE complexes have been shown to exert a regulatory effect on eosinophil activation in vitro and in vivo and on the ability of this cell population to kill parasites. The various observations reported in this review suggest that the characteristics of the Fc receptors, the composition and antigen-antibody ratio of immune complexes might be essential factors in the regulation of the immune response against parasites.

Animals↗

PubMedDate not supplied

Prospects for exosomes in immunotherapy of cancer.

Exosomes are nanometer sized membrane vesicles invaginating from multivesicular bodies and secreted from epithelial and hematopoietic cells. They were first described "in vitro" but vesicles with the hallmarks of exosomes are present in vivo in germinal centers and biological fluids. Their protein and lipid composition are unique and could account for their expanding functions such as eradication of obsolete proteins, antigen presentation or "Trojan horses" for viruses or prions. Exosome secretion could be a regulated process participating in the transfer of molecules inbetween immune cells. Despite numerous questions pertaining to their biological relevance, the potential of dendritic cell derived-exosomes as cell-free cancer vaccines is currently being assessed. This review will summarize the composition and formation of exosomes, preclinical data, Phase I trials and optimization protocols for improving their immunogenicity in tumor bearing patients.

Animals↗

PubMed2003

Brain slice culture for analysis of developmental brain disorders with special reference to congenital cytomegalovirus infection.

Cytomegalovirus (CMV) is the most significant infectious cause of congenital abnormalities of the central nervous system (CNS) with variation from the fatal cytomegalic inclusion disease to functional brain disorder. The phenotype and degree of the brain disorder depends on infection time during the developing stage, virulence, route of infection and the viral susceptibility of the cells. The pathogenesis of the CMV infection to the CNS seems to be strongly related to neural migration, neural death, cellular compositions and the immune system of the brain. To understand the complex mechanism of this disorder, we used organotypic brain slice cultures. In the brain slice culture system, migration of CMV-infected neuronal cells was observed, which reflects infectious dynamics in vivo. Neural progenitor cells or glial immature cells in the subventricular zone and marginal area are most susceptible to murine cytomegalovirus (MCMV) infection in this system. The susceptibility declined as the number of immature glial cells decreased with age. The immature glial cells proliferated in brain slice cultures during prolonged incubation, and the susceptibility to MCMV infection also increased in association with the proliferation of these cells. The brain slice from an immunocompromised mouse (Beige-SCID mouse) unexpectedly showed lower susceptibility than that of an immunocompetent mouse during any prolonged incubation. These results suggest that the number of immature glial cells might determine the susceptibility of CMV infection to the brain, independent of the immune system. We reviewed recent findings of CMV infection to the brain from the perspective of brain slice cultures and the possibility that this system could be a useful method to investigate mechanisms of congenital anomaly of the brain.

Animals↗

PubMed2000

Jet fuel-induced immunotoxicity.

Chronic exposure to jet fuel has been shown to cause human liver dysfunction, emotional dysfunction, abnormal electroencephalograms, shortened attention spans, and to decrease sensorimotor speed (3-5). Exposure to potential environmental toxicants such as jet fuel may have significant effects on host systems beyond those readily visible (e.g., physiology, cardiology, respiratory, etc.), e.g., the immune system. Significant changes in immune function, even if short-lived, may have serious consequences for the exposed host that may impinge affect susceptibility to infectious agents. Major alterations in immune function that are long lasting may result in an increased likelihood of development and/or progression of cancer, as well as autoimmune diseases. In the current study mice were exposed 1 h/day for 7 days to a 1000-mg/m3 concentration of aerosolized jet fuel obtained from various sources (JP-8, JP-8+100 and Jet A1) and of differing compositions to simulate occupational exposures. Twenty-four hours after the last exposure the mice were analyzed for effects on the immune system. It was observed that exposure to all jet fuel sources examined had detrimental effects on the immune system. Decreases in viable immune cell numbers and immune organ weights were found. Jet fuel exposure resulted in differential losses of immune cell populations in the thymus. Further, jet fuel exposure resulted in significantly decreased immune function, as analyzed by mitogenesis assays. Suppressed immune function could not be overcome by the addition of exogenous growth factors known to stimulate immune function. Thus, short-term, low-concentration exposure of mice to aerosolized jet fuel, regardless of source or composition, caused significant deleterious effects on the immune system.

Animals↗

PubMed2000

Characterization of superantigen-induced clonal deletion with a novel clan III-restricted avian monoclonal antibody: exploiting evolutionary distance to create antibodies specific for a conserved VH region surface.

Evolution of the Ab system has yielded three clans of VH region genes that are represented in almost every known higher species with an adaptive immune system. These clans are defined by sequence homologies primarily in highly conserved framework (FR) subdomains, which serve a scaffolding function maintaining the conformation of loops responsible for Ag binding. Structural analyses indicate that the VH FR1 and FR3 form a conserved composite exposed surface, which has been implicated in interactions with B cell superantigens. To directly investigate the expression of clan-defined supraclonal sets, we exploited the evolutionary distance of the chicken immune system and the selection power of phage display, to derive Abs diagnostic for clan III Ig. Using a specially tailored immunization and selection strategy, we created recombinant avian single chain Fv Abs specific for the clan III products, including those from the human VH3 family, and the analogous murine 7183, S107, J606, X24, and DNA4 families, and binding was competitive with natural B cell superantigens. The archetype, LJ-26, was demonstrated to recognize a clan-specific surface expressed in diverse mammalian, and also the Xenopus and chicken, immune systems. In flow-cytometric studies with LJ-26, we found that treatment of heterozygous T15i transgenic mice with a model B cell superantigen induced a clan III-restricted clonal deletion. These studies demonstrate the utility of a novel recombinant serologic reagent to study the composition of the B cell compartment and also the consequences of B cell superantigen exposure.

Amino Acid Sequence↗