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Diagnostic and prognostic value of monoclonal antibodies in immunophenotyping of T cell lymphomas.

6 cases of post-thymic T cell lymphoma (PTCL) and 4 cases of T lymphoblastic lymphoma were investigated with a panel of 21 monoclonal antibodies (MoAb). The PTCL group was composed of 2 by 2 cases of lymphoepithelioid cell lymphoma, T zone lymphoma and T immunoblastic lymphoma. In lymphoepithelioid cell lymphoma, the cell proliferating activity was low, and a malignant clone was not identifiable by the methods used. In the cases of T zone lymphoma and T immunoblastic lymphoma, malignant populations were detectable on the grounds of immunologic marker profile combined with cytologic particularities. The 4 cases of T lymphoblastic lymphoma were of a common cortical thymic phenotype (T4+, T8+, T6+) and presented with a mediastinal mass. In 3 of them, cell proliferation marker (Ki-67) was expressed by most tumor cells. Cell proliferating activity, however, did not inversely correlate with survival.

Adolescent↗

Immunogenetic susceptibility of atherosclerotic stroke: implications on current and future treatment of vascular inflammation.

The understanding of the pathophysiology governing atherosclerosis supports a prominent role for inflammation pathways in plaque initiation and progression that result in stroke and myocardial infarction. Elevated levels of inflammatory markers in the blood, such as C-reactive protein and CD40 ligand/CD40, in concert with increased expression of adhesion molecules, chemokines, cytokines, matrix metalloproteinases (MMP), and inflammatory cells in the plaque, characterize the symptomatic atherothrombotic state. Advances in predictive capabilities of vascular events using a number of these biomarkers are beginning to remodel our clinical practice in the use of medications such as statins and angiotensin receptor blockers for stroke prevention. Although the general inflammatory features of atherosclerosis are becoming widely recognized, factors resulting in individual variability in plaque formation and instability remain poorly defined. Emerging literature points toward several acquired and innate susceptibility factors in the immune pathways that may provide insight into why many plaques rapidly evolve from a "stable" to an "unstable" or symptomatic state. First, exposure of plaque memory T-lymphocytes to infectious or endogenous antigens may result in rapid clonal expansion of T-cell variable beta chain subtypes and stimulate macrophages to release MMPs, causing plaque destabilization. The effects of infectious agents can further be influenced by an individual's major histocompatibility complex class II molecule profiles, which can affect susceptibility to specific organisms. Second, functional polymorphisms of genes that regulate the immune pathway can predispose patients to a more robust inflammatory expression after risk factor exposure. Identification of a susceptibility gene profile and immunologic mediators that promote T-cell activation provides a unique opportunity for early identification of stroke risk and targets for future therapy.

Angiotensin II Type 1 Receptor Blockers↗

Fecal microbiota transplantation promotes type 2 mucosal immune responses with colonic epithelium proliferation in patients with recurrent Clostridioides difficile.

BACKGROUNDFecal microbiota transplantation (FMT) is the most effective therapy for recurrent Clostridioides difficile infection (rCDI), yet its mechanism of action remains poorly understood.METHODSWe report the results of a clinical trial of patients undergoing FMT therapy for rCDI (n = 16), which analyzed colon biopsies, plasma, PBMCs, and stool at the time of FMT and 2-month follow-up. Plasma and colon biopsy samples were also collected from healthy controls for comparison with patients with rCDI. Microbiome composition, colonic gene expression, and immune changes were evaluated through high-throughput sequencing and immunoprofiling via flow cytometry.RESULTSNo patients experienced recurrence at follow-up. FMT significantly altered the intestinal microbiome but had no significant impact on the systemic immune system. In contrast, FMT promoted broad changes in colonic transcriptional profiles compared with both pre-FMT and healthy control biopsies, inhibiting genes associated with proinflammatory signaling and upregulating type 2 immunity and proliferative pathways (Myc and mTORC1). FMT increased expression of IL-33 and the type 2 immune EGFR family ligand amphiregulin, potentially explaining upregulation of Myc and mTORC1 pathways. Spatial transcriptomics demonstrated that these changes were localized to the colonic epithelium. Comparison of transcriptional profiles with available single-cell gene sets determined that post-FMT biopsies were enriched in signatures associated with proliferative cell types while repressing signatures of differentiated colonocytes.CONCLUSIONWe conclude that FMT promotes proliferation of the colonic epithelium in patients with rCDI, which may drive regeneration and protect against subsequent CDI.TRIAL REGISTRATIONClinicaltrials.gov NCT02797288.FUNDINGThis work was funded by grants from the NIH.

Adult↗

Biosynthesis of proinsulin and insulin in newborn rat pancreas. Interaction of glucose, cyclic AMP, somatostatin, and sulfonylureas on the (3H) leucine incorporation into immunoreactive insulin.

The purpose of the present study was to investigate the regulation of insulin biosynthesis during the perinatal period. The incorporation of [3H]leucine into total immunoreactive insulin (IRI) and into IRI fractions was measured by a specific immunoprecipitation procedure after incubation, extraction, and gel filtration in isolated 3-day-old rat pancreases without prior isolation of islets. IRI fractions were identified by their elution profile, their immunological properties, and their ability to compete with the binding of 125 I-insulin in rat liver plasma membranes. No specific incorporation of [3H]leucine was found in the IRI eluted in the void volume, making it unlikely that this fraction behaves as a precursor of (pro) insulin in this system. In all conditions tested, the incorporation of [3H]leucine was linearly correlated with time. Optimal concentration of glucose (11 mM) activated six- to sevenfold the [3H]leucine incorporation into IRI. Theophylline or N6O2-dibutyryl- (db) cAMP at 1.6 mM glucose significantly increased the [3H]leucine incorporation. Glucose at 16.7 mM further enhanced the effect of both drugs. Contrarily, somatostatin (1-10 mug/ml) inhibits the rate of [3H]leucine incorporation into IRI in the presence of 11 mM glucose; this effect was observed at 5.5 mM glucose and was not modified by any further increase in glucose concentrations up to 27.5 mM. Theophylline or dbcAMP at 10 mM concentration did not reverse the somatostatin inhibitory effect on either insulin biosynthesis or release. Somatostatin also inhibited both processes in isolated islets from the 3-day-old rat pancreas. High Ca++ concentration in the incubation medium reversed the inhibitory effect of somatostatin on glucose-induced insulin biosynthesis as well as release. In both systems the inhibitory effect of somatostatin on insulin biosynthesis and release correlated well. Glipizide (10-100 muM) AND TOLBUTAMIDE (400 MUM) inhibited the stimulatory effect of glucose, dbcAMP, and theophylline on [3H]leucine incorporation into IRI. The concentrations of glipizide that were effective in inhibiting [3H]leucine incorporation into IRI were smaller than those required to inhibit the phosphodiesterase activity in isolated islets of 3-day-old rat pancreas. These data suggest the following conclusions: (a) the role of the cAMP-phosphodiesterase system on insulin biosynthesis is likely to be greater in newborns than in adults; (b) the greater effectiveness of glucose and the cAMP system on insulin biosynthesis than on insulin release might possibly be related to the rapid accumulation of pancreatic IRI which is observed in the perinatal period; (c) somatostatin, by direct interaction with the endocrine tissue, can inhibit glucose and cAMP-induced insulin biosynthesis as well as release; calcium reverses this inhibition; (d) sulfonylureas inhibit insulin biosynthesis in newborn rat pancreas an effect which has to be considered in the use of these agents in human disease.

Animals↗

Phenotype, immunological reactivity and cytokine production profile of Peyer's patch cells from mice immunized orally with allogeneic cells.

Mice of inbred strain BALB/c were immunized orally for 10 consecutive days with fresh spleen cells from allogeneic C57BL/10 (B10) donors. The immunized mice displayed significant allotransplantation immunity in vivo as demonstrated by resistance to the growth of allogeneic tumours induced by high doses of tumour cells. No significant changes in the proportion of the major T cell subsets in PP of immunized mice were found 1 or 7 days after the last immunization dose. However, PP cells from orally immunized mice displayed stronger proliferative response after stimulation with cells used for oral immunization than the cells from control animals. Similarly, after stimulation in vitro with specific alloantigens, PP cells from orally immunized mice produced more IFN-gamma than the cells from control recipients. On the contrary, the production of IL-4 was significantly decreased in the immunized mice. The production of IL-2 by PP cells after oral immunization was not significantly changed and IL-10 was only slightly increased. The results thus show that oral immunization with allogeneic cells induces systemic transplantation immunity which can be demonstrated already in Peyer's patches by increased cell proliferation after immunization with specific alloantigens and by changes in cytokine production.

Administration, Oral↗

RET/PTC-induced gene expression in thyroid PCCL3 cells reveals early activation of genes involved in regulation of the immune response.

RET/PTC rearrangements represent key genetic events involved in papillary thyroid carcinoma (PTC) initiation. The aim of the present study was to identify the early changes in gene expression induced by RET/PTC in thyroid cells. For this purpose, microarray analysis was conducted on PCCL3 cells conditionally expressing the RET/PTC3 oncogene. Gene expression profiling 48 h after activation of RET/PTC3 identified a statistically significant modification of expression of 270 genes. Quantitative PCR confirmation of 20 of these demonstrated 90% accuracy of the microarray. Functional clustering of genes with greater than or less than 1.75-fold expression change (86 genes) revealed RET/PTC3-induced regulation of genes with key functions in apoptosis (Ripk3, Tdga), cell-cell signaling (Cdh6, Fn1), cell cycle (Il24), immune and inflammation response (Cxcl10, Scya2, Il6, Gbp2, Oas1, Tap1, RT1Aw2, C2ta, Irf1, Lmp2, Psme2, Prkr), metabolism (Aldob, Ptges, Nd2, Gss, Gstt1), signal transduction (Socs3, Nf1, Jak2, Cpg21, Dusp6, Socs1, Stat1, Stat3, Cish) and transcription (Nr4a1, Junb, Hfh1, Runx1, Foxe1). Genes coding for proteins involved in the immune response and in intracellular signal transduction pathways activated by cytokines and chemokines were strongly represented, indicating a critical role of RET/PTC3 in the early modulation of the immune response.

Animals↗

Immunoinformatics Approach for Optimization of Targeted Vaccine Design: New Paradigm in Clinical Trials and Healthcare Management.

INTRODUCTION: The immunoinformatics approach combines bioinformatics and computational tools, offering a revolutionary method for improving vaccine development by analyzing immune responses at the molecular level. Immunoinformatics enables the creation of customized vaccines designed for specific infections or cancer cells. OBJECTIVE: The primary objective of immunoinformatics is to enhance the vaccine development process by predicting and boosting the body's immune response. It aims to identify potential immunogenic epitopes and biomarkers that are important for creating vaccines with greater specificity and efficacy, especially when dealing with large-scale data. METHODS: Immunoinformatics utilizes a combination of proteomic, genomic, and epigenomic data, as well as machine learning algorithms and artificial intelligence techniques. These tools predict how various immunological components, e.g., T-cell and B-cell epitopes, interact with the immune system. This approach allows researchers to avoid traditional trial-and-error methods, enabling the efficient identification of potential vaccine candidates. Additionally, personalized vaccines can be developed by considering individual genetic and immunological characteristics. RESULTS: The use of immunoinformatics techniques accelerates the screening of vaccine candidates, enhances patient stratification, and optimizes formulations for clinical trials. This approach has been shown to improve vaccine safety, efficacy, and development speed. It also holds promise for managing healthcare on a large scale by producing vaccines tailored to specific populations, thereby improving the overall effectiveness of vaccination programs. CONCLUSION: Immunoinformatics represents a transformative approach to vaccine research, improving clinical trial efficiency and enabling the development of more reliable, flexible, and personalized vaccines. This approach has the potential to significantly enhance global healthcare outcomes by accelerating the vaccine development process and optimizing vaccination strategies.

Immunoinformatics↗

Fusions of breast cancer and dendritic cells as a novel cancer vaccine.

The use of dendritic cell (DC)-based cancer vaccines has emerged as a promising area of investigation in the field of tumor immunotherapy. DCs are potent antigen-presenting cells that are essential for the initiation of primary immune responses. DCs that have been manipulated to express tumor antigens are capable of stimulating tumor-specific immunity. The fusion of tumor cells with DCs results in the presentation of a broad spectrum of tumor antigens in the context of the immune-stimulating machinery of the DC. Animal models have demonstrated that vaccination with DC/tumor fusions is protective from a lethal challenge with tumor cells and results in regression of established disease. Preclinical human studies in breast cancer have shown that fusion cells stimulate cellular immune responses capable of lysing autologous tumor cells. Based on these findings, a phase I clinical trial has been conducted in patients with metastatic breast cancer to examine the toxicity profile and immunologic impact associated with vaccination with DC/tumor fusions.

Breast Neoplasms↗

Functional specialization of memory Th cells revealed by expression of integrin CD49b.

Infection or immunization induces heterogeneous memory T cell subsets, but their origin and protective value against infection are unclear. In this study, we report the functional characterization of two memory Th subsets, defined by expression of integrin CD49b. Stable CD49b expression is induced in up to one-half of all memory Th cells. More importantly, the CD49b- and CD49b+ subsets display distinct helper activities, typified by the production of IL-10 and TNF-alpha, respectively. Although the inflammatory properties of the CD49b+ subset are protective against intracellular bacterial infection, they are associated with immunopathology in acute viral infection. Modulation of the CD49b-defined memory Th subsets may provide infection type-specific interventions, where either enhancement of the inflammatory response or reduction of immunopathology is essential.

Animals↗

Marmoset species variation in the humoral antibody response: in vivo and in vitro studies.

A comparison of the in vivo and in vitro antibody response capabilities of two marmoset species, Saguinus fuscicollis and Saguinus oedipus oedipus, revealed the former to be superior in elaborating humoral antibody. In vivo challenges with Escherichia coli lipopolysaccharide (LPS) and Salmonella typhi flagella consistently yielded higher antibody titres in S. fuscicollis; indeed, with LPS antigen, multiple inoculations of S.o. oedipus marmosets led ultimately to a decrease in antibody formation, in contrast to the anamnestic response of S. fuscicollis. This species differential in immune competence was also suggested in the in vitro stimulation of peripheral blood leucocytes (PBL) and spleen cells with sheep red blood cells (RBC). None of 55 S.o. oedipus PBL cultures and 49 of 89 (55%) S. fuscicollis cultures responded to the test antigen. A similar differential in response to sheep RBC was noted with the spleen cells of each species, although this report contrasts the antibody-forming potential of two marmoset species, a comparison of the immunological response profile of marmosets to those of other laboratory animals challenged with similar antigens suggests these primates may be relatively incompetent. The possible relationship between the haemopoietic chimerism of marmosets and a diminished immune competence is discussed.

Animals↗

[Neonatal herpes: recurrence after treatment with acyclovir].

A case of cutaneous herpes relapse with meningitis is reported in a 1.5 month-old infant treated during the first three weeks of life with acyclovir (ACV) for a neonatal herpes infection. Such a relapse has previously been described in older children as well as in adults. In this case report, there was immunological response to herpes virus infection, 2.5 months after the onset of the infection. The relapse is discussed taking into account the mechanism of action of ACV, the age of the patient and the immunological response profile. Because of the high risk of neurological involvement, we suggest that the relapse should be treated with ACV for a period of time longer than actually recommended.

Acyclovir↗

[Determination of blood profile of atherogenic lipids using immunologic techniques].

Apolipoprotein B (Apo B) exists in different types of particles in human plasma: Lp B containing only Apo B, Lp B:E containing Apo B and Apo E, Lp B:C-III containing Apo B and Apo C-III, Lp B: (a) containing Apo B and Apo (a) and so on. The physicochemically defined lipoproteins were found to be heterogeneous with respect to this concept. A particle such as Lp B, for example, may occur in any segment of the density spectrum depending on the composition and content of its lipid complement. These particles are metabolically distinct and their quantification is essential for better understanding of lipid transport disorders. Using new immunological procedures, we have identified some subpopulations of Apo B containing lipoproteins which are more abondant in atherosclerotic patients and which characterize some dyslipoproteinemic states. Drugs decreasing Apo B act differently on these different types of particles. The results presented substantiate the usefulness of the study of lipoprotein particles defined by their apolipoprotein composition for future clinical, pharmacological and epidemiological studies.

Apolipoproteins B↗

Establishment and characterization of a clonal human T-cell line, MKB-1 derived from a patient with acute myeloblastic leukemia.

A human T-cell line, designated as MKB-1, was established by cloning procedures in a suspension culture from a peripheral blood of a 17-year-old female patient with acute myeloblastic leukemia. The immunological marker profile of MKB-1 indicated that unlike a myeloid phenotype of the original leukemic cells, the cells were positive for CD3 (both cell surface and cytoplasm), T cell receptor (TcR) alpha/beta heterodimer, CD4, CD5, CD7, CD10, CD57 (Leu7), SN-1 and the cytoplasmic TcR beta chain. These findings indicate the T cell nature of the established cells. Terminal deoxynucleotidyl transferase (TdT) was also detected in 60%. We did not detect markers of human myeloid and B cell associated antigens, HLA-class II or immunoglobulin chains. Cytogenetic study revealed that the MKB-1 cells had a female hypo-tetraploid karyotype with chromosomal abnormalities including a translocation between chromosomes 10 and 14. The breakpoint of chromosome 14 of this translocation, 14q11.2, is known to be the location of TcR alpha and delta genes; t(10; 14) (q26; q11.2) is a variant type of a T cell neoplasm-associated translocation, t (10; 14) (q24; q11.2). The MKB-1 cell line is unusual in that its T cell characteristics are phenotypically and cytogenetically distinct from the original myeloid leukemia cells.

Adolescent↗

Immunologic thrombocytopenic purpura in human immunodeficiency virus--seropositive patients with hemophilia. Comparison with patients with classic autoimmune thrombocytopenic purpura, homosexuals with thrombocytopenia, and narcotic addicts with thrombocytopenia.

The immunologic platelet profile of 29 patients with hemophilia who had received multiple transfusions (14 had thrombocytopenia) was compared with profiles of 15 patients with classic autoimmune thrombocytopenia. Thrombocytopenic hemophiliacs who were seropositive for the human immunodeficiency virus (13 out of 14) had platelet-bound immunoglobulin G and C3C4 levels as well as circulating immune complexes that were 15.1-, 4.0-, and 2.4-fold greater, respectively, than normal control subjects' platelets and 3.4-, 2.6-, and 2.4-fold greater, respectively, than autoimmune thrombocytopenic patients' platelets. Hemophiliacs with normal platelet counts (nine out of 13 seropositive) had elevated values that were intermediate in level between those of thrombocytopenic hemophiliacs and those of classic autoimmune thrombocytopenic patients. The four seronegative hemophiliacs had normal values (except for one platelet-bound IgG measurement). An inverse correlation was noted between platelet count and platelet-bound IgG, r = -0.838, P less than 0.001. Serum antiplatelet reactivity (1:256 mean titer compared with control sera) resided predominantly in the 7S IgG fraction, and bound to autologous as well as homologous platelets at concentrations as low as 0.06 to 0.13 mg/ml. F(ab')2 fragments of the 7S IgG fraction inhibited binding of hemophilic IgG to normal platelets and bound to normal platelets at concentrations as low as 0.06 mg/ml. Antiplatelet IgG could be eluted from six of six hemophilic and eight of eight classic autoimmune thrombocytopenic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Anti-Idiotypic↗

Type I collagen synthesis by corneal endothelial cells modulated by polymorphonuclear leukocytes.

When primary corneal endothelial cells were grown in polymorphonuclear leukocyte (PMN)-conditioned medium, a minor population of cells acquired fibroblastic morphology. Such modulated endothelial cells supported by PMN-conditioned medium grew much faster than the major nonresponding polygonal endothelial cell. Upon serial passages, the modulated endothelial cells became the dominant cell type and eventually formed a homogeneous fibroblastic culture. At the same time, phenotypic changes of collagen were observed. The primary endothelial cells grown in PMN-conditioned medium, consisting of responding elongated cells and nonresponding polygonal endothelial cells, produced predominantly type IV collagen with type III collagen as a minor component. As cells were subcultured and fibroblastic cells became dominant, type IV collagen synthesis was dramatically decreased and type I collagen synthesis was increased in parallel. When they reached the fully modulated stage, the cultures synthesized types I and III collagen, with type I accounting for 75-85% of the total. Type I collagen synthesized by the fibroblastic endothelial cells shared common characteristics with known type I collagen, such as migration behavior on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, CNBr peptide profiles, and immunologic identity. Thus, PMNs apparently contribute to the modulation of corneal endothelial cells, causing them to acquire characteristics of fibroblasts, cell multilayering, and deposition of interstitial extracellular matrix composed predominantly of interstitial type I collagen.

Animals↗

Host defense systems in cattle exposed to polybrominated biphenyl.

In vivo and in vitro immunologic studies were undertaken in 114 Holstein cattle, 60 of which had detectable polybrominated biphenyls (PBB) in adipose tissue. The tissue PBB concentrations were between 0.02 and at least 1,000 mg/kg. An immunologic test profile was used to evaluate the influence of PBB on bovine immune competence. The profile included serum immunoglobulin determinations, autoantibody studies, lymphocyte subpopulation determinations, lymphoblastogenesis assays, delayed hypersensitivity skin testing, and neutrophil function studies. The results of the evaluation indicated that the host defenses are intact, both in quantity and function, in cattle with PBB body burdens ranging from 0.02 and 24.0 mg/kg for at least 2 years. Cattle fed 25 g of PBB daily during the acute toxicity study exhibited usual immune competence until they accumulated 500 g of PBB (tissue concentrations exceeding 1,000 mg/kg). Cattle that were fed more than 500 g of PBB became moribund and exhibited changes in neutrophil function tests and serum antibody titers.

Adipose Tissue↗

Gas-chromatographic screening of capsular polysaccharides of Neisseria meningitidis.

Thirteen systemic strains, i e strains isolated from systemic infections, and 77 carrier isolates of Neisseria meningitidis were serogrouped by agglutination and analyzed by gas chromatography (GC) of phenol extracts. For systemic strains the sugar patterns were in accordance with their group-specific capsular polysaccharides (CPS). Some carrier isolates revealed unexpected GC profiles. Upon immunological retesting with new sera, GC results were generally confirmed. Occasional isolates initially serogrouped as B or Y completely lacked neuraminic acid. Some non-groupable isolates were shown by ultracentrifugation and GC to have significant amounts of this sugar likely to originate from CPS of known composition or from unknown polysaccharides. One such originally non-groupable isolate showed a weak agglutination reaction specifically with group B antiserum when reexamined. Generally, carrier isolates had lower amounts of CPS than systemic strains of the same group. Five successive isolates from one carrier were first serogrouped as X, Z or non-groupable, but they had high amounts of galactosamine and 2-keto-3-deoxy octonate, sugars characterizing CPS of serogroup 29E. These isolates were confirmed by agglutination with recently available group 29E antiserum to be of this serogroup, which has not been reported before in Norway. Ultracentrifugation revealed the presence of unknown polysaccharides containing glucose, galactose or glucosamine, but further purification of these polymers is required to determine their composition and immunological importance.

Chromatography, Gas↗