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In vitro tests of cellular immunity in man.

There has been a recent rapid increase in the number of assays for cellular immunity in man and in information related to the mechanisms underlying the observed reactions. These tests have been applied clinically for three main purposes: (a) Evaluation of cell-mediated immune competence of patients with primary immune deficiencies and of possible immunological depression associated with cancer or other diseases. (b) Determination of major differences in histocompatibility antigens which might be important in rejection of organ transplants. Some cellular immune assays have become part of the routine battery of assays used for immunological evaluation of potential donors and recipients. (c) Measurement of specific immune reactivity against antigens associated with a variety of diseases, including infectious diseases, autoimmune diseases and cancer.

Antibody-Dependent Cell Cytotoxicity↗

Specific antitumor effects of tumor vaccine produced by electrofusion between osteosarcoma cell and dendritic cell in rats.

Dendritic cells (DCs) are potent antigen-presenting cells capable of inducing primary T-cell responses. Several immunotherapy treatment strategies involve manipulation of DCs, both in vivo and ex vivo, to promote the immunogenic presentation of tumor-associated antigens. In this study, an electrofusion protocol was developed to induce fusion between osteosarcoma cells and allogeneic bone marrow-derived DCs. Preimmunization with irradiated electrofusion products was found to provide partial or complete protection from tumor challenge in the UMR106 tumor model. Vaccinated survivors developed long immunological memory. The therapeutic potential of this type of approach was suggested by the ability of UMR106-DC electrofusion products which could induce tumor rejection in a substantial percentage (60%) of hosts bearing pre-established tumor cells. These results tended to indicate that treatment with electrofused tumor cells and allogeneic DCs might be capable of inducing a potent antitumor response and could conceivably be applied to a wide range of cancer indications for which tumor-associated antigens have not been identified.

Animals↗

Prevention of meningococcal disease.

Invasive disease caused by Neisseria meningitidis has an average annual incidence of one case per 100,000 in the United States. The disease can be rapidly fatal or result in severe neurologic and vascular sequelae despite antibiotic therapy. Antibiotic chemoprophylaxis with rifampin, ciprofloxacin, or ceftriaxone is required for household and other close contacts. Although the majority of cases of meningococcal disease are sporadic, outbreaks can occur, and vaccination of the affected population often is necessary. Serogroup B accounts for the highest incidence of disease in young infants but is not contained in any vaccine licensed in the United States. Adolescents and young adults 15 to 24 years of age have a higher incidence of disease and a higher fatality rate than other populations. Because 70 to 80 percent of these infections in the United States are caused by meningococcal serogroups C, Y, and W-135, which are contained in the tetravalent meningococcal vaccines, they are potentially preventable. The U.S. Food and Drug Administration recently approved a meningococcal conjugate vaccine containing serogroups A, C, Y, and W-135. This T-cell-dependent vaccine induces bactericidal antibody production and promotes immunologic memory that should result in a longer duration of immunity. The Advisory Committee on Immunization Practices recommends that this vaccine be given to 11- and 12-year-old adolescents, to adolescents entering high school, and to college freshmen living in dormitories. The vaccine also may be given to persons 11 to 55 years of age who belong to certain high-risk groups.

Adolescent↗

Personalized immunotherapy for the treatment of non-Hodgkin lymphoma: a promising approach.

The efficacy of immunotherapeutic strategies for the treatment of lymphoid malignancies has been demonstrated in recent years. In patients with B-cell lymphomas, particularly indolent lymphoma, the use of passive immunotherapy, such as the anti-CD20 monoclonal antibody rituximab, has made an impressive impact on patient outcome. Personalized immunotherapy, a method that triggers the immune system to mount a response against tumor cells, has shown promising results in early clinical trials in hematologic malignancies. This therapeutic modality appears safe, with the most common adverse events being transient, local reactions at the site of injection. Furthermore, personalized immunotherapy has the potential to generate immunologic memory, which could provide prolonged remission. Currently, 3 large phase III studies are evaluating the efficacy and safety of personalized immunotherapy in patients with follicular lymphoma. It is hoped that the results of these studies will lead to the incorporation of this promising approach into the standard treatment of patients with lymphoma.

Clinical Trials as Topic↗

[Diabetes mellitus and immunization].

Principles of prevention of infectious diseases have been known for several thousands of years. One of the most significant tools of infection prophylaxis is immunization. Vaccines containing thymus-dependent antigens produce massive and complex immune response and feature immunologic memory. That is why they can successfully protect patients with diabetes. Lately, it has been thought by general public and even experts that application of vaccines within national immunization programmes is one of the etiopathogenetic factors in the development of type 1 diabetes mellitus (DM). However, analysis of extensive studies performed by the experts of the Institute for Vaccine Safety proved that there is no positive or negative impact of immunization on the development of type 1 diabetes mellitus. The basic vaccinations recommended for diabetics include immunizations against influenza, pneumococcal infections, tetanus and viral hepatitis B. Other vaccines are administered only after individual assessment of benefits and risks for the diabetic patient. Most often, these are vaccinations against viral hepatitis A, tick-borne encephalitis, meningococcal infections and other infections that put in risk diabetic patients travelling abroad.

Aged↗

[Crosstalk between innate and adaptive immunity].

Most of microorganisms are detected and destroyed within hours by innate immunity which does not generate lasting protective immunity. Innate immunity is mainly mediated by macrophages, dendritic cells and NK cells. Adaptive response is mediated by antigen-specific lymphocytes, which generate specific immunological memory, providing long-lasting protection. Th1 cells produce interferon (IFN)-gamma which mediate cell-mediate immunity, while Th2 cells help B cell to produce antibody via IL-4, 5, 6 production. Tr cells producing IL-10 are responsible for termination of excessive immune inflammations. IFN are divided into two main classes: type I IFN such as IFN-alpha, beta and type II IFN (IFN -gamma), both of which serve not only to bridge the gap between innate and adaptive immunity but also to shape subsequent development of adaptive immunity.

Animals↗

[The development of mucosal vaccines].

The live oral polio vaccine was the first mucosal vaccine accepted for general use. Since then, similar vaccines have been developed against typhoid fever, cholera and rotavirus infection, and a nasal vaccine against influenza has recently been registered in the USA. The only non-living mucosal vaccine on the market today is an oral cholera vaccine consisting of inactivated Vibrio cholerae and the B subunit of cholera toxin. Several groups of scientists are at present working on the development of other mucosal vaccines based on inactivated microbes or parts of them. Results from animal trials at the Norwegian Institute of Public Health, suggest that non-living nasal vaccines can provide protective immunity and may be combined with the same types of vaccines for injection. Clinical trials with nasal vaccines consisting of beta-propiolactone inactivated influenza particles, showed that it was possible to achieve serum concentrations of antibodies at levels providing protection against influenza. IgA antibodies, which were formed in nasal secretions, were specifically aimed at influenza and ought to hinder the spread of the disease. By optimizing the immunization regimes so that the immunological memory is better exploited, and by adding adjuvants to the formulations, it is probable that non-living mucosal vaccines can be realistic alternatives to several of the vaccines now given by injection.

Administration, Intranasal↗

Analysis of Japanese encephalitis (JE) virus genome and implications for recombinant JE vaccine.

From the information of nucleotide sequences and deduced amino acid sequences of flaviviruses including JEV, we can postulate processing mechanisms of a polyprotein translated from single long open reading frame of the genome and mechanisms of construction of antigenic structures of structural proteins with biologically active forms after these proteins are translated. The results of comparative analysis of amino acid sequences among flaviviruses and epitope analysis on the E proteins which are the most important antigens for protective immunity suggest that the E protein of flaviviruses may have a similar structure closely related to each other. PrM and E proteins which had predictable signal sequences upstream on the N terminals were expressed with antigenically active form and molecular size the same as the authentic ones by the recombinant viruses. However, the recombinant viruses which had no such signal sequence expressed unprocessed proteins with antigenically denatured forms. These results suggest that normal proteolytic processing is needed to construct biologically active structures of JEV structural proteins. The E proteins which were expressed by the recombinant viruses as antigenically active form could elicit nutralizing and HI antibodies in animals and protective immunity in mice. The recombinant vaccinia viruses which express the E protein could induce strong immunologic memory against the E protein in mice. These results indicate that the development of a new type of vaccine against JEV will become possible in future.

Amino Acid Sequence↗

Recent developments in idiotypic network theory.

A recent class of mathematical models of the immune network is reviewed. The models in this class are based upon the bell-shaped activation function that is known to be characteristic for receptor cross-linking. These network models have a large number of self-regulatory properties. This review discusses of number of these properties, i.e. immunological memory, suppression, and repertoire selection.

B-Lymphocytes↗

[The role of macrophages in mediating the immunostimulating effects of low-frequency ultrasound].

The action of low-frequency ultrasound on the body has been shown to lead to the stimulation of specific immune response, as well as immunological memory cells. The effects of low-frequency ultrasound are seemingly realized through the macrophage system of immunity, i. e. the action of ultrasound leads to the stimulation of the functional activity of macrophages, their metabolism, while blocking the macrophage system of immunity with carraginal abolishing the effects of ultrasound.

Animals↗

[Insulin antibodies: methodology and clinical implications].

Anti-insulin antibodies detection is based on the demonstration of a specific and saturable binding to insulin either radiolabelled with 125 I (Radiobinding assay or RBA) or coated on a solid phase (Enzyme linked immunosorbent assay or EIA). The 2 assays are remarkably different by their sensitivity to the affinity of the antigen antibody reaction. In addition, RBA may be biased by the presence of the iodine atom on the radioiodinated insulin whereas, at least on theoretical grounds. EIA could be biased because of denaturation or non availability of some epitopes when insulin is coated. Anti-insulin antibodies may be induced by insulin therapy. When they "spontaneously" appear, they are called autoantibodies. Insulin autoantibodies may be detected in the normal population, in type 1 diabetic patients before any administration of exogenous insulin and in patients suffering from the autoimmune hypoglycemic syndrome. In some patients, this syndrome may be associated with administration of a thiol containing drug. In some cases, insulin antibodies may appear several years after a transient insulin therapy, possibly as a consequence of a disturbance of the immunologic memory. The properties of antibodies and autoantibodies (concentration, affinity, number and nature of epitopes, heavy and light chain composition and ability to form aggregates) are relatively characteristic of the disease with which they are associated and determine their potential effects on insulin bioavailability and plasma glucose homeostasis.

Autoantibodies↗

[Heat-shock proteins. Their clinical importance].

Heat-shock proteins (HSP) represents a protein superfamily comprising distinct molecular weights which are synthesized under conditions of cellular stress. The HSP constitute a phylogenetically-conserved response of cell preservation. Their functions are related to mechanisms such as thermotolerance and transport and scavenging of intracellular peptides. Some recent experimental evidence suggests that HSP participate directly in immune responses perhaps facilitating the recognition of exogenous antigens, and its levels are raised in inflammatory situations. Their pathogenic role in the chronic inflammation is still unclear, but the HSP could intervene as immunodominant antigens, mimicking structural proteins or evading the so-called immunological memory. In this review, we update the information concerning the relevance of HSP in medicine and discuss its potential role in autoimmune mechanisms.

Heat-Shock Proteins↗

Alloantigen-specific T suppressor-inducer and T suppressor-effector cells can be activated despite blocking the IL-2 receptor.

To determine IL-2 requirement for activation of suppressor cells, PBMC were primed in one-way MLR in the presence of 10 micrograms/ml anti-IL-2R beta-chain antibody 2A3 (CD25) or control antibody, then irradiated and added as regulators in a fresh MLR. Cells primed in the presence of antibody 2A3 suppressed the proliferative response to fresh autologous lymphocytes to specific alloantigen but had no effect on the response to cells from third party donors. Priming in the presence of an antibody of irrelevant specificity induced only limited suppressor activity. Activated suppressor cells did not show cytolytic activity specific for the stimulators when tested at the time of the suppressor cell assay. To identify the subset(s) responsible for suppression, cells primed in the presence of antibody 2A3 were separated into CD4+/CD45RA+, CD4+/CD45RA-, and CD8+ subsets, which were irradiated and then tested. The suppressive activity was found predominantly in the CD4+/CD45RA+ subset, whereas CD8+ cells had some activity and CD4+/CD45RA- cells had none. No subset suppressed the response of autologous cells to third-party cells. When primed CD4+/CD45RA+ cells were cocultured with fresh autologous lymphocytes depleted of CD8+ cells, no suppression was observed, indicating that, although the CD4+/CD45RA+ cells can function as inducers of suppressors, they cannot function as suppressor-effectors. Conversely, CD8+ cells activated in MLR in the presence of 2A3 caused suppression, regardless of whether the fresh autologous responder population contained CD8+ cells. CD4+/CD45RA+ and CD8+ subsets isolated after priming in the presence of 2A3 also demonstrated Ag-specific suppression in the generation of cytotoxic T lymphocytes whereas CD4+/CD45RA- cells had no activity. Our data are consistent with the model that suppression of alloreactivity requires the cooperation of two types of cells, a CD4+/CD45RA+ suppressor-inducer and a CD8+ suppressor-effector population. Activated Tsi and fresh Tse or activated Tse alone can suppress lymphocyte proliferation and generation of CTL in response to specific Ag. Activation of Ag-specific T suppressor-inducer and T suppressor-effector cells appears to be relatively IL-2 independent and presumably require one or more other growth factors.

Antibodies, Monoclonal↗

[Laryngeal cancer and the history of laryngeal diseases and other diseases].

The diseases of larynx carcinoma suffered by 150 patients in the course of their all lives has been analysed. The results have been compared with a control group (150 patients with non-neoplastic diseases). Infectious diseases and others were taken into consideration. The statistical analysis proves that 80% of patients with larynx carcinoma have not suffered from infectious or other diseases. 90% of patients with non-neoplastic diseases have suffered from infectious or other diseases.

Adolescent↗

[Pathogenetic and clinical significance of the adhesion molecule expression on T cells of the lung in sarcoid alveolitis].

A double immunofluorescence analysis of CD4+ cell population from bronchoalveolar lavage (BAL) fluid samples of patients with active pulmonary sarcoidosis was carried out. The results showed that, unlike BAL and peripheral blood CD4+ cells of healthy subjects, almost all BAL CD4+ cells of the patients highly express, besides CDw29 antigen, LFA-1 and ICAM-1 adhesion molecules. The co-expression of these molecules on BAL CD4+ cells during high intensity sarcoid alveolitis could represent a marker of immunological memory. The relevant pathogenetic and clinical implications of this observation are discussed.

Adhesiveness↗

[The nematode Haemonchus contortus: antigenic characterization and immune response in rabbits and sheep].

In the first part of the study, various tissues of L3 larvae and adult Haemonchus contortus were examined by indirect fluorescence to investigate their antigenicity. L3 larvae were studied in immunoblots as well. The following tissues contained antigens: the sheath and cuticle of L3 larvae; and the cuticle, muscles, epithelium and glandular tissue of the oesophagus and sheath of the spicules of adult nematodes. On the cuticle of exsheathed L3 larvae, we detected by light-microscope slightly raised patches: places where the cuticle differs from the surrounding cuticular morphology. We suggest that the patches are comparable to those found on exsheathed L3 larvae of the horse. Whether the patches produce excretory or secretory antigens or both is unknown, however. Somatic soluble extracts of L3 and adult worms were found to be complex mixtures of proteins by polyacrylamide gel electrophoresis. Results in immunoblots of L3 larvae suggested that the region between the 42 kDa protein and the 18 kDa protein may contain antigens specific for H. contortus. We injected rabbits with the 42-25 kDa fraction of the L3 larvae. The rabbit sera were probed in immunoblots with the total somatic soluble L3 extract for the presence of antibodies. Antibodies reacted with antigens in the 42-25 kDa fraction, however, cross-reactions occurred with antigens in the L3 fractions that were not injected into the rabbits. We found that antibodies against phosphorylcholine were induced and suggest that these cause some of the cross-reactions. In the second part of the study sheep were infected orally with H. contortus and their lymphocyte responses towards L3 antigen and mitogen were measured in a lymphocyte stimulation test. Lymphocyte responses to L3 antigen are expressed in a stimulation index. Two groups of worm-free raised sheep were inoculated (sheep older than 1 year and lambs that were 4 to 6 months old) as well as a group of hyperimmunized sheep. Some sheep were inoculated only once; others were inoculated and then challenged. Lymphocytes of sheep that were hyperimmunized replicated rapidly in the test resulting in significantly higher stimulation indices than those recorded for the lymphocytes of all other sheep. After inoculation the enhanced response further increased. We explain these lymphocyte responses as a result from the immunological memory induced during the hyperimmunization. Lymphocytes of sheep over 1 year old only respond in the test when sheep are infected.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗

A thymus-independent (type 1) phosphorylcholine antigen isolated from Trichinella spiralis protects mice against pneumococcal infection.

A phosphorylcholine (PC)-containing glycoprotein of 68,000 molecular weight (MW) was isolated from Trichinella spiralis. The potential of this antigen (Tsp) as a species-specific vaccine against Streptococcus pneumoniae was studied in both immunologically deficient (CBA/N) and normal (CFW) mice. Unlike the PC determinant found in S. pneumoniae, Tsp is a type 1 thymus-independent (TI-1) antigen, as it was able to stimulate PC-specific antibody production in CBA/N animals, though less well than in CFW mice. Immunological memory to this antigen was observed in both strains of mice, and the predominant class of antibodies formed was IgM. In further studies, Tsp-immunized CFW mice were protected against a fatal challenge of S. pneumoniae type 3. Protection in these animals is probably mediated by the PC-specific antibodies present, which comprised 87.9% of antibodies reactive to S. pneumoniae, or 58.7% of total antibodies formed.

Animals↗

[Relation of the immunosuppressivity of virulent Shigella to the structure of O antigen].

The capacity of filtrates of virulent Shigella cultures (VSC) and their different fractions to render avirulent strains, injected intraperitoneally into mice simultaneously with these filtrates, capable of suppressing immune response (delayed hypersensitivity) has been studied. Among the fractions of VSC filtrates, the lipoid fraction soluble in the mixture of ethanol and ether has proved to be active. Active factors can be extracted from VSC filtrates by means of immunosorbents obtained from antibodies of pertinent specificity. VSC filtrates are completely inactivated by treatment with phenol and trichloroacetic acid. These data suggest that the immunosuppressive factors of shigellae, responsible for their capacity to suppress immunological memory, are incorporated into the O-antigen of these bacteria.

Animals↗