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Renal tubular immune complex formation in mice immunized with Tamm-Horsfall protein.

Mice were given injections of rat Tamm-Horsfall protein (TH) in order to study immune complex formation in the distal nephron. After immunization, all mice had high serum levels of antibodies to TH; immune deposits consisting of IgG antibodies to TH and TH formed at the base of cells of the thick ascending limb of the loop of Henle (ALH) and distal convoluted tubule. These basal complexes were maximal in number and size within the cortical ALH, where they often radiated toward the luminal surfaces. Although the highest anti-TH antibody titers were found in animals with the most extensive deposits, antibody levels were not directly proportional to IgG deposits or to the time after immunization. The larger immune deposits were visualized by light microscopy as PAS-positive deposits. The quantity of these deposits was proportional to the time after immunization and was directly related to anti-TH antibody levels. Electron microscopy showed that these immune deposits were present within the basal and lateral intercellular spaces of the cells of the ALH. The distribution and localization of TH within the normal mouse kidney was very similar to that in rats. However, the distribution of immune complexes within the distal nephron in mice differed from rats similarly treated with TH and indicates either species differences in the distribution and/or organization of TH associated with tubular cell surfaces or that the accessibility of distal tubules to antibodies is species-dependent.

Animals↗

Cross-reactive cellular and humoral immunity to carcinogen-induced chicken fibrosarcomas. II. Effect of prior immunization with transplantable tumors on primary tumor incidence.

Primary carcinogen-induced (7,12-dimethyl-benz[a]anthracene; DMBA) tumor-bearing SC chickens (B2/B2) frequently showed antibodies in their sera which reacted with cells from their autochthonous tumors, chicken embryo fibroblasts (CEF), tumor cells from some transplantable tumor lines, and from approximately 10% of other primary tumors. Similar results were obtained by ELISA on glutaraldehyde-fixed cells and by immunofluorescence on viable cells. The serum antibody reactivity could be removed by absorption with CEF but not with non-cross-reacting primary tumor cells or a variety of normal tissues. Although sera from normal chickens never showed significant reactivity, a high percentage of sera from chickens that had been injected with DMBA but failed to develop detectable tumors showed antibody activity to a transplantable DMBA-induced tumor and to CEF. On the basis of previously established cross-reactivity patterns in protective immunity to transplantable carcinogen-induced fibrosarcomas, attempts were made to protect against chemical carcinogenesis by prior immunization with selected DMBA-induced transplantable tumors. Tumor-immune chickens showed a significant decrease in the development of tumors during the first 3 mo after injection of DMBA (p = 0.001) or methylcholanthrene (p = 0.033) when compared to controls. This resistance to tumor induction in immune chickens was correlated to the degree of tumor immunity to the immunizing tumor present 1 mo after carcinogen injection (p = 0.046). There was, however, no detectable difference in the incidence of tumors arising later than 3 mo after carcinogen injection. The reduction in tumor incidence in immune as compared to control chickens at 5 mo was therefore less striking than the reduction seen at 3 mo. Immunization with CEF and adjuvants or with adjuvants alone afforded no protection to tumor induction.

9,10-Dimethyl-1,2-benzanthracene↗

Development of protective immunity against bacterial and viral infections in tumor-bearing mice coincident with suppression of tumor immunity.

This report addresses the question whether Meth A (methylcholanthrene-induced fibrosarcoma) tumor bearing Balb/c mice are able to develop specific antimicrobial immunity. Although specific suppressor T lymphocytes appeared during tumor growth which prevented expression of antitumor immunity, the development of protective immunity to L monocytogenes, S. pneumoniae or ectromelia virus infections was unimpaired. The Meth A tumor produced a soluble immunosuppressive factor which inhibited lymphocyte and macrophage functions in vitro. Tumor growth failed to inhibit the formation of immunoglobulin essential to antipneumococcal immunity, or the development of a specific acquired cellular resistance of primary importance in immunity to listeria and ectromelia virus infections. That tumor growth did not interfere with the development of cell mediated immunity was demonstrated by the effective transfer of antilisteria immunity by immune spleen from tumor-bearing mice.

Animals↗

The effect of trace elements on the immune response of rats with intact or injured immune system.

We studied the effect of a trace element combination (Béres Drop Plus; BDP) on the immune response of rats, with intact and with injured immune system. Rats were treated with different doses of BDP for 26 days. The immune system was injured by 7.0 Gy whole body gamma irradiation on the first day of BDP treatment. Rats were immunized on the 31st day of the BDP treatment with sheep red blood cells. In the spleen the cell count and the number of antibody producing cells were determined. In the serum the titre of hemolysin was tested. In rats with intact immune system all used doses of BDP induced elevation of the immune response. The moderate high doses were especially effective. In rats with injured immune system the effect was less. Only the 250 microliters/kg body weight dose could elevate the immune response, and the highest (500 microliters/kg) dose reduced the response.

Animals↗

Routes of immunization and antigen delivery systems for optimal mucosal immune responses in humans.

Numerous experiments performed in humans and animals have revealed that stimulation of mucosal lymphoid inductive sites such as intestinal Peyer's patches results in parallel immune responses manifested by the appearance of S-IgA antibodies in the external secretions of remote glands. However, recent experiments suggest that inductive sites associated with the upper respiratory tract, rectum, and perhaps genital tract may also function as sources of lymphoid cells that populate, with some selectivity, certain remote mucosal effector sites. Furthermore, antigen-specific IgA antibodies can be induced in certain secretions (e.g., female genital tract) not only by immunization in the vicinity of corresponding mucosal tissues (e.g., vagina and rectum) but also by oral and especially intranasal immunization. The ineffectiveness of simple delivery of soluble antigens to mucosal membranes for immunization has stimulated extensive studies of strategies for effective delivery systems that would (a) increase the antigen absorption, (b) prevent its degradation, and (c) skew the outcome of immunization to a desired goal (protective response to infectious diseases vs. tolerance; B vs. T cell responses; mucosal vs. systemic). The induction of immune responses at a desired mucosal site can be accentuated with the use of a suitable antigen-delivery system including relevant bacterial or viral vectors, edible transgenic plants expressing microbial antigens, incorporation of antigens in biodegradable microspheres or liposomes, and linkage or coadministration of antigens with cholera toxin B subunit. However, only a few antigen-delivery systems extensively used in animal experimentation have been evaluated for their efficacy in humans. The combination of various immunization routes and the use of suitable antigen-delivery systems may accomplish an important task-the induction of mucosal immune responses at a location relevant to the site of entry of a given pathogen.

Animals↗

High immunization rates versus missed immunization opportunities in a private pediatric office.

OBJECTIVE: This prospective study examines coverage levels for immunization of two-year-old children in a large private pediatric practice, and delineates the frequency of missed opportunities for vaccination. SETTING: A private single-specialty group pediatric practice in a suburban locale. DESIGN: With the aid of our office billing computer, 218 children between the ages of 21 and 24 months who had ever received medical care in our practice were identified. A manual chart review was performed to identify those children no longer receiving care from us. Of the 189 patients remaining, the immunization records in the patients' charts were compared to the State of Delaware immunization registry to identify those who had not received the full panel of recommended vaccines. Those charts were examined to identify reasons for underimmunization. No patient recall was performed. The charts of underimmunized children were reexamined five months later to determine how many had become fully immunized. RESULTS: On initial review, 86 percent of 21-24 month old children in our practice had received all recommended vaccines. Only 15 percent of the underimmunized children had had a missed opportunity for vaccination in the initial chart review. About half of the underimmunized patients received their missing vaccines over the next five months, yielding an eventual immunization rate of 94 percent. Only two of the 11 children still underimmunized by the end of the study (aged 26 to 29 months) had appeared for an 18 month or a 24 month well child visit; only four of the 11 had had a missed opportunity to receive immunizations during the five month study period. A subsequent chart review showed that 90 percent of our patients were up-to-date at 24 months of age. CONCLUSIONS: Achievement of a 90 percent immunization rate for two year old children is possible in a large private practice. Most underimmunized children in our practice had failed to appear for recommended well visits; a minority experienced missed opportunities for immunization.

Child, Preschool↗

Hepatitis C virus envelope DNA-based immunization elicits humoral and cellular immune responses.

The vaccine development for hepatitis C virus (HCV) is highly urgent to prevent non A and non B hepatitis. It was recently shown that the HCV envelope proteins appeared to the key viral antigens to induce protective immunity. To generate immune responses to the HCV envelope proteins on the DNA-based immunization, various envelope gene-containing plasmids were constructed. For efficient expression and secretion of envelope proteins, the signal sequence of each envelope protein was replaced with either herpes simplex virus type-1 (HSV-1) gD or signal sequence of gD and truncated C-terminal hydrophobic regions of envelope proteins. The intramuscular injection of these plasmids generated a significant level of antibody titers to the E1 and E2 proteins, which maximally reached 850 and 25,000 respectively. The secreted form of each envelope protein and the fusion of the highly immunogenic gD proteins were shown to have no significant effect on generating immune responses to the envelope proteins. In addition, immunized rats appeared to generate antibodies directed to the homologous HVR-1 peptide. Splenic lymphocytes from immunized rats were shown to induce significant T-cell proliferative responses with the stimulation of recombinant E1 and E2 proteins. Our results demonstrated that the HCV envelope-DNA based immunization could elicit both humoral and cellular immune responses.

Amino Acid Sequence↗

Studies on the transfer of protective immunity with lymphoid cells from mice immune to malaria sporozoites.

In an effort to understand the mechanisms involved in the protective immunity to malarial sporozoites, an A/J mouse/Plasmodium berghei model was studied. Protective immunity could consistently be adoptively transferred only by using sublethal irradiation of recipients (500 R); a spleen equivalent (100 X 10(6))of donor cells from immune syngeneic mice; and a small booster immunization (1 X 10(4)) of recipients with irradiation-attenuated sporozoites. Recipient animals treated in this manner were protected from lethal challenge with 1 X 10(4) nonattenuated sporozoites. Immune and nonimmune serum and spleen cells from nonimmune animals did not protect recipient mice. Fewer immune spleen cells (50 X 10(6)) protected some recipients. In vitro treatment of immune spleen cells with anti-theta sera and complement abolished their ability to transfer protection. This preliminary study suggests that protective sporozoite immunity can be transferred with cells, and that it is T cell dependent.

Animals↗

Mucosal immunity in the brushtail possum (Trichosurus vulpecula): detection of antibody in serum and at female reproductive sites after intranasal immunization.

Vaccination strategies for the brushtail possum, which rely upon stimulation of mucosal immunity, are being developed for biocontrol purposes. As little is known about how to stimulate possum immune responses via a mucosal site, groups of possums were immunized intranasally with keyhole limpet haemocyanin (KLH) alone or in combination with known or novel mucosal adjuvants. Antigen-specific antibody titres in female reproductive secretions were measured by ELISA and compared with antibody titres in the serum. Antigen-induced lymphocyte proliferative responses were measured as an indicator of cell-mediated responses. Intranasal immunization with KLH alone stimulated a weak serum antibody response that was significantly increased when KLH was given with cholera toxin subunit B (CTB), recombinant possum tumour necrosis factor alpha (TNF alpha) or live Mycobacterium bovis bacillus Calmette Guerin (BCG). Antibody titres in secretions from ovarian follicles and the uterus were very low in animals administered KLH alone. Significantly higher antibody titres to KLH were present in the reproductive secretions of possums immunized with KLH plus CTB, BCG or heat-killed Mycobacterium vaccae. Antibody titres were lower in mucosal secretions than in the serum, but there was a significant correlation between the two. In addition, coadministration of live BCG with KLH produced a strong antigen-specific cell-mediated response to KLH. This study has shown that an immune response to a protein antigen can be stimulated in possums by intranasal immunization and that antigen-specific antibodies can be detected in secretions from the female reproductive tract.

Adjuvants, Immunologic↗

Maternal immunization and the immune response of neonates to pneumococcal polysaccharides.

The effect of maternal immunization on the immune response of neonates to pneumococcal polysaccharides and the characterization of IgG receptor molecules have been reviewed and studied. Maternal immunization with pneumococcal 19F polysaccharide during gestation and/or lactation induces a significantly stronger response in offspring. When young mice born to pregnant mice immunized with a polysaccharide-protein conjugate (e.g., 19F polysaccharide-human IgG) are given an additional dose of polysaccharide-protein conjugate immunogen, they develop an antibody response stronger than that of young mice not receiving additional immunogen. Injection of female mice (before their mating) with type 19F or type 3 polysaccharide may also induce a stronger antibody response in offspring. Combined passive immunization with immunoglobulin and active immunization do not cause suppression or observable harmful immunologic effects; rather, such immunization may elicit sufficient 19F antibody formation for protection against infection during early life. IgG receptor molecules have been isolated from rabbit yolk-sac membranes, and their physicochemical properties have been characterized.

Animals↗

Induction of protective immunity against Schistosoma mansoni by a non-living vaccine. V. Effects of varying the immunization and infection schedule and site.

Intradermal (i.d.) injection with non-living schistosome antigens plus bacterial adjuvant protects mice against subsequent infection with Schistosoma mansoni. This protection became apparent within 2 weeks after a single inoculation and persisted for at least 8 weeks. Administration of one or more booster immunizations enhanced the level of protection but never produced complete resistance to cercarial challenge under the conditions tested. All immunized mice recognized the Sm 97 antigen in adult worms, as measured by antibody reactivity in ELISA, although the level of reactivity did not correlate with the level of resistance. Significant protection was observed when mice were immunized in the skin of the chest, the footpad or at the base of the tail if challenge infection was administered percutaneously either on the abdomen or back. However, when mice were infected by cercarial exposure of the tail skin, the level of resistance was consistently lower regardless of the immunization site. Vaccinated mice were not resistant to infection with lung stage parasites. These results demonstrate that the i.d. vaccine induces significant and persistent resistance in mice, the level of which is strengthened by booster immunization. The resistance is unrelated to inflammation at the site of immunization. However, immune response at the challenge site may play a critical role in the effector mechanism of resistance in this model.

Animals↗

Mechanisms of immunity in typhus infection: analysis of immunity to Rickettsia mooseri infection of guinea pigs.

To study the mechanisms of immunity to Rickettsia mooseri (R. typhi) infection, sera and splenic cells collected from nonimmune and immune guinea pigs were inoculated separately into syngeneic nonimmune recipients which were subsequently challenged intradermally. Protection was measured by comparing the course of the challenge infections of recipients with infections initiated with the same rickettsial inocula in nonimmune animals. Recipients of splenic cells collected 21 days after donor infection were protected from lesion development at sites of intradermal challenge and showed fewer rickettsiae in their kidneys. Cells obtained from nonimmune donors did not protect against either skin lesion development at sites of challenge or kidney infection. Antibody-containing sera collected 21 days after donor infection, but not normal sera, reduced levels of kidney infection, but immune sera did not protect against the development of lesions at sites of intradermal challenge. It was concluded that both immune sera and immune splenic cells possess capacities to effect a partial control of the systemic phase of R. mooseri infection in guinea pigs, but that immune splenic cells possess a capacity not shared by immune sera, i.e., the capacity to protect from infection at local sites of intradermal inoculation.

Animals↗

Antitoxic cholera immunity in mice: influence of antigen deposition on antitoxin-containing cells and protective immunity in different parts of the intestine.

The importance of the mode of antigen presentation (intravenous, oral, or enteral restricted to the lower ileum) in the development of a local immune response and immunological memory for such a response in different parts of the intestine was studied in mice. Cholera toxin was used as antigen and the immune response was assayed by determining both the number of specific antitoxin-containing cells in the lamina propria and protection against experimental cholera. The results showed that all of these routes of antigen presentation could induce significant memory along the entire small intestine. In contrast, the actual production of antitoxin-containing cells or protective immune response elicited by booster immunization was restricted to those parts of the intestine that were directly exposed to antigen; i.e., lower ileum boosting resulted in immunity in the distal ileum but not in the proximal jejunum, whereas oral or intravenous boosting gave a response in both jejunum and ileum. Protection correlated closely with the number of antitoxin-containing cells in the lamina propria (correlation coefficient, 0.88); >/=4,000 antitoxin-containing cells per mm(3) conferred solid immunity to cholera toxin-induced diarrhea. The total number of immunoglobulin-containing cells in intestines was not significantly influenced by the specific immunizations. There were four times as many of these cells in the upper jejunum (167,000 cells per mm(3)) as in the lower ileum, but the proportions of immunoglobulin A-containing cells (80 to 85%), immunoglobulin M-containing cells (14 to 20%), and immunoglobulin G-containing cells (0.4 to 0.9%) were similar in various parts of the intestine. The results indicate a differential dependence on local tissue antigen for the intestinal antibody-secreting cells and their memory cell precursors.

Animals↗

[The characteristics of the development of immunity with a primary immunization complex using adsorbed DTP vaccine].

The intensity of immunity, depending on immune response variants characterized by the definite composition of the T and B lymphocyte subpopulation in peripheral blood, was studied in 70 practically healthy young children after the primary complex of immunization with adsorbed DPT vaccine. The most stable immune reaction was shown to appear in children with the hyperergic and normoergic variants of immune response to diphtheria and tetanus toxoids, while the reaction to pertussis antigen was essentially weaker both after the second vaccination and after the first revaccination. In children with the hypoergic variant of immune response to all components of adsorbed DPT vaccine the resulting immune reaction was 2.5-3 times weaker than in children of other groups.

Adsorption↗

General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP).

This report is a revision of General Recommendations on Immunization and updates the 2002 statement by the Advisory Committee on Immunization Practices (ACIP) (CDC. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices and the American Academy of Family Physicians. MMWR 2002;51[No. RR-2]). This report is intended to serve as a general reference on vaccines and immunization. The principal changes include 1) expansion of the discussion of vaccination spacing and timing; 2) an increased emphasis on the importance of injection technique/age/body mass in determining appropriate needle length; 3) expansion of the discussion of storage and handling of vaccines, with a table defining the appropriate storage temperature range for inactivated and live vaccines; 4) expansion of the discussion of altered immunocompetence, including new recommendations about use of live-attenuated vaccines with therapeutic monoclonal antibodies; and 5) minor changes to the recommendations about vaccination during pregnancy and vaccination of internationally adopted children, in accordance with new ACIP vaccine-specific recommendations for use of inactivated influenza vaccine and hepatitis B vaccine. The most recent ACIP recommendations for each specific vaccine should be consulted for comprehensive discussion. This report, ACIP recommendations for each vaccine, and other information about vaccination can be accessed at CDC's National Center for Immunization and Respiratory Diseases (proposed) (formerly known as the National Immunization Program) website at http//:www.cdc.gov/nip.

Adolescent↗

Duration of immunity following immunization with live measles vaccine: 15 years of observation in Zhejiang Province, China.

The duration of immunity following measles vaccination of 2882 immunized children has been investigated in a closed region of China for 15 years. A total of 1002 of the children were treated as primary immunization subjects, and 1547 as reimmunization subjects. These two cohorts were not in contact with known wild measles virus over the whole observation period, and the results obtained probably reflected the antibody responses to measles vaccine alone. The remaining 333 vaccinees came into contact with wild measles virus, and this permitted evaluation of the protective effect of the measles vaccines tested: 4 children experienced very mild clinical measles, and 329 experienced subclinical infection, including 12 who had had undetectable haemagglutination-inhibition antibodies for 9-10 years. These results indicate that the immunity induced by successful primary immunization may persist for at least 15 years. Within this period, a second dose of vaccine only induces low antibody responses which decrease rapidly to their original levels. This provides strong evidence that the immunity produced by primary immunization is long-lasting. However, there were some indications that reimmunization might produce better effects if live attenuated measles virus were used with a longer interval between doses.

Adolescent↗

The effect of respiratory immunization on cell-mediated immune effector cells of the lung.

In order to understand the mechanisms of cellular immune injury in hypersensitivity pneumonitis, the effect of type of antigen on cell-mediated immunity in guinea-pigs receiving respiratory immunization was studied. Lymphocytes obtained by pulmonary lavage were compared with those from peritoneal exudate following immunization with either a soluble protein, human serum albumin, or a particulate suspension of Thermoactinomyces vulgaris. Assays were obtained without mixing cells from these two sources. Statistically significant increases (13-22%) in the number of alveolar rosette-forming cells (RFC) were found in the animals immunized with either antigen, but only the particulate T. vulgaris was also capable of inducing a systemic increase of such cells. That this increase in RFC could be due to specifically reactive lymphocytes was demonstrated by the production of antigen-stimulated macrophage migration inhibition. Some evidence was obtained that indicated that T. vulgaris could act both as a non-specific B-cell stimulant and a specific T-cell activator. The concept of a hypothetical pulmonary 'barrier' is discussed which must be overcome to induce systemic immune responses following respiratory immunization. T. vulgaris must be added to the list of known agents or means for overcoming this 'barrier'.

Aerosols↗

Immune-Like Malignant Epithelial Programs Shape Tumor-Immune Interactions and Inform Prognostic Stratification in Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is characterized by marked cellular heterogeneity, yet how malignant epithelial states contribute to immune regulation and clinical outcomes remains incompletely defined. We integrated single-cell RNA-sequencing data to map the cellular landscape of LUAD and identify malignant epithelial cells based on inferred copy-number alterations. Epithelial states were further examined through trajectory inference, transcription factor analysis, and cell-cell communication profiling. Single-cell-derived genes were subsequently integrated with TCGA and independent GEO cohorts to construct and validate a machine learning-based prognostic signature. Malignant epithelial cells displayed distinct functional programs, including an immune-like state associated with genomic instability, immune-related transcriptional activity, tumor-immune communication, and patient outcomes. The resulting immune-like malignant epithelial cell signature (IMEC-Sig) consistently stratified survival across multiple cohorts. Low IMEC-Sig scores were accompanied by greater immune infiltration, higher immune checkpoint expression, and increased immunophenoscore, whereas high scores were linked to a comparatively immunosuppressive phenotype. Pan-cancer analyses further identified KRT8 as a gene associated with unfavorable prognosis, and functional experiments showed that KRT8 silencing suppressed proliferation, migration, invasion, and colony formation in LUAD cells. Together, these findings connect malignant epithelial heterogeneity with the immune context and clinical outcomes, support IMEC-Sig as a biologically informed prognostic tool, and nominate KRT8 as a potential therapeutic target in LUAD.

Humans↗