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PubMed1997

Immunization of cystic fibrosis patients with a Pseudomonas aeruginosa O-polysaccharide-toxin A conjugate vaccine.

Healthy, non-colonized cystic fibrosis (CF) patients (N = 26) were immunized with an octavalent Pseudomonas aeruginosa O-polysaccharide-toxin A conjugate vaccine. Vaccination was well tolerated and induced anti-lipopolysaccharide (LPS) antibodies of a high affinity capable of promoting the opsonophagocytic killing of P. aeruginosa by human peripheral lymphocytes. In contrast, anti-LPS antibodies acquired after natural infection possessed a very low affinity and were non-opsonic. To determine if immunization could prevent or delay infections due to P. aeruginosa, the infection rate among immunized patients was compared retrospectively to age and gender-matched controls. After 6 years of clinical follow-up, 15/20 (75%) of control and 8/23 (35%) of immunized subjects were classified as infected (p = 0.022). The persistence of high-affinity antibodies among immunized patients correlated with a significantly lower rate of infection after 4-6 years of observation. Infection of immunized patients was correlated with a dramatic decline in total antibody titer between year 2 and 3 of follow-up. Smooth, typeable strains of P. aeruginosa predominated among immunized patients. In contrast, rough, nontypeable strains were most frequently isolated from nonimmunized patients. Mucoid P. aeruginosa strains were isolated from 6 nonimmunized patients versus only I immunized subject.

ADP Ribose Transferases↗
PubMed1993

Host response to Mycobacterial cell wall subunit during experimental tuberculosis in mice.

The cell-wall protein-peptidoglycan complex (CW-PPC) of Mycobacterium tuberculosis, an immunologically potent component, was used to study the correlation between immune response and in vivo bacterial multiplication in the course of experimental tuberculosis infection in mice. Antibodies to CW-PPC were detected only after seven weeks of infection with M. tuberculosis H37Rv and afterwards no significant change was seen throughout the experiment. Delayed type hypersensitivity (DTH) to CW-PPC showed a gradual increase from the fifth week onward with a maximum during the 12th week after infection (p.in.) which did not change significantly afterward. The increased immune response in the course of infection correlated well with the multiplication rate of bacilli in the lungs. These results indicate a role of CW-PPC in antituberculous immunity.

Animals↗
PubMed1998

Skeletal muscle immune deposits in systemic lupus erythematosus. Correlation with histologic changes, autoantibodies, and clinical involvement.

Skeletal muscle biopsy and autopsy samples of 132 SLE patients were studied by immunofluorescence and light microscopic techniques. Immune deposits were compared to histologic abnormalities and clinical and serologic findings. Immune deposits with a mainly granular pattern were observed at different locations in 49 patients (37%). They correlated significantly (p<0.001) with inflammatory myopathy, demonstrated in 33(25%), with noninflammatory myopathy which occurred in 38 (29%) vasculitis, observed in 13(10%), and with noninflammatory vasculopathy which was noted in 10 patients (8%). The correlation of muscle immune deposits with anti-DNA antibodies was significant at p= 0.016. Anti-Sm and anti-U1 RNP antibodies were associated significantly with the intensity of immune deposits. Furthermore, a correlation of immune deposits with increased creatine phosphokinase and myopathic electromyogram, but not with evidence of clinical involvement, was shown. A key pathogenetic role of immune deposits in the development of skeletal muscle histologic abnormalities in SLE was demonstrated.

Adolescent↗
PubMed1996

Glycoconjugate vaccines: future combinations.

There is a large and growing base of knowledge about the protective immune response to encapsulated bacterial pathogens. This information is a clear advantage to the development of glycoconjugate vaccines. It is well understood for such pathogens as Haemophilus b, pneumococcus, meningococcus and group b streptococcus that the induction of a functional anti-saccharide antibody response is likely to be protective. The most important question for glycoconjugate vaccines is the magnitude of the response required for protection. Even after extensive field trials with Haemophilus b vaccines, there is not a precise antibody correlate of immunity. In fact, cited values still rely on older studies with polysaccharide vaccine [11]. For that reason, vaccine such as the multivalent pneumococcal formulations will require field trials to measure their efficacy and hopefully determine the appropriate correlates of immunity. However, the addition of new serotypes into a multivalent pneumococcal formulation after efficacy trials are completed will probably have to be based on antibody correlates since it will not be possible to do efficacy studies on individual serotypes especially since they will have low prevalence. A similar dilemma may be faced with a vaccine for the group C meningococcus where the low disease incidence will make efficacy studies difficult. As was the case with mixing DTP and Hib vaccines, in the future combinations of effective antigens will continue to rely on comparative immunogenicity studies to ensure efficacy. It is clear that the immune system is capable of responding to a diversity of antigens simultaneously. However, it is also clear that vaccine components can interfere with each other and this interference is not necessarily predictable [12]. The ability to measure the stability of each of the components of a combined product reliably will become even more critical as the complexity of the mixtures increases.

Animals↗
PubMed1986

Chronic idiopathic and secondary neutropenia: clinical and serological investigations.

Clinical data on 49 patients with chronic idiopathic neutropenia (CIN) and 42 patients with neutropenia secondary to a well-defined immunological disorder (SN) were collected and related to serological parameters. In 47% of the patients with CIN and 53% of those with SN, a positive direct immunofluorescence test was obtained with granulocytes from the patients. In the sera from the patients in the two groups, antibodies against donor granulocytes were detected by the indirect immunofluorescence test, the leucoagglutination test and/or the granulocytotoxicity test in 15%, 19% and 15%, respectively. The results of the above tests could not be correlated with any clinical or haematological parameter. Immune complexes in the serum were detected by the 125I-Clq-binding test in 29% of patients with CIN and in 58% of those with SN. The presence of serum immune complexes correlated well with the existence of a low neutrophil count, but not with the presence of recurrent infections, with bone-marrow abnormalities, or with positive reactions in other serological tests. The sera of eight out of 14 patients with CIN and seven out of 12 patients with SN had inhibitory activity for myeloid colony formation in vitro (CFU-GM). This CFU-GM inhibitory activity was correlated with the presence of recurrent infections and with hypoplasia of the myeloid compartment of the bone marrow, but not with positive reactions in other tests. We conclude that the 125I-Clq-binding test probably detects circulating immune complexes that induce a shift neutropenia, whereas serum activity inhibitory for CFU-GM possibly relates to clinically more serious forms of neutropenia. The significance of neutrophil-bound Ig and granulocyte-reactive antibodies in the serum is not clear.

Adolescent↗
PubMed2003

How well can a T-cell epitope replace its parent carrier protein? A dose-response study.

PURPOSE: This work examines the effectiveness of synthetic peptide immunogens derived from immunodominant T-cell epitopes as replacements for their intact parent protein in vaccines. METHODS: Fluorescein was conjugated to hen egg lysozyme (FL-HEL, positive control) and three synthetic peptide immunogens: (a) murine B10.A (H-2a) immunodominant T-cell epitope of HEL [FL-(T-cell epitope)]; (b) multiple antigenic peptide (MAP) multimer of this epitope ([FL-(T epitope)]n-MAP, n = 2-4); and (c) negative control MAP with T-cell epitope residues replaced with glycine [(FL-Gly18)4-MAP]. The dose response of each immunogen was examined over a 300-fold range in B10.A mice. The immune response was monitored using antifluorescein ELISA assays. RESULTS: FL-(T epitope)'s immune response correlated positively with dose, with maximum response comparable to that of [FL-(T epitope)]n-MAP, or FL-HEL. This trend was consistent across 1 degrees, 2 degrees, and 3 degrees responses, although interanimal variability was higher in the latter two because of an all-or-none response in mice immunized with this peptide. [FL-(T epitope)]n-MAP's immune response was consistently high and nearly dose independent, a trend observed across 1 degrees, 2 degrees, and 3 degrees responses. FL-HEL's immune response correlated negatively to dose in the 1 degrees response but was nearly dose independent in the 2 degrees and 3 degrees responses. The magnitude of these latter responses was comparable to that observed for [FL-(T epitope)]n-MAP. (FL-Gly18)4-MAP did not elicit an immune response except at the highest dose. This trend was consistent across 1 degrees, 2 degrees, and 3 degrees responses. CONCLUSIONS: The monomeric epitope was 300-fold less potent than its parent carrier protein, but increasing immunogen valency using MAP technology compensated totally for reduced potency. (FL-Gly18)4-MAP's lack of response at all but the highest dose strongly suggests that a specific immunodominant T-cell epitope sequence for HEL is necessary for successful peptide mimicry of HEL. This work also demonstrates the importance of quality assessment of commercial MAP core resins.

Animals↗
PubMed2006

Responses to selection on phenoloxidase activity in yellow dung flies.

Maintaining an immune system is costly. Resource allocation to immunity should therefore trade off against other fitness components. Numerous studies have found phenotypic trade-offs after immune challenge, but few have investigated genetic correlations between immune components and other traits. Furthermore, empirical evidence for the costs of maintaining an innate immune system in the absence of challenges is rare. We examined responses to artificial selection on phenoloxidase (PO) activity, an important part of the insect innate defense against multicellular pathogens, in yellow dung flies, Scathophaga stercoraria (L.). After 15 generations of successful selection on PO activity, we measured reproductive characters: clutch size, egg hatching rates, adult emergence rates, and adult longevity. We found no evidence for negative genetic correlations between PO activity and reproduction. In fact, flies of lines selected for increased PO activity had larger first clutches, and flies of lines selected for decreased PO activity had smaller ones. However, flies from high-PO lines died earlier than did low-PO flies when no food was available; that is, there is a survival cost of running at high PO levels in the absence of challenge. Variation in resource acquisition or use may lead to positive genetic correlations between PO and fertility and fecundity. The negative correlation between PO and longevity under starvation may indicate that variation for resource acquisition is maintained by a cost of acquisition, based on a genotype-environment interaction.

Animals↗
PubMed1986

Mechanisms of genetic control of immune responses. II. Nonresponsiveness in BALB/c GT-specific cell-mediated immune responses does not correlate with the absence of functional T cells or the induction of suppressor T cells.

The mechanisms underlying Ir gene control of CMI were addressed by examining the DTH and Tprlf responses specific for the synthetic polymers GT, GAT, and GA. We show that BALB/c mice (GAT/GA responders, GT nonresponders) primed with GT fail to develop DTH and Tprlf responses specific for GT, GAT, or GA. GAT immunization resulted in DTH responses that could be elicited not only with GAT and GA but also with GT, demonstrating that GT-specific TDH are present in nonresponder mice. GT-specific DTH was transferred with Thy-1+ Lyt-1+2-, H-2 I-restricted, nylon wool nonadherent cells. GA-primed BALB/c mice developed GAT- and GA-, but not GT-specific DTH responses, indicating that GA and GT do not cross-react at the T-cell level. The ability of GAT [but not a mixture of GA plus GT, or GT electrostatically complexed to the immunogenic carrier MBSA (GT-MBSA)] to induce GT-specific DTH suggested a requirement for covalent linkage of stimulatory 'GA' and nonstimulatory 'GT' determinants present on the GAT molecule. Similarly, GT-specific in vitro Tprlf responses could be demonstrated in GAT-primed mice exhibiting significant levels of GT-specific DTH but not in GT- or GT-MBSA-primed mice. Tolerization experiments also suggested that GT-specific Th were involved in the development of GT-specific DTH in GAT-primed mice. The GT nonresponsiveness of BALB/c mice for DTH and Tprlf responses could not be reversed by treatments designed to abrogate Ts activity (priming with GT-MBSA and CY injection), nor could GT-primed cells be shown to inhibit the development or elicitation of GT-specific CMI in GAT-primed mice during the afferent and/or efferent stages of DTH. Our results suggest that GT nonresponsiveness does not result from the absence of GT-specific T cells or preferential induction of Ts. The results are discussed in the context of hole-in-the-repertoire and antigen presentation (determinant selection) models of Ir gene control.

Alanine↗
PubMedDate not supplied

Circulating immune complexes in patients with rheumatoid arthritis: correlation with disease activity.

Circulating immune complexes (CIC) have been detected in the majority of patients with rheumatoid arthritis (RA). Their usefulness in monitoring disease activity is still controversial. Thirty-five patients with RA have been studied for the presence of CIC by the C1q binding assay. Abnormally high levels of CIC were detected in 83% of the patients and in 76% of 46 serum samples. Mean C1q binding activity for all serum samples was 27.4 +/- 25 compared to 7.5 /+- 2% in a control group of healthy individuals. A highly significant correlation was observed between C1q binding activity and the following indices of disease activity: the erythrocyte sedimentation rate, the latex and Rose-Waaler tests and a systemic index. The level of CIC in RA patients seems to be a reliable index of disease activity.

Antigen-Antibody Complex↗
PubMed1986

[Evaluation of malnutrition and immunity in alcoholic liver diseases].

Disorders of immunity and nutritional status are known to be present in alcohol-induced diseases of the liver, but their significance is still debated. Nutrition and immunity were evaluated at different stages of the disease in 58 alcoholic patients with steatosis (n = 20), alcoholic hepatitis (n = 14) or cirrhosis (n = 24). Most of the anthropometric data and biochemical values relating to nutrition were altered to the same degree in these 3 groups. Only patients with cirrhosis had significantly lower blood albumin and zinc levels (P less than 0.01). Humoral immunity was altered in cirrhosis only and cellular immunity in all 3 liver diseases. There was no correlation between immunity and nutrition (except for blood zinc and E rosettes; P less than 0.01) or between these and alcohol consumption. Like several nutritional parameters, blood lymphocyte values correlated negatively with a liver disease severity index. It is concluded that disorders of nutrition and immunity are broadly comparable in alcohol-induced liver diseases; there is no direct statistical correlation between these disorders which seem to be independent of the type of liver disease.

Adult↗
PubMed2001

Th1-polarizing immunization with egg antigens correlates with severe exacerbation of immunopathology and death in schistosome infection.

In schistosomiasis mansoni, parasite eggs precipitate an intrahepatic granulomatous and fibrosing inflammatory process, which is mediated by, and dependent on, MHC class II-restricted CD4 T helper (Th) lymphocytes specific for schistosome egg antigens (SEA). In the mouse model of the disease, CBA mice develop large granulomas, whereas in C57BL/6 (BL/6) mice these granulomas are significantly smaller. To further investigate how the prevailing cytokine environment influences the development of the egg-induced immunopathology, we immunized the low-pathology BL/6 mice with SEA in complete Freund's adjuvant (CFA) once before, and once again during, the course of a 7-week infection. This immunization caused a pronounced Th1 shift in the SEA-specific CD4 T cell response, which was detected in the mesenteric lymph nodes (MLNs) and spleens, as well as in the granulomatous lesions themselves. The immunized mice displayed a dramatic enhancement of hepatic egg-induced immunopathology manifested by a marked increase in granuloma size and parenchymal inflammation, leading to early death. Control mice immunized with equivalent amounts of SEA or CFA alone displayed the smaller hepatic lesions in a Th2-dominant environment typically seen in the unimmunized BL/6 mice. Analysis of granuloma and MLN lymphocytes from the SEA/CFA-immunized mice revealed that the proportion of CD4 T cells was unchanged in comparison with the control BL/6 groups and remained significantly lower than that seen in the normally high-pathology CBA strain. These results suggest that the shift toward Th1-type cytokine production by a numerically stable population of CD4 T cells correlates with severe exacerbation of immunopathology in schistosomiasis.

Animals↗
PubMedDate not supplied

Increased cyclooxygenase-2 expression is correlated with suppressed antitumor immunity in cervical adenocarcinomas.

Cyclooxygenase-2 (COX-2) inhibition suppressed the growth of various tumors. The augmentation of antitumor immunity by increasing cytotoxic lymphocytes may be an important mechanism for COX-2 inhibition. Among cervical cancers, adenocarcinomas present more aggressive behavior and overexpressed COX-2. The expression of COX-2 and the CD8+ lymphocyte infiltrations were evaluated in this study by immunohistochemistry. We studied COX-2 expression and CD8+ lymphocyte infiltration in 55 women with cervical adenocarcinomas. COX-2 expression and tumor stromal CD8+ lymphocytes were evaluated by semiquantified methods. Tumor intraepithelial lymphocytes were counted under microscopic field of x200. Correlations between these data and other clinicopathologic features were investigated. Thirty-seven out of 55 (67.3%) cervical adenocarcinomas significantly expressed COX-2. Patients who died within 5 years showed higher percentage of COX-2 expression than survivors (100% vs 58.1%, P < 0.05). Victims also showed lesser intraepithelial CD8+ lymphocyte counts than survived patients (3.4 vs 26.4, P < 0.05). COX-2 expression and tumor intraepithelial lymphocyte count were reversely correlated with each other (correlation index: -0.38, P < 0.01). Up-regulated COX-2 expression and lesser tumor intraepithelial CD8+ lymphocyte count are poor prognostic indicators for cervical adenocarcinoma patients. COX-2 may play an important role in the suppression of host antitumor immunity in cervical adenocarcinomas.

Adenocarcinoma↗
PubMed1998

Ratio of IgG:IgM antibodies to sialyl Lewis(x) and GM3 correlates with tumor growth after immunization with melanoma-cell vaccine with different adjuvants in mice.

Human melanoma cells (from biopsies and culture) express sialyl-Lewis(x) and sialyl Lewis(a), the ligands for ECAM. These ligands may facilitate tumor progression and metastasis in human cancers. To test whether the antibodies to these ligands inhibit tumor progression, IgG and IgM responses to sLe(x) and sLe(a) were induced in C57BL/6j mice (n = 76) by immunization with human melanoma cells, with or without adjuvants (BCG, MPL, KLH). Control mice were treated with saline or BCG. Tumor growth and antigen expression were monitored after challenge with B16 mouse melanoma cells expressing sLe(x), sLe(a) and the ganglioside GM3. Tumor growth was reduced in mice immunized with BCG alone or cells with BCG or MPL, while tumors in mice receiving cells without adjuvants grew larger than in the control. Augmentation of IgM titers to sLe(x) and GM3 after immunization with BCG, or with cells with BCG or MPL correlated with retarded tumor growth, while increased IgG titers to sLe(x) significantly correlated with aggressive tumor growth in mice immunized with cells without adjuvants. SLe(x), sLe(a) and GM3 were expressed in tumors from mice treated with saline or BCG. SLe(x) expression, in particular, was lost in tumors growing in mice immunized with cells with or without adjuvants. Anti-sLe(x) antibodies may promote or prevent tumor growth by antigenic modulation or by cytotoxic killing of tumor cells. Since early anti-sLe(x) IgM correlated with tumor regression, in contrast to anti-sLe(x) IgG, it may serve as a potential early endpoint for the effectiveness of melanoma vaccines expressing the antigens.

Animals↗
PubMed1988

Active and passive immunization of mice against larval Dirofilaria immitis.

The objective of this study was to determine if Dirofilaria immitis larvae would survive in diffusion chambers implanted in dogs and mice and secondly to determine if mice could be immunized against infection with D. immitis. Dirofilaria immitis third-stage larvae (L3) survived and grew in diffusion chambers implanted in dogs and mice for at least 3 wk. BALB/c mice, which were repeatedly infected with live L3, showed resistance to challenge infections. Dead L3, with or without adjuvants elicited no protective immunity. A correlation was found between the degree of immune protection seen in mice and antibody levels to soluble larval antigen but not to antibody levels to surface antigens. A monoclonal antibody was prepared that reacted with the surface of D. immitis and Onchocerca lienalis L3, but not to the surfaces of other stages and species of various filarial worms. When this antibody was administered to mice prior to challenge no significant reduction in larval survival was observed.

Animals↗
PubMed2003

Expression of matrix metalloproteinase 9 (MMP-9/gelatinase B) in adenocarcinomas strongly correlated with expression of immune response genes.

Matrix metalloproteinases (MMPs) are endopeptidases considered to be important regulators of the microenvironment of cancer. While MMPs are traditionally associated with the extracellular matrix (ECM), here we provide new evidence from an analysis of gene expression profiles from human tumor tissue that MMP-9 (gelatinase B) is associated with elements of the immune system in a way analogous to the association of other MMPs, such as MMP-2 (gelatinase A), with components of the ECM. An analysis of three independent microarray datasets of lung adenocarcinomas from previous studies [Nat. Med. 8, 816-824 (2002); Proc. Natl. Acad. Sci. USA 98, 13790-13795 (2001); Proc. Natl. Acad. Sci. USA, 98, 13784-13789 (2001)] showed that, in each dataset, out of the set of genes with significant correlations in mRNA expression to the expression of MMP9 (P < 0.005), a highly disproportionate number were found to be annotated in the Locuslink database as having a role in the anti-pathogen response. By comparison, out of the set of genes significantly correlated with the expression of MMP2, a highly disproportionate number were known components of the ECM. The same patterns observed in the lung data for both MMP2 and MMP9 were found as well in an additional published dataset of colon and ovarian adenocarcinomas [Am. J. Pathol. 159, 1231-1238 (2001)]. The results of this study suggest a greater functional role for MMP-9 in the immune response to cancer than what may previously have been thought.

Adenocarcinoma↗
PubMed1979

Immunologic response in onchocerciasis: relations to microfilaria density in the skin biopsy and to some frequent symptoms.

During physical and immunologic investigations on onchocerciasis in 1,298 persons in the Republic of Liberia, the following results were obtained. There is a significant correlation between immune response and Onchocerca volvulus infection detected by a microfilaria-positive skin biopsy. On the other hand, the immune response is not influenced by the number of parasites in the skin, and there is no correlation of the immune response with Onchocerca nodules and with pruritus. There is a high proportion of serologically false-positive and false-negative results, and thus a diagnosis cannot be made simply by establishing evidence for antibodies in one person.

Adolescent↗