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PubMedDate not supplied

Identification of frequently recognized dimorphic T-cell epitopes in plasmodium falciparum merozoite surface protein-1 in West and East Africans: lack of correlation of immune recognition and allelic prevalence.

The merozoite surface protein-1 (MSP1) is the most studied malaria blood-stage vaccine candidate. Lymphokines such as interferon gamma (IFN-gamma) and interleukin 4 (IL-4) may mediate blood-stage specific protection. Here we identify Plasmodiumfalciparum MSP1 T-cell epitopes capable of rapid induction of IFN-gamma and/or IL-4 from peripheral blood mononuclear cells of East and West African donors. Both allelic forms of these novel MSP1 T-cell epitopes were stimulatory. An unusually high numbers of Gambian responders (> 80%) to these epitopes were observed, suggesting that MSPI reactivity may have been underestimated previously in this population. Surprisingly, IFN-gamma responses to allelic T-cell epitopes failed to correlate with differential antigenic exposure in The Gambia compared to Kenya. These results suggest an unexpected level of immunoregulation of IFN-gamma response with variable allelic T-cell reactivity independent of the level of antigenic exposure. Further analysis of the mechanisms determining this response pattern may be required if vaccines are to overcome this allelic reactivity bias in malaria-exposed populations.

Adolescent↗
PubMed2001

The Gordon Wilson Lecture: viruses and human disease.

In many ways, Ebola virus infection provides a model for understanding the toxicity of viruses and their causal role in human disease. The highly aggressive course of Ebola virus infection provides a model for understanding the molecular mechanisms of viral cytotoxicity. In addition, the use of animal models and definition of immune correlates, which lead to protection, may provide lessons that are applicable to other viral infections. Perhaps the greatest challenge facing biomedical science today is the containment of the human immunodeficiency virus, the causative agent of AIDS. In many ways the critical obstacles to the development of a vaccine for HIV are similar to those observed with Ebola virus infection. Because the reservoir of infection is not known and human-to-human spread has been documented, vaccines may provide the best opportunity to contain and limit the spread of infection worldwide. Similar to Ebola virus, there are few convincing examples of immune resistance of HIV infection. In addition, it has been difficult to identify broadly neutralizing antibodies that can prevent infection in vitro or in vivo. In defining immune correlates, relevant animal models, and mechanisms of cytotoxicity, it is hoped that similar efforts may lead to effective vaccines for other infectious diseases. In this way, Ebola virus infection provides a useful paradigm for understanding the genetic determinants of viral disease and in facilitating the development of treatments and prevention of viral infections.

Animals↗
PubMed2005

Clinical and immune responses correlate in glatiramer acetate therapy of multiple sclerosis.

Glatiramer acetate (GA) treatment for relapsing remitting multiple sclerosis (RRMS) leads to decreased GA-specific proliferative responses and a Th2 cytokine shift. To study a possible correlation between immunological and clinical responses to GA therapy, we prospectively followed RRMS patients clinically, by magnetic resonance imaging and by primary immunological assays. Fluctuation of GA-specific proliferative responses was significantly lower in treatment responders than in untreated patients, and GA-specific proliferative responses were increased during relapses. These associations suggest a possible causal relationship between immunological and clinical responses to GA therapy. Primary proliferation assays may thus be a useful marker for treatment response.

Adult↗
PubMed2001

Two Listeria monocytogenes vaccine vectors that express different molecular forms of human papilloma virus-16 (HPV-16) E7 induce qualitatively different T cell immunity that correlates with their ability to induce regression of established tumors immortalized by HPV-16.

Two recombinant Listeria monocytogenes (rLm) strains were produced that secrete the human papilloma virus-16 (HPV-16) E7 protein expressed in HPV-16-associated cervical cancer cells. One, Lm-E7, expresses and secretes E7 protein, whereas a second, Lm-LLO-E7, secretes E7 as a fusion protein joined to a nonhemolytic listeriolysin O (LLO). Lm-LLO-E7, but not Lm-E7, induces the regression of the E7-expressing tumor, TC-1, established in syngeneic C57BL/6 mice. Both recombinant E7-expressing rLm vaccines induce measurable anti-E7 CTL responses that stain positively for H-2D(b) E7 tetramers. Depletion of the CD8+ T cell subset before treatment abrogates the ability of Lm-LLO-E7 to impact on tumor growth. In addition, the rLm strains induce markedly different CD4+ T cell subsets. Depletion of the CD4+ T cell subset considerably reduces the ability of Lm-LLO-E7 to eliminate established TC-1 tumors. Surprisingly, the reverse is the case for Lm-E7, which becomes an effective anti-tumor immunotherapeutic in mice lacking this T cell subset. Ab-mediated depletion of TGF-beta and CD25+ cells improves the effectiveness of Lm-E7 treatment, suggesting that TGF-beta and CD25+ cells are in part responsible for this suppressive response. CD4+ T cells from mice immunized with Lm-E7 are capable of suppressing the ability of Lm-LLO-E7 to induce the regression of TC-1 when transferred to tumor-bearing mice. These studies demonstrate the complexity of L. monocytogenes-mediated tumor immunotherapy targeting the human tumor Ag, HPV-16 E7.

Animals↗
PubMed1993

Differential binding of a minor histocompatibility antigen peptide to H-2 class I molecules correlates with immune responsiveness.

Minor histocompatibility (H) Ag are recognized in the context of MHC class I (K/D) molecules and can constitute a strong barrier to tissue transplantation. The products encoded by the MHC (H-2 in mice) have been shown recently to be Ag-presenting molecules that bind foreign and self peptides in their peptide binding sites. Different class I molecules preferentially bind different arrays of endogenous peptides for presentation to CTL. Previous studies showed that the Kb-restricted CTL response to one minor histocompatibility Ag, H-4, varied in different Kb mutants. One possible basis for this variation might be that the response is regulated by the level of binding of an H-4 peptide by class I molecules. To analyze this possibility, we initiated studies to identify the H-4 peptide that is included in the array of self peptides. The complete mixture of peptides eluted from Kb molecules of H-4+ tumor cells was able to sensitize H-4- targets for lysis by H-4-specific CTL. The presence of a specific H-4 peptide was confirmed when the radiolabeled peptide mix eluted from Kb molecules was separated by HPLC. Only one peak in the profile of H-4+ tumor peptides was capable of sensitizing H-4- targets for lysis by H-4-specific CTL; this active peak was absent in H-4 mutant cells. Peptide mixtures eluted from a panel of Kb mutant molecules extracted from H-4+ lymphocytes varied in their capacities to sensitize targets for H-4-specific lysis and the relative sensitization correlated with the demonstrated capacity of mutant mice to generate H-4-specific CTL. Therefore, the highly specific genetic control of the T cell response to the H-4 minor histocompatibility Ag appears to be due to the differential binding of an H-4 peptide by class I molecules.

Animals↗
PubMed1998

A search for serologic correlates of immunity to Bordetella pertussis cough illnesses.

In a pertussis vaccine efficacy trial in Germany we collected sera from vaccinees (DTaP or DTP) after the third and fourth doses of vaccine or at comparable time periods in DT vaccine recipients. In addition, sera were collected from a randomized sample of subjects in each vaccine group at approximately 3-month intervals from which antibody kinetic curves were constructed, which allowed us to estimate specific antibody values to pertussis toxin (PT), filamentous hemagglutinin (FHA), pertactin and fimbriae-2 at the time of exposure in the household setting. The imputed geometric mean antibody values to PT, pertactin and fimbriae-2 at the time of household exposure to Bordetella pertussis infection were higher (p < 0.07 or lower) in non-cases compared with cases. A multivariate (classification tree) analysis found that only pertactin and PT were significant in protection. Subjects with an imputed pertactin value of < 7 EU ml-1 had a 67% (18/27) chance of infection regardless of the PT value. If the pertactin value was > or = 7 EU ml-1 and the PT value > or = 66 EU ml-1 all subjects were non-cases. If the pertactin value was > or = 7 and the PT value was < 66 EU ml-1 the predicted probability of being a case was 31% (15/49). Logistic regression analysis also found that high versus low pertactin values were associated with illness prevention following household exposure. In the presence of antibody to pertactin, PT and fimbriae-2, the additional presence of antibody to FHA did not contribute to protection. Our data support historical data indicating that agglutinating antibodies are associated with protection and also recent serologic correlates data and clinical efficacy data which indicate that multicomponent vaccines containing pertactin and fimbriae have better efficacy than PT or PT/FHA vaccines.

Adhesins, Bacterial↗
PubMed1985

Liver macrophages in murine listeriosis. Cell-mediated immunity is correlated with an influx of macrophages capable of generating reactive oxygen intermediates.

Sublethal infection of mice with Listeria monocytogenes was accompanied by an influx of immigrant macrophages into the liver and the generation of substantial H2O2 by isolated liver macrophages. H2O2 production paralleled the course of infection and, after resolution of granulomata, returned to the low levels seen in normal livers. To assess the activation status of Kupffer cells and immigrant macrophages in listeriosis, a separation protocol was developed based on the differential adherence properties of the two macrophage populations. As in the steady state, Kupffer cells in listeriosis failed to generate significant levels of H2O2 and did support the replication of internalized toxoplasmas. Immigrant macrophages produced substantial levels of H2O2 and could quantitatively account for H2O2 production by total liver macrophages. Our findings suggest distinct functions for Kupffer cells and immigrant macrophages.

Animals↗
PubMed2006

Murine pre-eclampsia induced by unspecific activation of the immune system correlates with alterations in the eNOS and AT1 receptor expression in the kidneys and placenta.

It remains arguable if an animal model can be of use in pre-eclampsia (PE) studies, as it is clearly a human disease not observed spontaneously in other species. The aim of this study was to investigate whether PE-like signs in mice inoculated with activated Th1 cells were accompanied by abnormal expression of molecules related to the regulation of blood pressure, viz. nitric oxide synthase enzymes (eNOS and iNOS) and angiotensin (Ang) II receptors (AT1R and AT2R), in order to analyse the relevance of this model for human disease. In this model, C57/BL6-mated BALB/c females received lymphocytes crosslined with anti-CD3 and cultured with interleukin (IL)-2 and IL-12 to mimic PE pathology. Control mice received PBS. eNOS, iNOS and AT1R but not AT2R expression was augmented in the kidneys of PE-mice compared with control pregnant mice. The expression of eNOS but not of iNOS was augmented at the fetal-maternal interface of PE-mice as compared with the controls. NOSs regulate the synthesis of NO, a blood pressure and parturition mediator. As its expression is increased in PE patients, our data suggest that the Th1 cells-induced signs in this model are due to similar mechanisms as in humans. AT1R and AT2R mediate the effect of Ang II, and particularly the AT1R appears to be involved in the pathogenesis of human PE. The increased AT1R expression in the kidneys of PE-mice reinforces the theory that Th1 cells elicit a pathological situation closely resembling the human PE. All together, our data support the use of this animal model to study mechanisms underlying clinically overt PE.

Adoptive Transfer↗
PubMed2001

Anatomic site and immune function correlate with relative cytokine mRNA expression levels in lymphoid tissues of normal rhesus macaques.

Reverse transcriptase real-time polymerase chain reaction was used to determine pro-inflammatory, anti-viral and immunoregulatory cytokine mRNA expression levels in peripheral blood mononuclear cells (PBMC) of healthy juvenile, adolescent and adult rhesus macaques. Few age-related changes in cytokine mRNA expression levels were observed. Expression of interleukin 2 and Mx, a type I interferon-inducible gene, decreased with age, whereas interleukin 4 and macrophage inflammatory protein 1 (MIP-1) alpha and beta mRNA levels increased in older monkeys. Independent of age, the pro-inflammatory cytokines [tumour necrosis factor alpha (TNF-alpha) and chemokines] were expressed at higher mRNA levels in PBMC than the immunoregulatory cytokines (interleukins 2, 4, 12). Pro-inflammatory cytokine mRNA expression levels were highest in lymphoid tissues draining mucosal surfaces. Thus, a correlation exists between cytokine mRNA levels in lymphoid tissues and the anatomical site.

Animals↗
PubMed1987

Activities of purine metabolising enzymes in lymphocytes of neonates and young children: correlates with immune function.

Depressed activities of the following purine enzymes have been shown to result in immunodeficiencies: adenosine deaminase (ADA), hypoxanthine-guanine phosphoribosyltransferase (HGPRT), and purine nucleoside phosphorylase (PNP). These enzymes and adenosine kinase (AK) were measured in cord blood lymphocytes of premature and small-for-gestational age infants since they have partial immunodeficiencies of unknown biochemical etiology which can persist for many years. We also measured these enzymes in 3 infants with various immunodeficiencies. Activities were compared with appropriate matched control groups. The results indicated normal ADA and PNP but significantly depressed AK (P less than 0.05) and HGPRT (P less than 0.001) activities in 10 premature/SGA infants when compared to 35 full-term normal infants. In the 3 immunodeficient children the results were as follows: Child 1 had a 2- to 3-fold decrease in ADA with normal PNP and AK activities; Child 2 had a 2- to 3-fold decrease in AK, 4-fold decrease in HGPRT with normal PNP and ADA activities; Child 3 had confirmed AIDS and a 4-fold decrease in ADA, 6-fold decrease in HGPRT with normal PNP activity. The possible role of these depressed purine enzyme activities found in lymphocytes is discussed in relation to the imparied immunity seen in these infants.

Adenosine Deaminase↗
PubMed2004

Immune responses correlate with serum-metal in metal-on-metal hip arthroplasty.

Cell-mediated hypersensitivity associated with metal components may be related to levels of implant debris. We tested this hypothesis by comparing lymphocyte reactivity to soluble Co, Cr, Ni, and Ti of patients with metal-on-polyethylene and metal-on-metal arthroplasties with healthy controls, and patients with osteoarthritis. The metal-on-metal group (n=9) demonstrated significantly elevated serum Co and Cr concentrations (13- and 58-fold, P<.05, respectively) and significantly elevated lymphocyte reactivity to Co (SI>5, P<.004) and Ni (SI>2.5, P<.01) when compared to controls (n=12) and subjects with metal-on-poly implants (n=7). These elevated in vivo metal levels demonstrated positive linear correlation with lymphocyte reactivity supporting our hypothesis that lymphocyte metal-induced reactivity increases with increased metal exposure. These results represent the first direct link between in vivo metal exposure and lymphocyte reactivity. Whether this lymphocyte reactivity to metal debris is etiologically linked to poor implant performance remains uncertain.

Aged↗
PubMed2024

Exploring correlations between immune cell phenotypes and the risk of epilepsy: A bidirectional Mendelian randomization study.

BACKGROUND: Neuroinflammation plays an important pathophysiological role in epilepsy; however, the precise connection between immune cells and epilepsy remains unclear. This study used Mendelian randomization (MR) to analyze the causal relationship between 731 immune cell traits and epilepsy. METHODS: Based on data from a genome-wide association study (GWAS), a bidirectional two-sample MR analysis was conducted to investigate the potential influence of immune cell phenotypes on epilepsy. Five MR methods were used to analyze the results, with the inverse variance weighted (IVW) method as the primary method, and the results were corrected using the false discovery rate (FDR) method. Sensitivity analyses were performed to test for heterogeneity and horizontal pleiotropy. RESULTS: After correction for FDR, four immune traits remained significantly associated with epilepsy risk: CD25 expression on memory (OR&#xa0;=&#xa0;1.04, 95&#xa0;% CI&#xa0;=&#xa0;1.02&#xa0;&#x223c;&#xa0;1.06,P&#xa0;=&#xa0;2.55&#xa0;&#xd7;&#xa0;10-4), IgD+CD38dim (OR&#xa0;=&#xa0;1.05, 95&#xa0;% CI&#xa0;=&#xa0;1.02&#xa0;&#x223c;&#xa0;1.08, P&#xa0;=&#xa0;4.73&#xa0;&#xd7;&#xa0;10-4), CD24+CD27+ (OR&#xa0;=&#xa0;1.04, 95&#xa0;% CI&#xa0;=&#xa0;1.02&#xa0;&#x223c;&#xa0;1.06, P&#xa0;=&#xa0;4.82&#xa0;&#xd7;&#xa0;10-4), and IgD-CD38dim (OR&#xa0;=&#xa0;1.04, 95&#xa0;% CI&#xa0;=&#xa0;1.02&#xa0;&#x223c;&#xa0;1.06, P&#xa0;=&#xa0;1.04&#xa0;&#xd7;&#xa0;10-3) B cells. The risk of generalized epilepsy was significantly associated with two immune cell traits, whereas that of focal epilepsy was significantly associated with seven immune cell traits. Furthermore, immune cell phenotypes are not affected by genetically predicted epilepsy. CONCLUSION: This MR study affirms the causal connection between circulating immune cells and epilepsy, offering guidance for further understanding of the immune mechanisms that underlie epilepsy and the discovery of novel targets for therapy.

Humans↗