Immunoprofile studies for patients with bronchogenic carcinoma--III. Multivariate analysis of immune tests in correlation with survival.
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Blood Cell Count↗
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Results for “Immune correlation”
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In vitro simian virus 40 large tumor antigen expression correlates with differential immune responses following DNA immunization.
Simian virus 40 (SV40) contains an essential protein, large tumor antigen (Tag), which assists in viral replication and causes cell transformation and immortalization. Our laboratory has examined plasmid DNA, expressing SV40 Tag under two different promoters, for use in potential cancer vaccination strategies. One plasmid, pSV3-neo, failed to induce SV40 Tag antibody, produced a weak cell-mediated response, and only partial protection in murine experimental tumor challenge systems. The second plasmid, pCMV-Tag, induced antibodies to SV40 Tag, produced a robust cell-mediated response, and invoked complete tumor immunity in vivo. The induction of CD4+ and CD8+ T cell responses following plasmid DNA immunization and tumor cell challenge reflected a type 1 cytokine secretion profile. Our hypothesis for this differential immune response is that pCMV-Tag exhibits a higher level of transgene expression due to a more efficient promoter. We determined that pCMV-Tag levels of SV40 Tag mRNA and protein expression were higher when compared to pSV3-neo. A threshold amount of SV40 Tag may be required to stimulate antibody production and provide complete systemic tumor immunity.
Animals↗
DNA vaccines against dengue virus based on the ns1 gene: the influence of different signal sequences on the protein expression and its correlation to the immune response elicited in mice.
We analyzed four DNA vaccines based on DENV-2 NS1: pcENS1, encoding the C-terminal from E protein plus the NS1 region; pcENS1ANC, similar to pcENS1 plus the N-terminal sequence from NS2a (ANC); pcTPANS1, coding the t-PA signal sequence fused to NS1; and pcTPANS1ANC, similar to pcTPANS1 plus the ANC sequence. The NS1 was detected in lysates and culture supernatants from pcTPANS1-, pcENS1- and pcENS1ANC-transfected cells and not in cells with pcTPANS1ANC. Only the pcENS1ANC leads the expression of NS1 in plasma membrane, confirming the importance of ANC sequence for targeting NS1 to cell surface. High levels of antibodies recognizing conformational epitopes of NS1 were induced in mice immunized with pcTPANS1 and pcENS1, while only few pcENS1ANC-inoculated animals presented detectable anti-NS1 IgG. Protection against DENV-2 was verified in pcTPANS1- and pcENS1-immunized mice, although the plasmid pcTPANS1 induced slight higher protective immunity. These plasmids seem to activate distinct patterns of the immune system.
Animals↗
Inverse correlation of cellular immune responses specific to synthetic peptides from the E6 and E7 oncoproteins of HPV-16 with recurrence of cervical intraepithelial neoplasia in a cross-sectional study.
BACKGROUND: Epidemiological studies have clearly established that human papillomavirus (HPV) infection is the major risk factor for cervical cancer. Most cervical cancers and pre-cancers are HPV-positive. Not all pre-cancers progress to cancer; a significant number regress. The immunological basis for either spontaneous or treatment-mediated recovery from HPV-associated CIN is not clear. Currently, prophylactic vaccines are successfully inducing antibody responses in HPV negative patients. Therapeutic vaccines for HPV-positive patients with disease are needed. There is a need to understand the immunologic basis for the Cell-Mediated Immune (CMI) response and for histological regression to help the formulation of therapeutic vaccines. MATERIAL AND METHODS: Four groups of women were identified for this cross-sectional study of CMI. Group 1 consisted of six women without cytological or histological diagnosis of CIN and with an HPV negative test (CIN((-))/HPV((-))). Group 2 included 31 women with a new histological diagnosis of CIN and HPV positive test (CIN((+))/HPV((+))). Groups 3 and 4 were selected from women who had undergone ablative or excisional treatment for CIN at the colposcopy clinic at least 6 months before the study. The women in groups 3 and 4 were (CIN((+))/HPV((+))) before CIN treatment. Group 3 consisted of 22 women without evidence of recurrence of CIN (Recur((-))), and group 4 included 10 with histological diagnosis of recurrent CIN (Recur((+))). In particular, we investigated CMI responses to synthetic peptides from the E6 and E7 oncoproteins of HPV-16. RESULTS: Compared to patients with disease recurrence (Recur((+)), n = 10), the majority of individuals who remained recurrence-free post-treatment (Recur((-)), n = 22) exhibited significant proliferative responses to synthetic peptides from the E6 (P = 0.001) and the E7 (P = <0.001). In particular, significant responses were observed with the E6 peptide Q15L (aa 43-57, P = 0.006) and the E7 peptide Q19D (aa 44-62, P = 0.002) in Recur((-)) patients but not Recur((+)) individuals. Additionally, PBMC from women in the Recur((-)) group, but not the Recur((+)) group, produced predominantly TH1 cytokines upon stimulation with the peptides Q15L or Q19D. CONCLUSIONS: These results indicate an association between significant cellular immune responses specific to synthetic peptides from the E6 and E7 oncoproteins of HPV-16 and recurrence-free survival in HPV patients treated for CIN. We predict that these peptides may be useful as indicators of protective immunity for recovery from CIN and also for potential inclusion in designing immunotherapeutic and immunoprophylactic reagents for HPV-associated CIN.
Adolescent↗
Infection with Schistosoma mansoni correlates with altered immune responses to Ascaris lumbricoides and hookworm.
Studies were performed on humoral and cellular immune responses of patients from areas in Brazil endemic for hookworm and Ascaris lumbricoides, and either endemic or non-endemic for Schistosoma mansoni. Humoral and cellular responses were evaluated by enzyme-linked immunosorbant assay (ELISA) and peripheral blood mononuclear cell (PBMC) proliferation assays against larval hookworm antigens, A. lumbricoides egg antigens, and soluble egg antigens (SEA) or soluble whole adult antigenic preparation (SWAP) from S. mansoni. Patients from S. mansoni-endemic areas, who currently had only hookworm or Ascaris infections, expressed lower humoral and cellular responses to hookworm or Ascaris antigens, respectively, than did their counterparts from areas not endemic for S. mansoni. Individuals from S. mansoni endemic area, although without detectable S. mansoni infection, do mount humoral and cellular responses to SEA and SWAP. This group of individuals has been probably in contact with S. mansoni antigens, since the groups harboring A. lumbricoides or hookworm infections from non-S. mansoni endemic areas do not have detectable anti-S. mansoni responses. PBMC proliferative responses discriminated well between patients with active hookworm infections versus ascariasis, if they were from areas not endemic for S. mansoni.
Adolescent↗
In vitro correlate of tranplantation immunity: spleen cell migration inhibition in the lizard, Calotes Versicolor.
Sensitization to skin allografts in the lizard, Calotes versicolor, was assessed using the in vitro capillary migration inhibition (MI) assay. In the presence of the respective donor antigen, an appreciable degree of MI of sensitized spleen cells was observed as early as 4 days after grafting. A maximum level was attained on day 7 and this response was maintained as long as one month after grafting with only slight fluctuations in the level of MI. When the clinical manifestations of graft rejection culminated on day 35, the degree of MI was still at the maximum level. MI of allograft-sensitized spleen cells is an antigen specific event, and the same level of inhibition is observed whether the specific antigen is provided in the form of intact spleen cells or spleen extract.
Animals↗
NMR structure of Plasmodium falciparum malaria peptide correlates with protective immunity.
Apical membrane antigen-1 is an integral Plasmodium falciparum malaria parasite membrane protein. High activity binding peptides (HABPs) to human red blood cells (RBCs) have been identified in this protein. One of them (peptide 4313), for which critical binding residues have already been defined, is conserved and nonimmunogenic. Its critical binding residues were changed for amino acids having similar mass but different charge to change such immunological properties; these changes generated peptide analogues. Some of these peptide analogues became immunogenic and protective in Aotus monkeys.Three-dimensional models of peptide 4313 and three analogues having different immune characteristics, were calculated from nuclear magnetic resonance (NMR) experiments with distance geometry and restrained molecular dynamic methods. All peptides contained a beta-turn structure spanning amino acids 7 to 10, except randomly structured 4313. When analysing dihedral angle phi and psi values, distorted type III or III' turns were identified in the protective and/or immunogenic peptides, whilst classical type III turns were found for the nonimmunogenic nonprotective peptides. This data shows that some structural modifications may lead to induction of immunogenicity and/or protection, suggesting a new way to develop multicomponent, subunit-based malarial vaccines.
Amino Acid Sequence↗
Immunological cytokine correlates of protective immunity and pathogenesis in leprosy.
The in vitro production of interferon (IFN)-gamma, interleukin (IL)-5, tumour necrosis factor (TNF)-alpha and IL-10 by blood mononuclear cells in response to whole Mycobacterium leprae and polyclonal stimulii of 23 individuals, representing a variety of conditions in relation to exposure/susceptibility to M. leprae, was assayed. In most cases, healthy household contacts of newly diagnosed multibacillary leprosy patients, designated exposed household contacts (EC), showed low-to-undetectable in vitro IFN-gamma production in addition to substantial TNF-alpha production in response to M. leprae. In contrast, peripheral blood mononuclear cells from previously exposed contacts (R) regarded as resistant-to-leprosy released low-to-moderate levels of IFN-gamma together with a mixed cytokine profile resembling a T helper (Th)0-type response. TNF-alpha/IL-10 ratios in response to M. leprae and Concanavalin A were significantly higher in EC than in R contacts suggesting a role for the TNF-alpha/IL-10 ratio in restraining mycobacteria proliferation and spreading early in infection. The cytokine profiles of leprosy patients were taken as reference points. Post-treatment lepromatous leprosy patients secreted relatively high levels of IL-10 in response to M. leprae, whereas one self-cured tuberculoid leprosy patient produced simultaneously high levels of IFN-gamma and TNF-alpha. In addition, the quantitative changes in the cytokines released by peripheral blood mononuclear cells in EC contacts after Bacille Calmette-Guérin (BCG) vaccination were investigated. Vaccination induced amplification of IFN-gamma production with a concomitant decrease in TNF-alpha/IL-10 ratios that resembled the cytokine pattern observed in R contacts. IFN-gamma production was observed in response to both a cross-reactive antigen (Ag 85) and a M. leprae-specific protein (MMP-I), which attests to a BCG nonspecific stimulation of the immune system, thereby casting these antigens as likely candidates for inclusion in a subunit vaccine against leprosy. Finally, a model for protective x pathologic response to mycobacteria is presented.
Adolescent↗
beta-chemokines and neutralizing antibody titers correlate with sterilizing immunity generated in HIV-1 vaccinated macaques.
One of the obstacles to AIDS vaccine development is the variability of HIV-1 within individuals and within infected populations, enabling viral escape from highly specific vaccine induced immune responses. An understanding of the different immune mechanisms capable of inhibiting HIV infection may be of benefit in the eventual design of vaccines effective against HIV-1 variants. To study this we first compared the immune responses induced in Rhesus monkeys by using two different immunization strategies based on the same vaccine strain of HIV-1. We then utilized a chimeric simian/HIV that expressed the envelope of a dual tropic HIV-1 escape variant isolated from a later time point from the same patient from which the vaccine strain was isolated. Upon challenge, one vaccine group was completely protected from infection, whereas all of the other vaccinees and controls became infected. Protected macaques developed highest titers of heterologous neutralizing antibodies, and consistently elevated HIV-1-specific T helper responses. Furthermore, only protected animals had markedly increased concentrations of RANTES, macrophage inflammatory proteins 1alpha and 1beta produced by circulating CD8(+) T cells. These results suggest that vaccine strategies that induce multiple effector mechanisms in concert with beta-chemokines may be desired in the generation of protective immune responses by HIV-1 vaccines.
AIDS Vaccines↗
Ontogeny of the immune response. II. Correlations between the development of the afferent and efferent limbs.
The development of the ability of young rats to generate a prompt primary antibody response to polymerized flagellin, with IgM to IgG transition, is correlated in time with the development of structures in the cortex of lymph nodes that localize antigen to spherical areas which subsequently become primary lymphoid follicles. Throughout development the increased magnitude of the antibody response parallels the increased ability of lymphoid structures to retain antigen. During the first week of life primitive lymphoid tissue appears capable of undergoing the initial steps in differentiation toward antibody production in response to neonatal injections of polymerized flagellin. However, further maturation appears to be blocked resulting in a complex immunological state at the age of 2 weeks characterized by increased IgM and decreased IgG antibody response to antigenic challenge at this time. The possible relationship between the block in cellular differentiation toward antibody formation and the ease of tolerance induction is discussed.
Aging↗
Analysis of intercurrent human immunodeficiency virus type 1 infections in phase I and II trials of candidate AIDS vaccines. AIDS Vaccine Evaluation Group, and the Correlates of HIV Immune Protection Group.
Among 2099 uninfected subjects in phase I and II trials of candidate AIDS vaccines, 23 were diagnosed with intercurrent human immunodeficiency virus type 1 (HIV-1) infection. High-risk sexual exposures accounted for 17 infections, and intravenous drug use accounted for 6. Four subjects received placebo, 13 received a complete immunization schedule (> or = 3 injections), and 6 were partially immunized (< or = 2 injections). There was no significant difference between vaccine recipients and control groups in incidence of HIV-1 infection, virus load, CD4 lymphocyte count, or V3 loop amino acid sequence. In summary, 19 vaccinated subjects acquired HIV-1 infection during phase I and II trials, indicating that immunization with the products described is < 100% effective in preventing or rapidly clearing infection. Laboratory analysis suggested that vaccine-induced immune responses did not significantly affect the genotypic or phenotypic characteristics of transmitted virus or the early clinical course of HIV-1 infection.
AIDS Vaccines↗
Correlates of antiviral immune restoration in acute and chronic HIV type 1 infection: sustained viral suppression and normalization of T cell subsets.
Highly active antiretroviral therapy (HAART) has suppressed viral replication and facilitated normalization of T cell subsets, resulting in restoration of immunity against opportunistic pathogens. Induction of full immune restoration in chronically infected individuals, including HIV-specific helper T cell responses, is considered a priority, particularly if immunological control of HIV is to be achieved. Regimens containing dual protease inhibitors (PIs) have provided greater suppression of viremia than single-PI regimens. We therefore conducted a prospective analysis of factors associated with immune restoration after 3 years of therapy in two cohorts of acutely and chronically HIV-infected patients, comparing dual- versus single-PI regimens. Earlier and more durable returns of p24-specific proliferation were demonstrated in patients receiving dual-PI compared with single-PI regimens. Individuals with restored p24 responses had larger reductions in total HIV-specific cytotoxic T lymphocytes (CTLs) associated with stronger viral suppression, but Gag-specific CTLs remained higher, demonstrating that Gag-specific helper T cell responses were a critical component of functional immune restoration. On examination of clinical factors associated with immune restoration, we demonstrated that decreasing activation of CD8+ T cells (%CD8+ CD38+) and increasing proportions of CD4+ T cells were independently associated with restoration of p24 responses. Minimal immune activation, resulting from maximal suppression of viral replication, was required for long-term restoration and maintenance of Gag-specific T cell responses. This study uniquely demonstrates that dual-PI regimens are superior in achieving these levels of virological control and immune restoration in both chronic and acute infection, compared with single-PI or non-PI regimens.
Acute Disease↗
Paediatric HIV infection: correlates of protective immunity and global perspectives in prevention and management.
The impact of the HIV epidemic on child health globally is beginning to be appreciated. With the burden of new infections falling on young women, there is a skyrocketing number of AIDS orphans, and a rapidly increasing number of children infected via mother-to-child-transmission (MTCT). An estimated 600,000 new paediatric infections occur each year, of which some 1500/day (> 90%) occur in sub-Saharan Africa. But whereas children account for only 4% of those currently living with HIV infection, 20% of AIDS deaths have been in children. This reflects the rapid progression to disease in paediatric HIV infection. Whereas a dramatic reduction in viraemia follows acute adult infection, corresponding to the appearance of a vigorous anti-HIV cytotoxic T lymphocyte response, virtually no impact of the immune response is observed in acute paediatric infection following MTCT. Two specific challenges for the paediatric immune response are: (i) infection occurs before the immune system itself is fully developed; and (ii) the viruses transmitted by MTCT have already evaded an immune system sharing close genetic relatedness to that of the child. Accumulating evidence indicates that the immune system is potentially capable of effective control of HIV infection, and that events occurring in acute infection critically determine the ultimate outcome. Technological advances that have transformed the study of T-cell immunity now enable the developing immune system in childhood to be better understood. Via novel immunotherapeutic approaches described, it may be possible to modulate the infant's immune response to reach effective and durable suppression of HIV, as can be achieved by the rare long-term non-progressors of HIV infection. The feasibility of adopting these approaches globally are as yet untested. Finally, the striking disparity between the burden of paediatric HIV infection and access to the necessary infrastructure and therapeutic options required for its optimal management is addressed in a comparison between three sites of paediatric HIV care: Durban, South Africa; London, UK; and Boston, USA.
Adult↗
Clinical correlates of circulating immune complexes in patients with recent yersiniosis.
Circulating immune complexes (CICs) and rheumatoid factor were studied in 31 patients with serologically confirmed yersiniosis (12 in a pilot series and 19 in a prospective series). Yersiniosis is an intestinal infection complicated occasionally by extraintestinal symptoms such as aseptic arthritis. Four tests representing three main principles (affinity of human platelets and of C1q for complexed IgG and of conglutinin for C3) were used for the detection of CICs, which were found in all patients. Fifty-five of 62 specimens of serum from the prospective series of 19 patients reacted positively in at least one test. The conglutinin-binding assay and the platelet-125I-labeled staphylococcal protein A test gave positive results most frequently (74% and 84% of the time). Mean levels of CICs were significantly higher in patients with prolonged gastroenteritis than in those with histocompatibility leukocyte antigen B27-positive arthritis. During follow-up, the mean level of CICs (as measured by the platelet-protein A test) decreased significantly in patients with arthritis, while CICs and rheumatoid factor persisted in patients with prolonged gastroenteritis.
Adult↗
The C1q binding test for soluble immune complexes: clinical correlations obtained in patients with cancer.
Sera from 134 selected patients with various types of cancer were tested for soluble antigen-antibody complexes by the C1q binding method. Sera from 85 healthy blood bank donors served as normal controls. C1q binding activity (C1q BA) values above the 95th percentile for healthy subjects were found in 83% of sera from patients with neoplastic diseases. The incidence of abnormal C1q BA values among patients with malignant melanoma was 83%, with breast cancer 74%, with colon cancer 75%, with lung cancer 88%, with leukemia and lymphoma 85%, and with miscellaneous tumors 94%. High C1q BA values were found most frequently in sera of patients who had been diagnosed relatively recently (within 5 mo) and who had evident residual disease after surgical treatment. Recurrence or progression of tumor growth occurred significantly more frequently in lung cancer patients with high C1q BA. DNA was not detected in cancer patients' sera and treatment with DNase did not decrease in C1q BA. C1q BA in sera could not be explained by the presence of antiglobulin antibodies. Sucrose density gradient ultracentrifugation studies of the serum C1q BA in 4 cancer patients showed that the major binding activity was found between 19S and 7S.
Antibodies, Anti-Idiotypic↗
Correlation of humoral immunity to Lewis blood group antigens with renal transplant rejection.
Recent studies suggest that the Lewis blood group antigens are important for human renal transplantation. A possible mechanism by which Lewis blood group incompatibility could influence allograft rejection was investigated by measuring Lewis antibodies in sera from renal transplant recipients and appropriate controls using conventional hemagglutination and a sensitive and specific kinetic enzyme-linked immunosorbent assay (k-ELISA). The two methods yielded identical results with 14 positive control sera known to contain Lewis antibodies and with 43 sera from negative controls. Antibody was not detected in 16 Lewis-positive transplant patients. However, antibody was detected by k-ELISA in 4/11 Lewis-negative transplant candidates and in 8/8 Lewis-negative recipients of Lewis-incompatible grafts. All 8 grafts were rejected. The one Lewis-negative recipient of a Lewis-negative graft did not develop Lewis antibody nor reject his graft. Of the 12 renal patients in whom antibody was detected by k-ELISA, in only 4 was antibody also demonstrable by hemagglutination. These results indicate that hemagglutination may not be sensitive enough for antibody detection and that Lewis antibodies may play a role in renal allograft rejection.
Blood Group Incompatibility↗
Correlation between the immune response elicited in rabbits by env-recombinant avipox vaccines and the inhibition of HIV-1-specific functions.
The fine immunoreactivity of the rabbit humoral response elicited by four env-recombinant avipoxviruses and their ability to stimulate a memory T-cell response and a protective immunity have been studied. The antibody specificity was compared with the serum neutralizing activity and virus-specific T-cell proliferative response. Resistance to challenge by cell-associated HIV-1 was monitored by PCR. Canarypox (CP) and fowlpox (FP) constructs, containing the complete env gene (IS(+)) from the HIV-1(SF2) strain, induced a higher profile of epitope recognition than their counterparts expressing the env gene deleted of the putative immunosuppressive region (IS(-)). Serum neutralizing activity was in agreement with fusion inhibition and lymphoproliferative response in rabbits immunized with CPIS(+), and only partially with FPIS(+). Rabbits failed to be infected, but anti- p55 gag-specific antibodies could be demonstrated by Western blot. This study confirms the ability of these non-replicative live recombinant viruses to elicit a complete immune response, capable of inhibiting specific HIV-1 functions.
AIDS Vaccines↗
Adenosine deaminase and immune dysfunction. Biochemical correlates defined by molecular analysis throughout a disease course.
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Adenosine Deaminase↗