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Mapping HIV-1 vaccine induced T-cell responses: bias towards less-conserved regions and potential impact on vaccine efficacy in the Step study.
Li, F, Finnefrock, AC, Dubey, SA, Korber, BT, Szinger, J, Cole, S, McElrath, MJ, Shiver, JW, Casimiro, DR, Corey, L, et al
PloS one. 2011;(6):e20479
Abstract
UNLABELLED T cell directed HIV vaccines are based upon the induction of CD8+ T cell memory responses that would be effective in inhibiting infection and subsequent replication of an infecting HIV-1 strain, a process that requires a match or near-match between the epitope induced by vaccination and the infecting viral strain. We compared the frequency and specificity of the CTL epitope responses elicited by the replication-defective Ad5 gag/pol/nef vaccine used in the Step trial with the likelihood of encountering those epitopes among recently sequenced Clade B isolates of HIV-1. Among vaccinees with detectable 15-mer peptide pool ELISpot responses, there was a median of four (one Gag, one Nef and two Pol) CD8 epitopes per vaccinee detected by 9-mer peptide ELISpot assay. Importantly, frequency analysis of the mapped epitopes indicated that there was a significant skewing of the T cell response; variable epitopes were detected more frequently than would be expected from an unbiased sampling of the vaccine sequences. Correspondingly, the most highly conserved epitopes in Gag, Pol, and Nef (defined by presence in >80% of sequences currently in the Los Alamos database www.hiv.lanl.gov) were detected at a lower frequency than unbiased sampling, similar to the frequency reported for responses to natural infection, suggesting potential epitope masking of these responses. This may be a generic mechanism used by the virus in both contexts to escape effective T cell immune surveillance. The disappointing results of the Step trial raise the bar for future HIV vaccine candidates. This report highlights the bias towards less-conserved epitopes present in the same vaccine used in the Step trial. Development of vaccine strategies that can elicit a greater breadth of responses, and towards conserved regions of the genome in particular, are critical requirements for effective T-cell based vaccines against HIV-1. TRIAL REGISTRATION ClinicalTrials.gov NCT00849680, A Study of Safety, Tolerability, and Immunogenicity of the MRKAd5 Gag/Pol/Nef Vaccine in Healthy Adults.
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[T cell proliferative response and antibody formation to citrullinated collagen type II in patients with rheumatoid arthritis].
Tian, X, Zhao, Y, Li, ZG
Zhonghua yi xue za zhi. 2009;(10):673-6
Abstract
OBJECTIVE To investigate the T cell proliferative response and antibody formation to citrullinated collagen type II (Cit-CII) in patients with rheumatoid arthritis (RA), and explore whether autoreactive T cells responding to Cit-CII plays a role in the pathogenesis of RA. METHODS Arginine residues of bovine collagen type II (CII) were converted to citrulline residues by peptidylarginine deiminase (PAD). Peripheral blood samples were collected from 34 RA patients, and 18 sex- and age-matched controls, including 6 osteoarthritis patients and 12 healthy blood donors. Peripheral blood mononuclear cells (PBMCs) were isolated and cultured with Cit-CII, CII, or fetal bovine serum RPMI 1640 fluid, phytohemagglutinin (PHA), or citrullinated buffer as controls. Cellular reactivity levels against Cit-CII and CII were investigated by measuring the proliferation of PBMCs to calculate the stimulation index (SI). ELISA was used to detect the presence of antibodies against Cit-CII and CII. RESULTS The positive rate of T cell proliferative response to Cit-CII of the RA group was 32.4% (11/34), significantly higher than that of the control group (0, P < 0.05). The positive rate of T cell proliferative response to CII of the RA group was 35.3% (12/34), significantly higher than that of the control group (11.1%, P < 0.05). Interestingly, Cit-CII could not elicit a better T cell proliferative response than CII did. In the RA patients, the anti-Cit-CII antibody positive rate was 52.9% (18/34), significantly higher than that of the anti-CII antibody positive rate [32.4% (11/34), P < 0.05). The serum IgG anti-CII antibody positive rate of the patients with positive T cell responses to CII was 58.3% (7/12), significantly higher than that of the patients with negative T cell responses to CII [18.2% (4/22), P < 0.05]. The serum IgG anti-CII antibody positive rate of the patients with positive T cell responses to Cit-CII was 72.7% (8/11), significantly higher than that of the patients with negative T cell responses to Cit-CII [43.5% (10/23), P < 0.05]. CONCLUSION The recognition of Cit-CII by circulating IgG antibodies is a RA-specific serological phenomenon. The formation of CII antibody in the RA patients may be related to B cell activation mediated by CII specific T cells. The role of Cit-CII in RA cellular immune need be further studied.
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In chronic fatigue syndrome, the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation.
Maes, M, Mihaylova, I, Leunis, JC
Neuro endocrinology letters. 2005;(6):745-51
Abstract
There is now evidence that major depression is accompanied by decreased levels of omega3 poly-unsaturated fatty acids (PUFA), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). There is a strong comorbidity between major depression and chronic fatigue syndrome (CFS). The present study has been carried out in order to examine PUFA levels in CFS. In twenty-two CFS patients and 12 normal controls we measured serum PUFA levels using gas chromatography and mass spectrometry. We found that CFS was accompanied by increased levels of omega6 PUFAs, i.e. linoleic acid and arachidonic acid (AA), and mono-unsaturated fatty acids (MUFAs), i.e. oleic acid. The EPA/AA and total omega3/omega6 ratios were significantly lower in CFS patients than in normal controls. The omega3/omega6 ratio was significantly and negatively correlated to the severity of illness and some items of the FibroFatigue scale, i.e. aches and pain, fatigue and failing memory. The severity of illness was significantly and positively correlated to linoleic and arachidonic acid, oleic acid, omega9 fatty acids and one of the saturated fatty acids, i.e. palmitic acid. In CFS subjects, we found significant positive correlations between the omega3/omega6 ratio and lowered serum zinc levels and the lowered mitogen-stimulated CD69 expression on CD3+, CD3+ CD4+, and CD3+ CD8+ T cells, which indicate defects in early T cell activation. The results of this study show that a decreased availability of omega3 PUFAs plays a role in the pathophysiology of CFS and is related to the immune pathophysiology of CFS. The results suggest that patients with CFS should respond favourably to treatment with--amongst other things--omega3 PUFAs, such as EPA and DHA.
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Preliminary evidence for lymphocyte distribution differences at rest and after acute psychological stress in PTSD-symptomatic women.
Glover, DA, Steele, AC, Stuber, ML, Fahey, JL
Brain, behavior, and immunity. 2005;(3):243-51
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Abstract
This study investigated circulating natural killer (NK), CD4+ and CD8+ cells in response to acute psychological challenge among mothers of child cancer survivors with and without posttraumatic stress symptoms (PTSS). Control mothers of healthy children (n=9) were compared to 17 cancer mothers with (PTSS: n=9) and without PTSS (No PTSS n=7) under conditions of rest, after a generic stressor (MAT: mental arithmetic task) and a personalized stressor (script-driven trauma imagery), and after recovery from each stressor. Results indicate the PTSS group had higher percentage CD4+ and lower CD8+ levels than non-symptomatic women and blunted NK reactivity to generic challenge. Multiple regression analyses indicated PTSS effects were independent of self-reported distress. Contrary to expectations, cancer mothers without PTSS were not significantly different from controls on tonic or phasic immune outcomes. Also unlike predictions, reactivity to challenge was greatest to the non-social MAT stressor compared to the personalized challenge for all groups. Conclusions are constrained by study limitations (e.g., small sample size and potential phase order effects). Nonetheless, results are consistent with an emerging literature on PTSS-associated immune differences and further suggest these effects may be distinct from that associated with subjective distress more generally.
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Phenotypic and functional lymphocyte recovery after CD34+-enriched versus non-T cell-depleted autologous peripheral blood stem cell transplantation.
Nachbaur, D, Kropshofer, G, Heitger, A, Lätzer, K, Glassl, H, Ludescher, C, Nussbaumer, W, Niederwieser, D
Journal of hematotherapy & stem cell research. 2000;(5):727-36
Abstract
To determine the effect of CD34+ selection on immune recovery after high-dose chemo/radiotherapy in the setting of autologous stem cell transplantation (ASCT), we analyzed quantitative and qualitative lymphocyte reconstitution for up to 1 year post-transplantation in 27 consecutive adult patients receiving either CD34+-enriched or unmanipulated autologous stem cell (SC) grafts. Pretransplant immunological parameters were identical for both treatment groups. Total lymphocyte counts as well as CD3+ T cells provided a similar course of recovery in both cohorts, returning to baseline values within the first 3 months. There were no significant differences in the reconstitution kinetics of CD4+, CD8+, CD45RA+, and CD45RO+ T cells. CD4+ and CD45RA+ T cells between the two groups were significantly decreased within the first 6 months, returning to pretransplant baseline values by 1 year. Although within the first 3 months the majority of CD3+ cells were activated as demonstrated by expression of HLA-DR, we observed a significant loss of CD25+ T cells in both groups within the first 6 months. B cell numbers returned to baseline values within 3 months but in vivo B cell function measured by serum immunoglobulin M (IgM) and IgA levels did not recover as early as 6 months post-transplantation. T cell function measured by proliferation in response to the lectins phytohemagglutinin (PHA) and Concanavalin A (ConA) and to alloantigens in the mixed lymphocyte reaction (MLR) was significantly impaired, but tended to return to pretransplant baseline values by 1 year. Although preliminary, our results provide strong evidence that T cell depletion (TCD) by CD34+ enrichment using the CellPro device does not result in delayed phenotypic immune reconstitution after autologous peripheral blood stem cell transplantation (PB-SCT). Even in the absence of a high thymic T cell regenerative capacity in adults, T cell numbers and subset distributions were restored within the time frame studied. T and B cell function, however, remained significantly impaired for a prolonged period of time (>6 months after SCT) with a more profound defect in patients autografted with CD34+-enriched SC.