First Author: Anavelys Ortiz-SuĂˇrez
All Authors: Ortiz-SuĂˇrez A, Miller RA
Journal Title: The journals of gerontology. Series A, Biological sciences and medical sciences
Abstract: Memory CD8+ T cells from old mice can proliferate in nonirradiated recipients. Transfer of labeled cells from aged donors into young recipients showed that proliferation of aged donor CD8 cells requires host cells that can both respond to interferon-gamma and produce interleukin-15. Reisolation of transferred CD8 cells from host mice showed that LAT (linker for activated T cells) translocation to the immunological synapse, and translocation of NF (nuclear factor)-kappaB to the nucleus were diminished in recovered CD8 T cells from old donors, whether they had divided in vivo or not. Cells able to proliferate in vivo could be isolated based on their unusually high levels of CD28 expression, but were found not to differ from other aged CD8 cells in their low levels of LAT and protein kinase C-theta (PKC-theta) translocation to the immunological synapse. Thus in vivo proliferation of CD28hi CD8 cells from aged mice cannot be attributed to retention of T-cell receptor signaling.
Authors: Chattopadhyay G, Shevach EM
Abstract: Foxp3(+) T regulatory cells (Tregs) are critically important for the maintenance of immunological tolerance, immune homeostasis, and prevention of autoimmunity. Dendritic cells (DCs) are one of the major targets of Treg-mediated suppression. Some studies have suggested that Treg-mediated suppression of DC function is mediated by the interaction of CTLA-4 on Tregs with CD80/CD86 on the DCs resulting in downregulation of CD80/CD86 expression and a decrease in costimulation. We have re-examined the effects of Tregs on mouse DC function in a model in which Ag-specific, induced Tregs (iTregs) are cocultured with DCs in the absence of T effector cells. iTreg-treated DCs are markedly defective in their capacity to activate naive T cells. iTregs from CTLA-4-deficient mice failed to induce downregulation of CD80/CD86, but DCs treated with CTLA-4-deficient iTregs still exhibited impaired capacity to activate naive T cells. The iTreg-induced defect in DC function could be completely reversed by anti-IL-10, and IL-10-deficient iTregs failed to downregulate DC function. iTreg-treated DCs expressed high levels of MARCH1, an E3 ubiquitin ligase, recently found to degrade CD86 and MHC class II on the DCs and expressed lower levels of CD83, a molecule involved in neutralizing the function of MARCH1. Both the enhanced expression of MARCH1 and the decreased expression of CD83 were mediated by IL-10 produced by the iTregs. Taken together, these studies demonstrate that a major suppressive mechanism of DC function by iTregs is secondary to the effects of IL-10 on MARCH1 and CD83 expression.
Authors: Fournier P, Schirrmacher V
Abstract: New approaches of therapeutic cancer vaccination are needed to improve the antitumor activity of T cells from cancer patients. We studied over the last years the activation of human T cells for tumor attack. To this end, we combined the personalized therapeutic tumor vaccine ATV-NDV--which is obtained by isolation, short in vitro culture, irradiation, and infection of patient's tumor cells by Newcastle Disease Virus (NDV)--with bispecific antibodies (bsAbs) binding to this vaccine and introducing anti-CD3 (signal 1) and anti-CD28 (signal 2) antibody activities. This vaccine called ATV-NDV/bsAb showed the unique ability to reactivate a preexisting potentially anergized antitumor memory T cell repertoire. But it also activated naive T cells to have antitumor properties in vitro and in vivo. This innovative concept of direct activation of cancer patients' T cells via cognate and noncognate interactions provides potential for inducing strong antitumor activities aiming at overriding T cell anergy and tumor immune escape mechanisms.
Authors: Zhou W, Li H, Zhang Y, Huang M, He Q, Li P, Zhang F, Shi Y, Su X
Abstract: The objective of this study was to compare the diagnostic value of galactomannan (GM) detection in bronchoalveolar lavage fluid (BALF) and serum samples from nonneutropenic patients with invasive pulmonary aspergillosis (IPA) and determine the optimal BALF GM cutoff value for pulmonary aspergillosis. GM detection in BALF and serum samples was performed by enzyme-linked immunosorbent assay (ELISA) in 128 patients with clinically suspected nonneutropenic pulmonary aspergillosis between June 2014 and June 2016. On the basis of the clinical and pathological diagnoses, 8 patients were excluded because their diagnosis was uncertain. The remaining 120 patients were diagnosed with either IPA (n = 37), community-acquired pneumonia (CAP; n = 59), noninfectious diseases (n = 19), or tuberculosis (n = 5). At a cutoff optical density index (ODI) value of ?0.5, the sensitivity of BALF GM detection was much higher than that of serum GM detection (75.68% versus 37.84%; P = 0.001), but there was no significant difference between their specificities (80.72% versus 87.14%; P = 0.286). At a cutoff value of ?1.0, the sensitivity of BALF GM detection was still much higher than that of serum GM detection (64.86% versus 24.32%; P < 0.001), and their specificities were similar (90.36% versus 95.71%; P = 0.202). Receiver operating characteristic (ROC) curve analysis showed that when the BALF GM detection cutoff value was 0.7, its diagnostic value for pulmonary aspergillosis was optimized, and the sensitivity and specificity reached 72.97% and 89.16%, respectively. BALF GM detection was valuable for the diagnosis of IPA in nonneutropenic patients, and its diagnostic value was superior to that of serum GM detection. The optimal BALF GM cutoff value was 0.7.
Authors: Monteiro KM, Zaha A, Ferreira HB
Abstract: Antigen B (AgB) is a major protein component of the Echinococcus granulosus metacestode. It is oligomeric and this raises several questions regarding the subunit structure and composition of AgB. Several genes that encode different AgB subunits have been identified, and some of these have been cloned and expressed to produce recombinant subunits. The study of these recombinant subunits may provide new insights into the structure, physical-chemical properties, and functional aspects of AgB. Like native AgB, the AgB8/1, AgB8/2, and AgB8/3 recombinant subunits produced in our laboratory form 120-160 kDa oligomers that have stable secondary structures, are strongly antigenic and immunogenic, and selectively bind hydrophobic compounds. Here, we review these results and discuss their implications for the elucidation of the structure and function of AgB. This includes a possible role for AgB in host-parasite interactions.
Authors: Rovere-Querini P, Manfredi AA
Abstract: Antigen presenting cells (APCs) activate helper and cytotoxic T cells specific for antigens expressed by tissue cells, including neoplastic cells. This event occurs after the antigen transfer from tissue cells to APC, and is referred to as "cross-presentation". The number and the state of activation of APC in the tumor control the outcome of cross-presentation, including the establishment of protective immune responses. Cell death favors cross-presentation. Cancer cells normally die, either spontaneously or as a consequence of targeted therapies. The transfer of tumor antigens from dying tumor cells to APCs in vivo, exploiting the cross-presentation pathway, has the potential of yielding novel immunotherapeutic strategies. Their success will depend on at least two factors: the induction of synchronized cell death in the tumor, and the recruitment of activated dendritic cells in the tumor. Under normal conditions, pancreatic cancer represents a privileged environment; its profound chemoresistance reflects limited apoptosis after chemotherapy. Moreover, it usually contains only a few cells endowed with APC function. Endoscopic ultrasonography offers attractive possibilities of circumventing this privilege, including the delivery of ultrasound, radiofrequency or radiation in order to destroy the tumor and the delivery in situ of autologous APC or appropriate chemotactic signals. In general, loco-regional approaches offer the possibility of using the tumor of each patient as a complex antigen source, thus limiting the risk of tumor escape and reducing the need for extensive ex vivo handling of the neoplasm and of the patient APCs.
Authors: Galetto-Lacour A, Alcoba G, Posfay-Barbe KM, Cevey-Macherel M, Gehri M, Ochs MM, Brookes RH, Siegrist CA, Gervaix A
Abstract: Our objective was to evaluate procalcitonin (PCT) and C-reactive protein (CRP) as predictors of a pneumococcal etiology in community-acquired pneumonia (CAP) in hospitalized children.Children requiring hospitalization for CAP were prospectively enrolled. The following indices were determined: antibodies against pneumococcal surface proteins (anti-PLY, pneumococcal histidine triad D, pneumococcal histidine triad E, LytB and pneumococcal choline-binding protein A), viral serology, nasopharyngeal cultures and polymerase chain reaction for 13 respiratory viruses, blood pneumococcal polymerase chain reaction, pneumococcal urinary antigen, PCT and CRP. Presumed pneumococcal CAP (P-CAP) was defined as a positive blood culture or polymerase chain reaction for Streptococcus pneumoniae or as a pneumococcal surface protein seroresponse (?2-fold increase).Seventy-five patients were included from which 37 (49%) met the criteria of P-CAP. Elevated PCT and CRP values were strongly associated with P-CAP with odds ratios of 23 (95% confidence interval: 5-117) for PCT and 19 (95% confidence interval: 5-75) for CRP in multivariate analysis. The sensitivity was 94.4% for PCT (cutoff: 1.5 ng/mL) and 91.9% for CRP (cutoff: 100 mg/L). A value?0.5 ng/mL of PCT ruled out P-CAP in >90% of cases (negative likelihood ratio: 0.08). Conversely, a PCT value?1.5 ng/mL associated with a positive pneumococcal urinary antigen had a diagnostic probability for P-CAP of almost 80% (positive likelihood ratio: 4.59).PCT and CRP are reliable predictors of P-CAP. Low cutoff values of PCT allow identification of children at low risk of P-CAP. The association of elevated PCT or CRP with a positive pneumococcal urinary antigen is a strong predictor of P-CAP.
Authors: Lo YC, Chang SY, Sheng WH, Hung CC, Chang SC
Abstract: Diabetes mellitus (DM) is a well known complication of interferon therapy for chronic hepatitis C virus (HCV) infection, but resolution of interferon-induced DM was rarely reported. In HIV and HCV co-infected patients, only two cases of incident DM during interferon therapy were reported and both cases required permanent insulin treatment. We report the first case of HIV/HCV co-infected patient who developed diabetic ketoacidosis during treatment for chronic HCV infection with complete resolution of DM after treatment cessation. Review of reported cases indicates that pancreatic autoantibodies and human leukocyte antigen haplotypes may predict the outcome of interferon-induced diabetes.
Authors: Krejci J, Nechvatalova K, Kudlackova H, Leva L, Bernardy J, Toman M, Faldyna M
Abstract: The ability of different adjuvants to enhance immune responses to intradermal (ID) immunisation with a model antigen was studied in pigs. Immune responses were evaluated with respect to the intensity of systemic and mucosal antibody formation, their isotype characterisation and rate of cell-mediated immunity. These findings were compared with the intensity of adverse local reactions. Six groups of piglets were immunised with keyhole limpet haemocyanin (KLH) antigen alone or in combination with aluminium hydroxide or selected oil-based adjuvants (complete and incomplete Freund's adjuvants, Montanide ISA 206 and Emulsigen). Systemic specific antibody responses were significantly increased following ID administration of antigen together with any of the adjuvants used. IgG antibody responses were most pronounced after the first administration of antigen, being stimulated with both Freund's and Montanide ISA 206 adjuvants. The oil adjuvants also enhanced the cell-mediated immune responses and the levels of local IgA antibodies in the respiratory mucosa. On the other hand, they elicited more pronounced adverse local reactions.
Authors: Wu C, Zhang X, Tian Y, Song J, Yang D, Roggendorf M, Lu M, Chen X
Abstract: Amino acid substitutions of hepatitis B surface antigen (HBsAg) may affect the antigenicity and immunogenicity of HBsAg, leading to immune escape and diagnostic failure. The amino acid positions 122 and 160 are known as determinants for HBsAg subtypes d/y and w/r, respectively. The substitution K122I has been shown to strongly affect HBsAg antigenicity. In this study, we investigated the significance of naturally occurring amino acid substitutions K122I, T123N, A159G and K160N. Both T123N and K160N substitutions resulted in additional N-glycosylated forms of HBsAg, while the other mutations produced more glycosylated HBsAg compared with the wild type (wt). Detection of HBsAg by ELISA and immunofluorescence staining indicated that variant HBsAg (vtHBsAg) with K122I was not recognized by HBsAg immunoassays, while vtHBsAg with T123N, A159G, K160N and A159G/K160N had reduced antigenicity. DNA immunization in BALB/c mice revealed that wtHBsAg and vtHBsAg with T123N and K160N are able to induce antibodies to HBsAg (anti-HBs), whereas K122I and A159G greatly impair the ability of HBsAg to trigger anti-HBs responses. The cellular immune response to the HBsAg aa 29-38 epitope was enhanced by the K160N substitution. Using replication competent clones of hepatitis B virus (HBV), T123N and A159G substitutions were shown to strongly reduce virion assembly. The amino acid substitution K160N appeared to compensate for the negative effect of A159G on virion production. These results reveal complex effects of amino acid substitutions on biochemical properties of HBsAg, on antigenicity and immunogenicity, and on the replication of HBV.
Authors: Kirkman LA, Deitsch KW
Abstract: The most severe form of human malaria is caused by the protozoan parasite Plasmodium falciparum. These parasites invade and replicate within the circulating red blood cells of infected individuals leading to numerous disease manifestations, including severe anemia, altered circulation, and tissue inflammation. Malaria parasites are also known for their ability to maintain a chronic infection through antigenic variation, the ability to systematically alter the antigens displayed on the surface of infected cells and thereby avoid clearance by the host's antibody response. The genome of P. falciparum includes several large, multicopy gene families that encode highly variable forms of the surface proteins that are the targets of host immunity. Alterations in expression of genes within these families are responsible for antigenic variation. This process requires the continuous generation of new antigenic variants within these gene families, and studies have shown that new variants arise through extensive recombination and gene conversion events between family members. Malaria parasites possess an unusual complement of DNA repair pathways, thus the study of recombination between variant antigen encoding genes provides a unique view into the evolution of mobile DNA in an organism distantly related to the more closely studied model eukaryotes.