Mucosal prior to systemic application of recombinant adenovirus boosting is more immunogenic than systemic application twice but confers similar protection against SIV-challenge in DNA vaccine-primed macaques

AbstractWe investigated the immunogenicity and efficacy of a bimodal prime/boost vaccine regimen given by various routes in the Simian immunodeficiency virus (SIV) rhesus monkey model for AIDS. Twelve animals were immunized with SIV DNA-vectors followed by the application of a recombinant adenovirus (rAd5) expressing the same genes either intramuscularly (i.m.) or by oropharyngeal spray. The second rAd5-application was given i.m. All vaccinees plus six controls were challenged orally with SIVmac239 12 weeks post-final immunization.Both immunization strategies induced strong SIV Gag-specific IFN-γ and T-cell proliferation responses and mediated a conservation of CD4+ memory T-cells and a reduction of viral load during peak viremia following infection. Interestingly, the mucosal group was superior to the systemic group regarding breadth and strength of SIV-specific T-cell responses and exhibited lower vector specific immune responses. Therefore, our data warrant the inclusion of mucosal vector application in a vaccination regimen which makes it less invasive and easier to apply

Immune cell contexture in the bone marrow tumor microenvironment impacts therapy response in CML

Increasing evidence suggests that the immune system affects prognosis of chronic myeloid leukemia (CML), but the detailed immunological composition of the leukemia bone marrow (BM) microenvironment is unknown. We aimed to characterize the immune landscape of the CML BM and predict the current treatment goal of tyrosine kinase inhibitor (TKI) therapy, molecular remission 4.0 (MR4.0). Using multiplex immunohistochemistry (mIHC) and automated image analysis, we studied BM tissues of CML patients (n = 56) and controls (n = 14) with a total of 30 immunophenotype markers essential in cancer immunology. CML patients' CD4+ and CD8+ T-cells expressed higher levels of putative exhaustion markers PD1, TIM3, and CTLA4 when compared to control. PD1 expression was higher in BM compared to paired peripheral blood (PB) samples, and decreased during TKI therapy. By combining clinical parameters and immune profiles, low CD4+ T-cell proportion, high proportion of PD1+ TIM3-CD8+ T cells, and high PB neutrophil count were most predictive of lower MR4.0 likelihood. Low CD4+ T-cell proportion and high PB neutrophil counts predicted MR4.0 also in a validation cohort (n = 52) analyzed with flow cytometry. In summary, the CML BM is characterized by immune suppression and immune biomarkers predicted MR4.0, thus warranting further testing of immunomodulatory drugs in CML treatment.Peer reviewe

1971

Shop Talk by Frank Santos (page 1) You\u27ve Come a Long Way, Lawn-Mower Pusher by Alan B. Albin (2) In The Eyes of the Laymen by Eugene P. Elcik (2) The Importance of Water Management by Fred V. Grau (A-1) Automatic Irrigation Systems Integrated with Pumping Systems by Michael O. Mattwell (A-5) Installation of a Complete Water Source and Automatic System by Richard C. Blake (A-19) How the Soil Conservation Service Can Help in Golf Course Management by Christopher G. Mousitakis (A-22) Our Shrinking Environment by Haim B. Gunner (A-24) Pesticides\u27 Dilemma - Emotion vs. Science by Allen H. Morgan (A-28) Effects of Turf Grasses and Trees in Neutralizing Waste Water by William E. Sopper (A-34) Unsolved and New Problems Developing in Golf Course Management by Alexander M. Radko (A-44) Coming of the Conglomerate Director of Golf Courses by Edmund B. Ault (A-48) Aquatic Weed Control by John E. Gallagher (A-52) What Project Apollo Has Done for Golf and Golf Course Architecture by Mal Purdy (A-54) Maintenance of Grass Tennis Courts by Wayne Zoppo (A-59) Diseases of Ornametnals Growing in Turf Areas by R.E. Partyka (A-62) Control of Turf Insects by John C. Schread (A-65) Lime for Turf by Henry W. Indyk (A-68) How to Stop Guessing When You Buy Seed by Dale Kern (A-71) Broad Aspects of Turf Grass Culture Other Than Golf Courses by Geoffrey S. Cornish (A-79) Establishing and Maintaining Turf int he national Capitol Parks by Alton E. Rabbitt (A-81) Preventive Maintenance on Small One Cylinder Air Cooled Engine by F. W. Hazle (A-85) Top Fairway Mower Performance by James R. Maloney (A-95) Grinding Reel Type Mowers by Ray Christopherson (A-99

Evidence for predilection of macrophage infiltration patterns in the deeper midline and mesial temporal structures of the brain uniquely in patients with HIV-associated dementia

<p>Abstract</p> <p>Background</p> <p>HIV-1 penetrates the central nervous system, which is vital for HIV-associated dementia (HAD). But the role of cellular infiltration and activation together with HIV in the development of HAD is poorly understood.</p> <p>Methods</p> <p>To study activation and infiltration patterns of macrophages, CD8+ T cells in relation to HIV in diverse CNS areas of patients with and without dementia. 46 brain regions from two rapidly progressing severely demented patients and 53 regions from 4 HIV+ non-dementia patients were analyzed. Macrophage and CD8+ T cell infiltration of the CNS in relation to HIV was assessed using immuno-histochemical analysis with anti-HIV (P24), anti-CD8 and anti-CD68, anti-S-100A8 and granzyme B antibodies (cellular activation). Statistical analysis was performed with SPSS 12.0 with Student's t test and ANOVA.</p> <p>Results</p> <p>Overall, the patterns of infiltration of macrophages and CD8+ T cells were indiscernible between patients with and without dementia, but the co-localization of macrophages and CD8+ T cells along with HIV P24 antigen in the deeper midline and mesial temporal structures of the brain segregated the two groups. This predilection of infected macrophages and CD8+ T cells to the middle part of the brain was unique to both HAD patients, along with unique nature of provirus gag gene sequences derived from macrophages in the midline and mesial temporal structures.</p> <p>Conclusion</p> <p>Strong predilection of infected macrophages and CD8+ T cells was typical of the deeper midline and mesial temporal structures uniquely in HAD patients, which has some influence on neurocognitive impairment during HIV infection.</p

On the general theory of the origins of retroviruses

<p>Abstract</p> <p>Background</p> <p>The order retroviridae comprises viruses based on ribonucleic acids (RNA). Some, such as HIV and HTLV, are human pathogens. Newly emerged human retroviruses have zoonotic origins. As far as has been established, both repeated infections (themselves possibly responsible for the evolution of viral mutations <b>(Vm) </b>and host adaptability <b>(Ha)</b>); along with interplay between <it>inhibitors </it>and <it>promoters </it>of cell tropism, are needed to effect retroviral cross-species transmissions. However, the exact <it>modus operadi </it>of intertwine between these factors at molecular level remains to be established. Knowledge of such intertwine could lead to a better understanding of retrovirology and possibly other infectious processes. This study was conducted to derive the mathematical equation of a general theory of the origins of retroviruses.</p> <p>Methods and results</p> <p>On the basis of an arbitrarily non-Euclidian geometrical "thought experiment" involving the cross-species transmission of simian foamy virus (sfv) from a non-primate species <it>Xy </it>to <it>Homo sapiens </it>(<it>Hs</it>), initially excluding all social factors, the following was derived. At the port of exit from <it>Xy </it>(where the species barrier, SB, is defined by the <it>Index of Origin</it>, IO), sfv shedding is (1) enhanced by two transmitting tensors <b>(Tt)</b>, (i) virus-specific immunity (VSI) and (ii) evolutionary defenses such as APOBEC, RNA interference pathways, and (when present) expedited therapeutics (denoted e²D); and (2) opposed by the five accepting scalars <b>(At)</b>: (a) genomic integration hot spots, gIHS, (b) nuclear envelope transit <b>(</b>NMt) vectors, (c) virus-specific cellular biochemistry, VSCB, (d) virus-specific cellular receptor repertoire, VSCR, and (e) pH-mediated cell membrane transit, (↓_pHCMat). Assuming <b>As </b>and <b>Tt </b>to be independent variables, <b>IO = Tt/As</b>. The same forces acting in an opposing manner determine SB at the port of sfv entry (defined here by the <it>Index of Entry</it>, <b>IE = As/Tt</b>). Overall, If sfv encounters no unforeseen effects on transit between X<it>y </it>and <it>Hs</it>, then the square root of the combined index of sfv transmissibility (√<b>|RTI|) </b>is proportional to the product IO* IE (or ~Vm* Ha* ∑Tt*∑As*<b>Ω</b>), where <b>Ω </b>is the retrovirological constant and ∑ is a function of the ratio Tt/As or As/Tt for sfv transmission from <it>Xy </it>to <it>Hs</it>.</p> <p>Conclusions</p> <p>I present a mathematical formalism encapsulating the general theory of the origins of retroviruses. It summarizes the choreography for the intertwined interplay of factors influencing the probability of retroviral cross-species transmission: <b>Vm, Ha, Tt, As, </b>and <b>Ω</b>.</p

Signaling Signatures and Functional Properties of Anti-Human CD28 Superagonistic Antibodies

Superagonistic CD28 antibodies (CD28SAs) activate T lymphocytes without concomitant perturbation of the TCR/CD3-complex. In rodents these reagents induce the preferential expansion of regulatory T cells and can be used for the treatment of autoimmune diseases. Unexpectedly, the humanized CD28 superagonist TGN1412 caused severe and life threatening adverse effects during a recently conducted phase I clinical trail. The underlying molecular mechanisms are as yet unclear. We show that TGN1412 as well as the commercially available CD28 superagonist ANC28.1 induce a delayed but extremely sustained calcium response in human naïve and memory CD4+ T cells but not in cynomolgus T lymphocytes. The sustained Ca++-signal was associated with the activation of multiple intracellular signaling pathways and together these events culminated in the rapid de novo synthesis of high amounts of pro-inflammatory cytokines, most notably IFN-γ and TNF-α. Importantly, sustained transmembranous calcium flux, activation of Src-kinases as well as activation of PI3K were found to be absolutely required for CD28SA-mediated production of IFN-γ and IL-2. Collectively, our data suggest a molecular basis for the severe side effects caused by TGN1412 and impinge upon the relevance of non-human primates as preclinical models for reagents that are supposed to modify the function of human T cells

On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver

Iron is an essential component of the erythrocyte protein hemoglobin and is crucial to oxygen transport in vertebrates. In the steady state, erythrocyte production is in equilibrium with erythrocyte removal1. In various pathophysiological conditions, however, erythrocyte life span is severely compromised, which threatens the organism with anemia and iron toxicity2,3. Here we identify an on-demand mechanism that clears erythrocytes and recycles iron. We show that Ly-6Chigh monocytes ingest stressed and senescent erythrocytes, accumulate in the liver via coordinated chemotactic cues, and differentiate to ferroportin 1 (FPN1)-expressing macrophages that can deliver iron to hepatocytes. Monocyte-derived FPN1+ Tim-4neg macrophages are transient, reside alongside embryonically-derived Tim-4high Kupffer cells, and depend on Csf1 and Nrf2. The spleen likewise recruits iron-loaded Ly-6Chigh monocytes, but these do not differentiate into iron-recycling macrophages due to the suppressive action of Csf2. Inhibiting monocyte recruitment to the liver leads to kidney and liver damage. These observations identify the liver as the primary organ supporting rapid erythrocyte removal and iron recycling and uncover a mechanism by which the body adapts to fluctuations in erythrocyte integrity