A Paradigm of Translational Medicine

Antimicrobial peptides (AMPs) are small, cationic, amphiphilic peptides with broad-spectrum microbicidal activity against both bacteria and fungi. In mammals, AMPs form the first line of host defense against infections and generally play an important role as effector agents of the innate immune system. The AMP era was born more than 6 decades ago when the first cationic cyclic peptide antibiotics, namely polymyxins and tyrothricin, found their way into clinical use. Due to the good clinical experience in the treatment of, for example, infections of mucus membranes as well as the subsequent understanding of mode of action, AMPs are now considered for treatment of inflammatory skin diseases and for improving healing of infected wounds. Based on the preclinical findings, including pathobiochemistry and molecular medicine, targeted therapy strategies are developed and first results indicate that AMPs influence processes of diseased skin. Importantly, in contrast to other antibiotics, AMPs do not seem to propagate the development of antibiotic-resistant micro-organisms. Therefore, AMPs should be tested in clinical trials for their efficacy and tolerability in inflammatory skin diseases and chronic wounds. Apart from possible fields of application, these peptides appear suited as an example of the paradigm of translational medicine for skin diseases which is today seen as a ‘two-way road’ – from bench to bedside and backwards from bedside to bench

Magnetic and Structural Studies of the Quasi-Two-Dimensional Spin-Gap System (CuCl)LaNb2O7

We report magnetization, nuclear magnetic resonance (NMR), nuclear quadrupole resonance (NQR), and transmission electron microscopy (TEM) studies on the quasi-two-dimensional spin-gap system (CuCl)LaNb2O7, a possible candidate for the J1-J2 model on a square lattice. A sharp single NQR line is observed at the Cu and Cl sites, indicating that both Cu and Cl atoms occupy a unique site. However, the electric field gradient tensors at the Cu, Cl, and La sites do not have axial symmetry. This is incompatible with the reported crystal structure. Thus the J1-J2 model has to be modified. We propose alternative two-dimensional dimer models based on the NMR, NQR, and TEM results. The value of the hyperfine coupling constant at the Cu sites indicates that the spin density is mainly on the d(3z2-r2) orbital (z parallel c). At 1.5 K, Cu- and Nb-NMR signals disappear above the critical field Bc1 = 10.3 T determined from the onset of the magnetization, indicating a field-induced magnetic phase transition at Bc1.Comment: 9 pages, 16 figure

P16-48. Immunologic and virologic characterization of an ART-treated HIV-1 patients cohort with long-term control of viremia

Background Long-term treatment of primary HIV-1 infection (PHI) may allow the immune reconstitution of responses lost during the acute viremic phase and decrease of peripheral reservoirs. This in turn may represent the best setting for the use of therapeutic vaccines in order to lower the viral set-point or control of viral rebound upon ART discontinuation. Methods We investigated a cohort of 16 patients who started ART at PHI, with treatment duration of ≥4 years and persistent aviremia (<50 HIV-1 copies/ml). The cohort was characterized in terms of viral subtype, cell-associated RNA, proviral DNA and HLA genotype. Secretion of IFN-γ, IL-2 and TNF-α by CD8 T-cells was analysed by polychromatic flowcytometry using a panel of 192 HIV-1-derived epitopes. Results This cohort is highly homogenous in terms of viral subtype: 81% clade B. We identified 44 epitope-specific responses: all patients had detectable responses to >1 epitope and the mean number of responding epitopes per patient was 3. The mean frequency of cytokines-secreting CD8 T-cells was 0.32%. CD8 T-cells secreting simultaneously IFN-γ, IL-2 and TNF-α made up for about 40% of the response and cells secreting at least 2 cytokines for about 80%, consistent with a highly polyfunctional CD8 T-cell profile. There was no difference in term of polyfunctionality when HLA restriction, or recognized viral regions and epitopes were considered. Proviral DNA was detectable in all patients but at low levels (mean = 108 copies/1 million PBMCs) while cell-associated mRNA was not detectable in 19% of patients (mean = 11 copies/1 million PBMCs when detectable). Conclusion Patients with sustained virological suppression after initiation of ART at PHI show polyfunctional CD8 T-cell and low levels of proviral DNA with an absence of residual replication in a substantial percentage of patients. The use of therapeutic vaccines in this population may promote low level of rebound viremia or control of viral replication upon ART cessation

The transcriptional coactivator Bob1 promotes the development of follicular T helper cells via Bcl6

Follicular T helper (Tfh) cells are key regulators of the germinal center reaction and long-term humoral immunity. Tfh cell differentiation requires the sustained expression of the transcriptional repressor Bcl6; however, its regulation in CD4(+) T cells is incompletely understood. Here, we report that the transcriptional coactivator Bob1, encoded by the Pou2af1 gene, promotes Bcl6 expression and Tfh cell development. We found that Bob1 together with the octamer transcription factors Oct1/Oct2 can directly bind to and transactivate the Bcl6 and Btla promoters. Mixed bone marrow chimeras revealed that Bob1 is required for the expression of normal levels of Bcl6 and BTLA, thereby controlling the pool size and composition of the Tfh compartment in a T cell-intrinsic manner. Our data indicate that T cell-expressed Bob1 is directly involved in Tfh cell differentiation and required for mounting normal T cell-dependent B-cell responses

Transitional B cell cytokines predict renal allograft outcomes

Early immunological biomarkers that predict rejection and chronic allograft loss are needed to inform preemptive therapy and improve long-term outcomes. Here, we prospectively examined the ratio of interleukin-10 (IL-10) to tumor necrosis factor–α (TNFα) produced by transitional-1 B cells (T1B) 3 months after transplantation as a predictive biomarker for clinical and subclinical renal allograft rejection and subsequent clinical course. In both Training (n = 162) and Internal Validation (n = 82) Sets, the T1B IL-10/TNFα ratio 3 months after transplantation predicted both clinical and subclinical rejection anytime in the first year. The biomarker also predicted subsequent late rejection with a lead time averaging 8 months. Among biomarker high-risk patients, 60% had early rejection, of which 48% recurred later in the first posttransplant year. Among high-risk patients without early rejection, 74% developed rejection later in the first year. In contrast, only 5% of low-risk patients had early and 5% late rejection. The biomarker also predicted rejection in an External Validation Set (n = 95) and in key patient subgroups, confirming generalizability. Biomarker high-risk patients exhibited progressively worse renal function and decreased 5-year graft survival compared to low-risk patients. Treatment of B cells with anti-TNFα in vitro augmented the IL-10/TNFα ratio, restored regulatory activity, and inhibited plasmablast differentiation. To conclude, the T1B IL-10/TNFα ratio was validated as a strong predictive biomarker of renal allograft outcomes and provides a rationale for preemptive therapeutic intervention with TNF blockade

CD27 is required for protective lytic EBV antigen-specific CD8+ T-cell expansion

Primary immunodeficiencies in the costimulatory molecule CD27 and its ligand, CD70, predispose for pathologies of uncontrolled Epstein-Barr virus (EBV) infection in nearly all affected patients. We demonstrate that both depletion of CD27+ cells and antibody blocking of CD27 interaction with CD70 cause uncontrolled EBV infection in mice with reconstituted human immune system components. While overall CD8+ T-cell expansion and composition are unaltered after antibody blocking of CD27, only some EBV-specific CD8+ T-cell responses, exemplified by early lytic EBV antigen BMLF1-specific CD8+ T cells, are inhibited in their proliferation and killing of EBV-transformed B cells. This suggests that CD27 is not required for all CD8+ T-cell expansions and cytotoxicity but is required for a subset of CD8+ T-cell responses that protect us from EBV pathology

CD8(+) T cells retain protective functions despite sustained inhibitory receptor expression during Epstein-Barr virus infection in vivo

Epstein Barr virus (EBV) is one of the most ubiquitous human pathogens in the world, persistently infecting more than 90% of the adult human population. It drives some of the strongest human CD8+ T cell responses, which can be observed during symptomatic primary infection known as infectious mononucleosis (IM). Despite high viral loads and prolonged CD8+ T cell stimulation during IM, EBV enters latency and is under lifelong immune control in most individuals that experience this disease. We investigated whether changes in T cell function, as frequently characterized by PD-1 up-regulation, occur during IM due to the prolonged exposure to high antigen levels. We readily detected the expansion of PD-1 positive CD8+ T cells together with high frequencies of Tim-3, 2B4, and KLRG1 expression during IM and in mice with reconstituted human immune system components (huNSG mice) that had been infected with a high dose of EBV. These PD-1 positive CD8+ T cells, however, retained proliferation, cytokine production, and cytotoxic abilities. Multiple subsets of CD8+ T cells expanded during EBV infection, including PD-1+ Tim-3+ KLRG1+ cells that express CXCR5 and TCF-1 germinal center homing and memory markers, and may also contain BATF3. Moreover, blocking the PD-1 axis compromised EBV specific immune control and resulted in virus-associated lymphomagenesis. Finally, PD-1+ , Tim-3+ , and KLRG1+ CD8+ T cell expansion coincided with declining viral loads during low dose EBV infection. These findings suggest that EBV infection primes PD-1 positive CD8+ T cell populations that rely on this receptor axis for the efficient immune control of this ubiquitous human tumor virus

Sexual Size Dimorphism and Body Condition in the Australasian Gannet

Funding: The research was financially supported by the Holsworth Wildlife Research Endowment. Acknowledgments We thank the Victorian Marine Science Consortium, Sea All Dolphin Swim, Parks Victoria, and the Point Danger Management Committee for logistical support. We are grateful for the assistance of the many field volunteers involved in the study.Peer reviewedPublisher PD

Targeting human Acyl-CoA:cholesterol acyltransferase as a dual viral and T cell metabolic checkpoint

Determining divergent metabolic requirements of T cells, and the viruses and tumours they fail to combat, could provide new therapeutic checkpoints. Inhibition of acyl-CoA:cholesterol acyltransferase (ACAT) has direct anti-carcinogenic activity. Here, we show that ACAT inhibition has antiviral activity against hepatitis B (HBV), as well as boosting protective anti-HBV and anti-hepatocellular carcinoma (HCC) T cells. ACAT inhibition reduces CD8+ T cell neutral lipid droplets and promotes lipid microdomains, enhancing TCR signalling and TCR-independent bioenergetics. Dysfunctional HBV- and HCC-specific T cells are rescued by ACAT inhibitors directly ex vivo from human liver and tumour tissue respectively, including tissue-resident responses. ACAT inhibition enhances in vitro responsiveness of HBV-specific CD8+ T cells to PD-1 blockade and increases the functional avidity of TCR-gene-modified T cells. Finally, ACAT regulates HBV particle genesis in vitro, with inhibitors reducing both virions and subviral particles. Thus, ACAT inhibition provides a paradigm of a metabolic checkpoint able to constrain tumours and viruses but rescue exhausted T cells, rendering it an attractive therapeutic target for the functional cure of HBV and HBV-related HCC