Dual CD47 and PD-L1 blockade elicits anti-tumor immunity by intratumoral CD8 T cells.

Objectives: Bispecific antibodies targeting CD47 and PD-L1 (CD47 × PD-L1 BisAb) demonstrate efficacy against a range of solid cancers. While dual blockade negates anti-CD47-mediated toxicity, the effect of combined innate and adaptive immune activation on protective tumor-resident CD8 T cells has yet to be fully elucidated.

Methods: CD8 T cell populations were tracked upon CD47 × PD-L1 BisAb treatment in an orthotopic model of murine breast cancer where anti-tumor immunity is mediated by CD8 T cells.

A critical role for Macrophage-derived Cysteinyl-Leukotrienes in HIV-1 induced neuronal injury.

Macrophages (MΦ) infected with human immunodeficiency virus (HIV)-1 or activated by its envelope protein gp120 exert neurotoxicity. We found previously that signaling via p38 mitogen-activated protein kinase (p38 MAPK) is essential to the neurotoxicity of HIVgp120-stimulated MΦ. However, the associated downstream pathways remained elusive.

Lipocalin-2 mediates HIV-1 induced neuronal injury and behavioral deficits by overriding CCR5-dependent protection.

People living with HIV (PLWH) continue to develop HIV-associated neurocognitive disorders despite combination anti-retroviral therapy. Lipocalin-2 (LCN2) is an acute phase protein that has been implicated in neurodegeneration and is upregulated in a transgenic mouse model of HIV-associated brain injury. Here we show that LCN2 is significantly upregulated in neocortex of a subset of HIV-infected individuals with brain pathology and correlates with viral load in CSF and pro-viral DNA in neocortex.

Absence of HIF1A Leads to Glycogen Accumulation and an Inflammatory Response That Enables Pancreatic Tumor Growth.

Cancer cells respond to hypoxia by upregulating the hypoxia-inducible factor 1α (HIF1A) transcription factor, which drives survival mechanisms that include metabolic adaptation and induction of angiogenesis by VEGF. Pancreatic tumors are poorly vascularized and severely hypoxic. To study the angiogenic role of HIF1A, and specifically probe whether tumors are able to use alternative pathways in its absence, we created a xenograft mouse tumor model of pancreatic cancer lacking HIF1A.

Gut microbiota dependent anti-tumor immunity restricts melanoma growth in Rnf5 mice.

Accumulating evidence points to an important role for the gut microbiome in anti-tumor immunity. Here, we show that altered intestinal microbiota contributes to anti-tumor immunity, limiting tumor expansion. Mice lacking the ubiquitin ligase RNF5 exhibit attenuated activation of the unfolded protein response (UPR) components, which coincides with increased expression of inflammasome components, recruitment and activation of dendritic cells and reduced expression of antimicrobial peptides in intestinal epithelial cells.

Simultaneous Loss of Both Atypical Protein Kinase C Genes in the Intestinal Epithelium Drives Serrated Intestinal Cancer by Impairing Immunosurveillance.

Serrated adenocarcinoma, an alternative pathway for colorectal cancer (CRC) development, accounts for 15%-30% of all CRCs and is aggressive and treatment resistant. We show that the expression of atypical protein kinase C ζ (PKCζ) and PKCλ/ι was reduced in human serrated tumors. Simultaneous inactivation of the encoding genes in the mouse intestinal epithelium resulted in spontaneous serrated tumorigenesis that progressed to advanced cancer with a strongly reactive and immunosuppressive stroma.

Location, location, location: the impact of migratory heterogeneity on T cell function.

T cell migration is crucial for an effective adaptive immune response to invading pathogens. Naive and memory T cells encounter pathogen antigens, become activated, and differentiate into effector cells in secondary lymphoid tissues, and then migrate to the site(s) of infection where they exert effector activities that control and eliminate pathogens. To achieve activation, efficient effector function, and good memory formation, T cells must traffic between lymphoid and non-lymphoid tissues within the body.

Identification of small molecules that interfere with H1N1 influenza A viral replication.

Successful replication of the influenza A virus requires both viral proteins and host cellular factors. In this study we used a cellular assay to screen for small molecules capable of interfering with any of such necessary viral or cellular components. We used an established reporter assay to assess influenza viral replication by monitoring the activity of co-expressed luciferase.

Regulation of Antigen-Experienced T Cells: Lessons from the Quintessential Memory Marker CD44.

Despite the widespread use of the cell-surface receptor CD44 as a marker for antigen (Ag)-experienced, effector and memory T cells, surprisingly little is known regarding its function on these cells. The best-established function of CD44 is the regulation of cell adhesion and migration. As such, the interactions of CD44, primarily with its major ligand, the extracellular matrix (ECM) component hyaluronic acid (HA), can be crucial for the recruitment and function of effector and memory T cells into/within inflamed tissues.

Matrix metalloprotease 9 mediates neutrophil migration into the airways in response to influenza virus-induced toll-like receptor signaling.

The early inflammatory response to influenza virus infection contributes to severe lung disease and continues to pose a serious threat to human health. The mechanisms by which neutrophils gain entry to the respiratory tract and their role during pathogenesis remain unclear. Here, we report that neutrophils significantly contributed to morbidity in a pathological mouse model of influenza virus infection.

Harnessing memory adaptive regulatory T cells to control autoimmunity in type 1 diabetes.

Type 1 diabetes (T1D) results from autoimmune destruction of insulin-producing β-cells in the pancreatic islets. There is an immediate need to restore both β-cell function and immune tolerance to control disease progression and ultimately cure T1D. Currently, there is no effective treatment strategy to restore glucose regulation in patients with T1D.

Multifaceted regulation of T cells by CD44.

CD44 is a widely-expressed adhesion receptor that is associated with diverse biological processes involving migrating cells, including inflammation, angiogenesis, bone metabolism and wound healing. In the immune system, CD44 is upregulated after activation of naive T lymphocytes during their responses against invading microbes. Once an infection is cleared, elevated levels of CD44 remain on the surface of memory T cells that mediate protection against re-infection.

Nasal mucosal administration of chitin microparticles boosts innate immunity against influenza A virus in the local pulmonary tissue.

Influenza virus infection remains a major health concern due to morbidity and mortality associated with epidemics and occasional pandemics. The absence of acquired immunity to antigenically distinct, emerging virus strains stresses the need for a generic drug that protects independent of vaccination. Here, we demonstrate that prophylactic administration of chitin microparticles (CMP) via the intranasal route significantly reduced lung viral titres and clinical signs.

CD44 regulates survival and memory development in Th1 cells.

Optimal immunity to microorganisms depends upon the regulated death of clonally expanded effector cells and the survival of a cohort of cells that become memory cells. After activation of naive T cells, CD44, a widely expressed receptor for extracellular matrix components, is upregulated. High expression of CD44 remains on memory cells and despite its wide usage as a "memory marker," its function is unknown.

Early replication in pulmonary B cells after infection with Marek's disease herpesvirus by the respiratory route.

Abstract Natural infection with Marek's disease virus occurs through the respiratory mucosa after chickens inhale dander shed from infected chickens. The early events in the lung following exposure to the feather and squamous epithelial cell debris containing the viral particles remain unclear. In order to elucidate the virological and immunological consequences of MDV infection for the respiratory tract, chickens were infected by intratracheal administration of infective dander.

Polyclonal adaptive regulatory CD4 cells that can reverse type I diabetes become oligoclonal long-term protective memory cells.

Type 1 diabetes is a CD4 cell-dependent disease that results from destruction of insulin-producing beta cells in pancreatic islets. An ideal therapy would reverse diabetes shortly after onset when islet function in not yet fully ablated, and also prevent re-emergence of disease through the generation of memory cells that control the autoimmune response. In this study, we show that adaptive/induced polyclonal regulatory (TR) cells, which contain islet-reactive cells, fulfill these criteria in the NOD mouse model.

Route of challenge is critical in determining the clinical outcome of infection with a very virulent oncogenic herpesvirus, Marek's disease virus.

The majority of experimental studies examining Marek's disease virus infection have used parenteral injection of cell-associated virus. The aim of this study was to examine whether the route of entry of virus was critical in determining the outcome of infection. Susceptible (L7) and resistant (L6) White Leghorn chickens were infected with a very virulent Marek's disease virus, RB1B, by either the intra-abdominal or intra-tracheal route.

Intranasal immunisation with inactivated RSV and bacterial adjuvants induces mucosal protection and abrogates eosinophilia upon challenge.

We have previously shown that following intranasal exposure to influenza virus, specific plasma cells are generated in the nasal-associated lymphoid tissue (NALT) and maintained for the life of the animal. However, we also showed that following infection with respiratory syncytial virus (RSV), specific plasma cells are generated in the NALT but wane quickly and are not maintained even after challenge, even though RSV-specific serum antibody responses remain robust. Only infection with influenza virus generated sterilising immunity, implying a role for these long-lived plasma cells in protection.

Bone marrow immunosuppression in Salmonella-infected mice is prolonged following influenza virus infection.

Objective: It has been shown previously that infection with diverse viruses induces alterations in bone marrow lineage-specific progenitor cells. As complications arising from secondary bacterial infections can adversely affect the host, we investigated whether virally induced hematological alterations could contribute to the enhanced illness observed in such cases.

Materials And Methods: Mice were infected with influenza virus alone or influenza virus followed by a vaccine strain of Salmonella typhimurium.

Marek's disease is a natural model for lymphomas overexpressing Hodgkin's disease antigen (CD30).

Animal models are essential for elucidating the molecular mechanisms of carcinogenesis. Hodgkin's and many diverse non-Hodgkin's lymphomas overexpress the Hodgkin's disease antigen CD30 (CD30(hi)), a tumor necrosis factor receptor II family member. Here we show that chicken Marek's disease (MD) lymphoma cells are also CD30(hi) and are a unique natural model for CD30(hi) lymphoma.

Study of host-pathogen interactions to identify sustainable vaccine strategies to Marek's disease.

Marek's disease virus is a highly cell-associated, lymphotropic alpha-herpesvirus that causes paralysis and neoplastic disease in chickens. The disease has been contained by vaccination with attenuated viruses and provides the first evidence for a malignant cancer being controlled by an antiviral vaccine. Marek's disease pathogenesis is complex, involving cytolytic and latent infection of lymphoid cells and oncogenic transformation of CD4+ T cells in susceptible chickens.

Protection from infectious bursal disease virus (IBDV)-induced immunosuppression by immunization with a fowlpox recombinant containing IBDV-VP2.

Immunosuppression resulting from infectious bursal disease virus (IBDV) infection has critical health and welfare implications for birds, yet it is incompletely understood and largely overlooked as a measure of vaccine efficacy. The ability of a fowlpoxvirus recombinant (fpIBD1) containing the VP2 protein of IBDV to protect against IBDV-induced immunosuppression was investigated by measuring the convalescent chicken's ability to mount antibody responses to IBDV infection, and to inactivated IBDV and salmonella vaccines. An immunoglobulin (Ig)M response, but no IgG response, occurred after IBDV infection.

Intravenous treatment with liposome-encapsulated dichloromethylene bisphosphonate (Cl2MBP) suppresses nitric oxide production and reduces genetic resistance to Marek's disease.

In this study the functional effectiveness of in vivo macrophage depletion using liposome-encapsulated dichloromethylene bisphosphonate (Cl(2)MBP) was examined in the chicken. The main target organs for systemic liposome-encapsulated Cl(2)MBP treatment are the spleen and the liver. Intravenous treatment with Cl(2)MBP of B(21)/B(21) chickens, genetically resistant to Marek's disease (MD), before challenge with the very virulent strain RB-1B, increased viral load in the blood and spleen after the first week and up to 6 weeks post-infection.