Differential effects of radiation fractionation regimens on glioblastoma.

Background: Radiotherapy (RT) is a mainstay of treatment for patients with glioblastoma (GB). Early clinical trials show that short course hypofractionation showed no survival benefit compared to conventional regimens with or without temozolomide chemotherapy (TMZ) but reduces the number of doses required. Concerns around delayed neurological deficits and reduced cognition from short course hypofractionated RT remain a concern.

Are In Vitro Human Blood-Brain-Tumor-Barriers Suitable Replacements for In Vivo Models of Brain Permeability for Novel Therapeutics?

Background: High grade gliomas (HGG) are incapacitating and prematurely fatal diseases. To overcome the poor prognosis, novel therapies must overcome the selective and restricted permeability of the blood-brain barrier (BBB). This study critically evaluated whether in vitro human normal BBB and tumor BBB (BBTB) are suitable alternatives to "gold standard" in vivo models to determine brain permeability.

Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates.

Antibody-drug conjugates (ADCs) represent a new class of cancer therapeutics. Their design involves a tumor-specific antibody, a linker and a cytotoxic payload. They were designed to allow specific targeting of highly potent cytotoxic agents to tumor cells whilst sparing normal cells.

Herpes simplex virus type 2-infected dendritic cells produce TNF-α, which enhances CCR5 expression and stimulates HIV production from adjacent infected cells.

Prior HSV-2 infection enhances the acquisition of HIV-1 >3-fold. In genital herpes lesions, the superficial layers of stratified squamous epithelium are disrupted, allowing easier access of HIV-1 to Langerhans cells (LC) in the epidermis and perhaps even dendritic cells (DCs) in the outer dermis, as well as to lesion infiltrating activated T lymphocytes and macrophages. Therefore, we examined the effects of coinfection with HIV-1 and HSV-2 on monocyte-derived DCs (MDDC).

The microvesicle component of HIV-1 inocula modulates dendritic cell infection and maturation and enhances adhesion to and activation of T lymphocytes.

HIV-1 is taken up by immature monocyte derived dendritic cells (iMDDCs) into tetraspanin rich caves from which the virus can either be transferred to T lymphocytes or enter into endosomes resulting in degradation. HIV-1 binding and fusion with the DC membrane results in low level de novo infection that can also be transferred to T lymphocytes at a later stage. We have previously reported that HIV-1 can induce partial maturation of iMDDCs at both stages of trafficking.

HIV-1 infection of human macrophages directly induces viperin which inhibits viral production.

Macrophages are key target cells for HIV-1. HIV-1(BaL) induced a subset of interferon-stimulated genes in monocyte-derived macrophages (MDMs), which differed from that in monocyte-derived dendritic cells and CD4 T cells, without inducing any interferons. Inhibition of type I interferon induction was mediated by HIV-1 inhibition of interferon-regulated factor (IRF3) nuclear translocation.

Herpes simplex virus antigens directly activate NK cells via TLR2, thus facilitating their presentation to CD4 T lymphocytes.

NK cells infiltrate human herpetic lesions, but their role has been underexplored. HSV can stimulate innate immune responses via surface TLR2, which is expressed on monocyte-derived dendritic cells (DCs) and NK cells. In this study, UV-inactivated HSV1/2 and immunodominant HSV2 glycoprotein D peptides conjugated to the TLR2 agonist dipalmitoyl-S-glyceryl cysteine stimulated CD4 T lymphocyte IFN-γ responses within PBMCs or in coculture with monocyte-derived DCs.

HIV infection of dendritic cells subverts the IFN induction pathway via IRF-1 and inhibits type 1 IFN production.

Many viruses have developed mechanisms to evade the IFN response. Here, HIV-1 was shown to induce a distinct subset of IFN-stimulated genes (ISGs) in monocyte-derived dendritic cells (DCs), without detectable type I or II IFN. These ISGs all contained an IFN regulatory factor 1 (IRF-1) binding site in their promoters, and their expression was shown to be driven by IRF-1, indicating this subset was induced directly by viral infection by IRF-1.

Manipulation of dendritic cell function by viruses.

Viruses manipulate the function of dendritic cells (DCs) to enhance their entry, spread, survival and transmission. This review summarises recently published work identifying how viruses alter the expression of receptors, antiviral molecules, disrupt signalling pathways, subvert trafficking pathways and even affect DC function via interactions with second or third cell types. Different viruses such as human immunodeficiency virus (HIV) and herpes viruses may have widely divergent and even opposite effects on DC function, determined by the need for transfer to a primary target cell, replication within the DC or various immunoevasive mechanisms.

Human NK Cell Up-regulation of CD69, HLA-DR, Interferon γ Secretion and Cytotoxic Activity by Plasmacytoid Dendritic Cells is Regulated through Overlapping but Different Pathways.

Human plasmacytoid dendritic cells secrete high levels of IFNα and are thus implicated in the activation of NK cells. Activated NK cells are characterised by the up-regulation of CD69 and MHC class II DR expression, secretion of IFN γ and enhanced cytotoxicity. We show that pDC mediate these processes by different mechanisms, some of which overlap.

Role for plasmacytoid dendritic cells in the immune control of recurrent human herpes simplex virus infection.

Plasmacytoid dendritic cells (pDC) are an important component of the innate immune response, producing large amounts of alpha interferon in response to viral stimulation in vitro. Under noninflammatory conditions, pDC are not found in the skin and are restricted in location to the blood and lymph nodes. Therefore, their role in mucosal and cutaneous herpes simplex virus (HSV) infection has not been well-defined.

HIV interactions with dendritic cells: has our focus been too narrow?

Although few in number, dendritic cells (DCs) are heterogeneous, ubiquitous, and are crucial for protection against pathogens. In this review, the different DC subpopulations have been described and aspects of DC biology are discussed. DCs are important, not only in the pathogenesis of HIV, but also in the generation of anti-HIV immune responses.

Human BDCA-1-positive blood dendritic cells differentiate into phenotypically distinct immature and mature populations in the absence of exogenous maturational stimuli: differentiation failure in HIV infection.

Current immunological opinion holds that myeloid dendritic cell (mDC) precursors migrate from the blood to the tissues, where they differentiate into immature dermal- and Langerhans-type dendritic cells (DC). Tissue DC require appropriate signals from pathogens or inflammatory cytokines to mature and migrate to secondary lymphoid tissue. We show that purified blood mDC cultured in vitro with GM-CSF and IL-4, but in the absence of added exogenous maturation stimuli, rapidly differentiate into two maturational and phenotypically distinct populations.

Antigen presentation and the role of dendritic cells in HIV.

Purpose Of Review: As initiators of primary immune responses and one of the first cell types encountered and infected by HIV, the role of dendritic cells in retroviral infection has been the subject of intense scrutiny. We review recent publications regarding the effect of HIV-1 infection on the numbers and function of dendritic cells, as well as progress in the use of dendritic cells in immunotherapeutic protocols.

Recent Findings: The numbers of both plasmacytoid and myeloid dendritic cells in the blood are reduced during HIV-1 infection.

Dysfunction and infection of freshly isolated blood myeloid and plasmacytoid dendritic cells in patients infected with HIV-1.

Recently it has been shown that the 2 populations of blood dendritic cells (DCs), termed plasmacytoid (pcDCs) and myeloid (myDCs), are reduced in HIV-1 infection. This study aimed to determine whether these 2 populations are targets for HIV-1 infection and whether their ability to stimulate T-lymphocyte proliferation is affected. Highly purified populations of myDCs and pcDCs were isolated from the blood of antiretroviral treatment-naive patients and assessed for the level of HIV provirus by polymerase chain reaction (PCR).