High-affinity T cell receptor ImmTAC® bispecific efficiently redirects T cells to kill tumor cells expressing the cancer-testis antigen PRAME.

Background: PRAME (eferentially expressed ntigen in lanoma) is a cancer-testis antigen expressed in several tumor indications, representing an attractive anticancer target. However, its intracellular location limits targeting by traditional methods. PRAME peptides are presented on the surface of tumor cells by human leukocyte antigen (HLA) molecules, indicating that a T cell receptor (TCR)-based strategy that redirects T cells to kill PRAME tumors could be a novel immunotherapeutic option.

Tebentafusp Induces a T-Cell-Driven Rash in Melanocyte-Bearing Skin as an Adverse Event Consistent with the Mechanism of Action.

Tebentafusp is a gp100xCD3-bispecific ImmTAC designed to redirect polyclonal T cells against cells presenting the melanocyte lineage-specific antigen gp100 on HLA-A∗02:01. Skin-related adverse events, predominantly rash, are frequent and occur within a few hours after initial infusions; yet, the mechanisms are unknown. In this study, we analyzed clinical data from the randomized phase 3 trial (NCT03070392) of tebentafusp (n = 252) versus investigator's choice (n = 126).

Vaccination of Macaques with DNA Followed by Adenoviral Vectors Encoding Simian Immunodeficiency Virus (SIV) Gag Alone Delays Infection by Repeated Mucosal Challenge with SIV.

Vaccines aimed at inducing T cell responses to protect against human immunodeficiency virus (HIV) infection have been under development for more than 15 years. Replication-defective adenovirus (rAd) vaccine vectors are at the forefront of this work and have been tested extensively in the simian immunodeficiency virus (SIV) challenge macaque model. Vaccination with rAd vectors coding for SIV Gag or other nonenvelope proteins induces T cell responses that control virus load but disappointingly is unsuccessful so far in preventing infection, and attention has turned to inducing antibodies to the envelope.

Changes in T Cell and Dendritic Cell Phenotype from Mid to Late Pregnancy Are Indicative of a Shift from Immune Tolerance to Immune Activation.

During pregnancy, the mother allows the immunologically distinct fetoplacental unit to develop and grow. Opinions are divided as to whether this represents a state of fetal-specific tolerance or of a generalized suppression of the maternal immune system. We hypothesized that antigen-specific T cell responses are modulated by an inhibitory T cell phenotype and modified dendritic cell (DC) phenotype in a gestation-dependent manner.

M1-like monocytes are a major immunological determinant of severity in previously healthy adults with life-threatening influenza.

In each influenza season, a distinct group of young, otherwise healthy individuals with no risk factors succumbs to life-threatening infection. To better understand the cause for this, we analyzed a broad range of immune responses in blood from a unique cohort of patients, comprising previously healthy individuals hospitalized with and without respiratory failure during one influenza season, and infected with one specific influenza A strain. This analysis was compared with similarly hospitalized influenza patients with known risk factors (total of = 60 patients recruited).

Micheliolide provides protection of mice against Staphylococcus aureus and MRSA infection by down-regulating inflammatory response.

A major obstacle to therapy in intensive care units is sepsis caused by severe infection. In recent years gram-positive (G) bacteria, most commonly staphylococci, are thought to be the main pathogens. Micheliolide (MCL) was demonstrated to provide a therapeutic role in rheumatoid arthritis, inflammatory intestinal disease, colitis-associated cancer, and lipopolysaccharide (LPS, the main component of G bacterial cell wall) induced septic shock.

Restriction by SAMHD1 Limits cGAS/STING-Dependent Innate and Adaptive Immune Responses to HIV-1.

SAMHD1 is a restriction factor for HIV-1 infection. SAMHD1 mutations cause the autoinflammatory Aicardi-Goutières syndrome that is characterized by chronic type I interferon (IFN) secretion. We show that the spontaneous IFN response in SAMHD1-deficient cells and mice requires the cGAS/STING cytosolic DNA-sensing pathway.

Human blood CD1c dendritic cells stimulate IL-12-independent IFN- responses and have a strikingly low inflammatory profile.

Adaptive immune responses are initiated by resident myeloid tissue DC. A major fraction of tissue DC express CD1c and is thought to be derived from blood CD1c DC, an idea supported here by the observation that they express tissue-homing molecules and rapidly differentiate into cells with a tissue DC phenotype. Responses are thought to be augmented/modulated further by inflammatory moDC.

Fusion of ubiquitin to HIV gag impairs human monocyte-derived dendritic cell maturation and reduces ability to induce gag T cell responses.

The efficient induction of CD8 T cell immunity is dependent on the processing and presentation of antigen on MHC class I molecules by professional antigen presenting cells (APC). To develop an improved T cell vaccine for HIV we investigated whether fusing the ubiquitin gene to the N terminus of the HIV gag gene enhanced targeting to the proteasome resulting in better CD8 T cell responses. Human monocyte derived dendritic cells (moDC), transduced with adenovirus vectors carrying either ubiquitinated or non-ubiquitinated gag transgene constructs, were co-cultured with autologous naïve T cells and T cell responses were measured after several weekly cycles of stimulation.

Increased activity of extrinsic and intrinsic apoptosis pathways in different mononuclear cell types in HIV type 1-infected patients regardless of whether they are depleted in disease.

Myeloid dendritic cells (mDCs) are essential for initiation of adaptive immune responses but are depleted in HIV infection. Evidence suggests that apoptosis mediates loss, and to further understand the pathways involved, expression of caspases mediating apoptosis via the extrinsic and intrinsic pathways was analyzed. Blood samples were obtained from 14 HIV-infected patients (nine HAART and five antiretroviral naive) and 10 healthy controls.

Fragmentation of SIV-gag vaccine induces broader T cell responses.

Background: High mutation rates of human immunodeficiency virus (HIV) allows escape from T cell recognition preventing development of effective T cell vaccines. Vaccines that induce diverse T cell immune responses would help overcome this problem. Using SIV gag as a model vaccine, we investigated two approaches to increase the breadth of the CD8 T cell response.

HIV-1 infection and induction of interferon alpha in plasmacytoid dendritic cells.

Purpose Of Review: Loss of blood plasmacytoid dendritic cell (pDC) in HIV-1 infection is thought to impact on adaptive immune responses whilst the virus also induces aberrant interferon alpha (IFN-α) production that may fuel chronic immune activation and drive disease progression. Recent attention has focussed on the pathway of HIV-induced IFN-α production by pDC and the new data are reviewed here together with the pathway leading to infection.

Recent Findings: Attachment to CD4 and chemokine co-receptors is essential for HIV-1 infection.

Loss of NK stimulatory capacity by plasmacytoid and monocyte-derived DC but not myeloid DC in HIV-1 infected patients.

Dendritic cells (DC) are potent inducers of natural killer (NK) cells. There are two distinct populations in blood, myeloid (mDC) and plasmacytoid (pDC) but they can also be generated In vitro from monocytes (mdDC). Although it is established that blood DC are lost in HIV-1 infection, the full impact of HIV-1 infection on DC-NK cell interactions remains elusive.

Adenovirus vector vaccination induces expansion of memory CD4 T cells with a mucosal homing phenotype that are readily susceptible to HIV-1.

In the recently halted HIV type 1 (HIV-1) vaccine STEP trial, individuals that were seropositive for adenovirus serotype 5 (Ad5) showed increased rates of HIV-1 infection on vaccination with an Ad5 vaccine. We propose that this was due to activation and expansion of Ad5-specific mucosal-homing memory CD4 T cells. To test this hypothesis, Ad5 and Ad11 antibody titers were measured in 20 healthy volunteers.

Monocyte-derived dendritic cells from HIV type 1-infected individuals show reduced ability to stimulate T cells and have altered production of interleukin (IL)-12 and IL-10.

Monocyte-derived dendritic cells (MDDCs) have been used in therapeutic vaccination for cancer. A small number of studies have employed a similar approach to vaccinate human immunodeficiency virus (HIV)-infected individuals. We have thus analyzed the functional properties of MDDCs generated from HIV-infected individuals who either are receiving highly active antiretroviral therapy or are therapy naive.

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.

Use of adenovirus in vaccines for HIV.

The best hope of controlling the HIV pandemic is the development of an effective vaccine. In addition to the stimulation of virus neutralising antibodies, a vaccine will need an effective T-cell response against the virus. Vaccines based on recombinant adenoviruses (rAd) are promising candidates to stimulate anti-HIV T-cell responses.

Human Langerhans' cells and dermal-type dendritic cells generated from CD34 stem cells express different toll-like receptors and secrete different cytokines in response to toll-like receptor ligands.

Langerhans' cells (LC) and dermal dendritic cells (dDC) are located in the superficial and deeper layers of the skin respectively and represent the main dendritic cell (DC) populations of the skin. LC-like and dDC-like DC can be generated from CD34 stem cells and this system is widely used as a model for investigating these cells and in therapeutic vaccination. Here we report toll-like receptor (TLR) expression in human LC and dDC derived from CD34 stem cells.

Langerhans cells are more efficiently transduced than dermal dendritic cells by adenovirus vectors expressing either group C or group B fibre protein: implications for mucosal vaccines.

Vaccines against viruses need to target dendritic cells (DC) and stimulate mucosal immunity. Most vaccine studies have focussed on monocyte-derived or dermal DC (dDC) but recent evidence suggests that Langerhans cells (LC) may stimulate mucosal immunity more effectively. New chimeric adenovirus vectors expressing fibre protein from group B adenoviruses (rAd5/11), which utilise CD46 rather than the Coxsackie adenovirus receptor (CAR), have been developed as vaccines to improve transduction and overcome problems of pre-existing vector immunity.

Natural killer cells are not infected by Kaposi's sarcoma-associated herpesvirus in vivo, and natural killer cell counts do not correlate with the risk of developing Kaposi's sarcoma.

Although the innate immune system is implicated in the control of Kaposi's sarcoma (KS), the risk of developing KS is not associated with the nadir natural killer (NK) cell count, and NK cell counts do not significantly increase or decrease during KS resolution. KS-associated herpesvirus replication was not demonstrated in vivo or in vitro within NK cells, suggesting that NK cells do not contribute to the resolution of KS. Their role appears limited to events occurring during early infection.