Molecular pathways of senescence regulate placental structure and function.

The placenta is an autonomous organ that maintains fetal growth and development. Its multinucleated syncytiotrophoblast layer, providing fetal nourishment during gestation, exhibits characteristics of cellular senescence. We show that in human placentas from pregnancies with intrauterine growth restriction, these characteristics are decreased.

Impaired immune surveillance accelerates accumulation of senescent cells and aging.

Cellular senescence is a stress response that imposes stable cell-cycle arrest in damaged cells, preventing their propagation in tissues. However, senescent cells accumulate in tissues in advanced age, where they might promote tissue degeneration and malignant transformation. The extent of immune-system involvement in regulating age-related accumulation of senescent cells, and its consequences, are unknown.

p53 in Bronchial Club Cells Facilitates Chronic Lung Inflammation by Promoting Senescence.

The tumor suppressor p53 limits tumorigenesis by inducing apoptosis, cell cycle arrest, and senescence. Although p53 is known to limit inflammation during tumor development, its role in regulating chronic lung inflammation is less well understood. To elucidate the function of airway epithelial p53 in such inflammation, we subjected genetically modified mice, whose bronchial epithelial club cells lack p53, to repetitive inhalations of lipopolysaccharide (LPS), an exposure that leads to severe chronic bronchitis and airway senescence in wild-type mice.

p21 maintains senescent cell viability under persistent DNA damage response by restraining JNK and caspase signaling.

Cellular senescence is a permanent state of cell cycle arrest that protects the organism from tumorigenesis and regulates tissue integrity upon damage and during tissue remodeling. However, accumulation of senescent cells in tissues during aging contributes to age-related pathologies. A deeper understanding of the mechanisms regulating the viability of senescent cells is therefore required.

Quantitative identification of senescent cells in aging and disease.

Senescent cells are present in premalignant lesions and sites of tissue damage and accumulate in tissues with age. In vivo identification, quantification and characterization of senescent cells are challenging tasks that limit our understanding of the role of senescent cells in diseases and aging. Here, we present a new way to precisely quantify and identify senescent cells in tissues on a single-cell basis.

Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL.

Senescent cells, formed in response to physiological and oncogenic stresses, facilitate protection from tumourigenesis and aid in tissue repair. However, accumulation of such cells in tissues contributes to age-related pathologies. Resistance of senescent cells to apoptotic stimuli may contribute to their accumulation, yet the molecular mechanisms allowing their prolonged viability are poorly characterized.

NKG2D ligands mediate immunosurveillance of senescent cells.

Cellular senescence is a stress response mechanism that limits tumorigenesis and tissue damage. Induction of cellular senescence commonly coincides with an immunogenic phenotype that promotes self-elimination by components of the immune system, thereby facilitating tumor suppression and limiting excess fibrosis during wound repair. The mechanisms by which senescent cells regulate their immune surveillance are not completely understood.

mRNA-transfected Dendritic Cells Expressing Polypeptides That Link MHC-I Presentation to Constitutive TLR4 Activation Confer Tumor Immunity.

Recently, we have developed a novel genetic platform for improving dendritic cell (DC) induction of peptide-specific CD8 T cells, based on membrane-anchored β2-microglobulin (β2m) linked to a selected antigenic peptide at its N-terminus and to the cytosolic domain of toll-like receptor (TLR)4 C-terminally. In vitro transcribed mRNA transfection of antigen presenting cells resulted in polypeptides that efficiently coupled peptide presentation to cellular activation. In the present study, we evaluated the immunogenicity of such constructs in mRNA-transfected immature murine bone marrow-derived DCs.

Cryoimmunotherapy with local co-administration of ex vivo generated dendritic cells and CpG-ODN immune adjuvant, elicits a specific antitumor immunity.

Cryoablation is a low-invasive surgical procedure for management of malignant tumors. Tissue destruction is obtained by repeated deep freezing and thawing and results in coagulative necrosis and in apoptosis. This procedure induces the release of tumor-associated antigens and proinflammatory factors into the microenvironment.

Amelioration of brain pathology and behavioral dysfunction in mice with lupus following treatment with a tolerogenic peptide.

Objective: Central nervous system (CNS) involvement in systemic lupus erythematosus (SLE) is manifested by neurologic deficits and psychiatric disorders. The aim of this study was to examine SLE-associated CNS pathology in lupus-prone (NZBxNZW)F1 (NZB/NZW) mice, and to evaluate the ameliorating effects of treatment with a tolerogenic peptide, hCDR1 (human first complementarity-determining region), on these manifestations.

Methods: Histopathologic analyses of brains from lupus-prone NZB/NZW mice treated with vehicle, hCDR1, or a control scrambled peptide were performed.

A systems immunology approach to the host-tumor interaction: large-scale patterns of natural autoantibodies distinguish healthy and tumor-bearing mice.

Traditionally, immunology has considered a meaningful antibody response to be marked by large amounts of high-affinity antibodies reactive with the specific inciting antigen; the detection of small amounts of low-affinity antibodies binding to seemingly unrelated antigens has been considered to be beneath the threshold of immunological meaning. A systems-biology approach to immunology, however, suggests that large-scale patterns in the antibody repertoire might also reflect the functional state of the immune system. To investigate such global patterns of antibodies, we have used an antigen-microarray device combined with informatic analysis.

Exuberated numbers of tumor-specific T cells result in tumor escape.

Cytotoxic T cells (CTL) play a major role in tumor rejection. Expansion of CTLs, either by immunization or adoptive transfer, is a prominent goal in current immunotherapy. The antigen-specific nature of these expansion processes inevitably initiates a clonotypic attack on the tumor.

Preventive and therapeutic vaccination with PAP-3, a novel human prostate cancer peptide, inhibits carcinoma development in HLA transgenic mice.

Conventional treatment of recurrent and metastasized prostate cancer (CaP) remains inadequate; this fact mandates development of alternative therapeutic modalities, such as specific active or passive immunotherapy. Previously, we reported the identification of a novel highly immunogenic HLA-A*0201-restricted Prostatic Acid Phosphatase-derived peptide (PAP-3) by a two-step in vivo screening in an HLA-transgenic (HHD) mouse system. In the present study we aimed at elucidating the efficiency of PAP-3-based vaccine upon active antitumor immunization.

Human CTL epitopes prostatic acid phosphatase-3 and six-transmembrane epithelial antigen of prostate-3 as candidates for prostate cancer immunotherapy.

Specific immunotherapy of prostate cancer may be an alternative or be complementary to other approaches for treatment of recurrent or metastasized disease. This study aims at identifying and characterizing prostate cancer-associated peptides capable of eliciting specific CTL responses in vivo. Evaluation of peptide-induced CTL activity in vitro was done following immunization of HLA-A2 transgenic (HHD) mice.

Combined dendritic cell cryotherapy of tumor induces systemic antimetastatic immunity.

Purpose: Cryotherapy of localized prostate, renal, and hepatic primary tumors and metastases is considered a minimally invasive treatment demonstrating a low complication rate in comparison with conventional surgery. The main drawback of cryotherapy is that it has no systemic effect on distant metastases. We investigated whether intratumoral injections of dendritic cells following cryotherapy of local tumors (cryoimmunotherapy) provides an improved approach to cancer treatment, combining local tumor destruction and systemic anticancer immunity.

Expression of FasL by tumor cells does not abrogate anti-tumor CTL function.

The effects of Fas-ligand (FasL) expression by tumor cells on their tumorigenicity and immunogenicity have been reported as opposite, contradictory results. In some systems the killing of Fas positive cytotoxic T-cells (CTL) by FasL expressing tumors resulted in increased tumorigenicity while in other systems tumors expressing FasL were eliminated by neutrophil mediated inflammation. In the present study, we investigated how FasL expression influences the low immunogenic Lewis lung carcinoma clone D122 and its highly immunogenic MHC I (H-2Kb) and B7-1 (CD80) transfectant 39.

In vivo rejection of tumor cells dependent on CD8 cells that kill independently of perforin and FasL.

Perforin/granzyme B- and Fas/FasL-mediated killing pathways are the main effector mechanisms of CTL and NK cells in antitumor immune responses. In this study, we investigated the relative role of these two lytic mechanisms in protection of the host from tumor progression, as well as spontaneous metastasis, using the D122 Lewis lung carcinoma and its gene-modified cells. Utilizing perforin knockout mice (B6-PKO) and Fas and FasL mutant (B6-MRL and B6-Smn) mice, we found that perforin expression in the host plays a crucial function in the prevention of metastasis.

Cu/Zn superoxide dismutase plays a role in angiogenesis.

Endothelial cells produce oxygen radicals spontaneously and this process is augmented by hypoxia/reoxygenation. Cu/Zn superoxide dismutase (SOD-1) is an important enzyme in cellular oxygen metabolism. To determine whether alterations in SOD-1 activity affect angiogenesis we used transgenic SOD-1 (Tg-SOD) mice with elevated level of SOD-1.