Cytokines in Male Fertility and Reproductive Pathologies: Immunoregulation and Beyond.

Germline development is dependent on the environment formed by somatic cells and the differentiation cues they provide; hence, the impact of local factors is highly relevant to the production of sperm. Knowledge of how somatic and germline cells interact is central to achieving biomedical goals relating to restoring, preserving or restricting fertility in humans. This review discusses the growing understanding of how cytokines contribute to testicular function and maintenance of male reproductive health, and to the pathologies associated with their abnormal activity in this organ.

A phase 2, single-arm study of an autologous dendritic cell treatment against mucin 1 in patients with advanced epithelial ovarian cancer.

Background: Mucin 1 antigen, highly expressed by epithelial ovarian cancer (EOC), is a potential target for immunotherapy. A previous successful phase 1 trial was conducted in patients with adenocarcinoma who were injected with Cvac, autologous monocyte-derived dendritic cells (DCs) incubated with mannosylated mucin 1 protein (M-FP). The present study was a phase 2 trial of Cvac in patients with advanced EOC.

Induction of multi-functional T cells in a phase I clinical trial of dendritic cell immunotherapy in hepatitis C virus infected individuals.

We have previously reported a world-first phase I clinical trial to treat HCV patients using monocyte-derived dendritic cells (Mo-DC) loaded with HCV-specific lipopeptides. While the brief treatment proved to be safe, it failed to reduce the viral load and induced only transient cell-mediated immune responses, measured by IFNγ ELIspot. Here we reanalysed the PBMC samples from this trial to further elucidate the immunological events associated with the Mo-DC therapy.

Anti-Pim-1 mAb inhibits activation and proliferation of T lymphocytes and prolongs mouse skin allograft survival.

Pim-1 is an important signaling molecule mediating cell proliferation and survival. Our previous study identified a Pim-1 specific monoclonal antibody, P9, with significant inhibitory effect on cell proliferation. Herein, we report that P9 inhibited the activation and proliferation of PHA-stimulated human PBMC and induced them to undergo apoptosis.

Analysis of FOXP3+ regulatory T cells that display apparent viral antigen specificity during chronic hepatitis C virus infection.

We reported previously that a proportion of natural CD25(+) cells isolated from the PBMC of HCV patients can further upregulate CD25 expression in response to HCV peptide stimulation in vitro, and proposed that virus-specific regulatory T cells (Treg) were primed and expanded during the disease. Here we describe epigenetic analysis of the FOXP3 locus in HCV-responsive natural CD25(+) cells and show that these cells are not activated conventional T cells expressing FOXP3, but hard-wired Treg with a stable FOXP3 phenotype and function. Of approximately 46,000 genes analyzed in genome wide transcription profiling, about 1% were differentially expressed between HCV-responsive Treg, HCV-non-responsive natural CD25(+) cells and conventional T cells.

Pim-1 expression and monoclonal antibody targeting in human leukemia cell lines.

Objective: Based on our previous findings that Pim-1 was expressed on the cell surface and could be targeted with a highly specific anti-Pim-1 monoclonal antibody (P9), this study aims to evaluate the possibility that Pim-1 could be targeted for the treatment of human leukemia.

Materials And Methods: Pim-1 expression was investigated in a series of human leukemia cell lines with immunohistochemistry and flow cytometry. The inhibitory effect of P9 on cell proliferation was evaluated with (3)H-thymidine incorporation assay.

The tetraspanin protein CD37 regulates IgA responses and anti-fungal immunity.

Immunoglobulin A (IgA) secretion by plasma cells in the immune system is critical for protecting the host from environmental and microbial infections. However, the molecular mechanisms underlying the generation of IgA(+) plasma cells remain poorly understood. Here, we report that the B cell-expressed tetraspanin CD37 inhibits IgA immune responses in vivo.

Dendritic cell vaccination.

There has been a surge of interest in the use of dendritic cell (DC) vaccination as cellular immunotherapy for numerous cancers. Despite some encouraging results, this therapeutic modality is far from being considered as a therapy for cancer. This review will first discuss preclinical DC vaccination in murine models of cancer, with an emphasis on comparative studies investigating different methods of antigen priming.

Pilot phase III immunotherapy study in early-stage breast cancer patients using oxidized mannan-MUC1 [ISRCTN71711835].

Introduction: Mucin 1 (MUC1) is a high molecular weight glycoprotein overexpressed on adenocarcinoma cells and is a target for immunotherapy protocols. To date, clinical trials against MUC1 have included advanced cancer patients. Herein, we report a trial using early stage breast cancer patients and injection of oxidized mannan-MUC1.

Delivery of tumor associated antigens to antigen presenting cells using penetratin induces potent immune responses.

Cytoplasmic delivery of proteins or CTL epitopes is crucial for the presentation of antigen for the generation of CTL. We previously described the use of the 16-amino acid peptide penetratin from the Drosophila Antennapedia domain (Int) to transport CTL epitopes into cells. Here we show that, Int, incorporating MUC1 CTL epitopes in tandem is able to facilitate their rapid uptake by macrophages and dendritic cells (DC) in an energy-dependent endocytic pathway.

Mannan-MUC1-pulsed dendritic cell immunotherapy: a phase I trial in patients with adenocarcinoma.

Purpose: Tumor antigen-loaded dendritic cells show promise for cancer immunotherapy. This phase I study evaluated immunization with autologous dendritic cells pulsed with mannan-MUC1 fusion protein (MFP) to treat patients with advanced malignancy.

Experimental Design: Eligible patients had adenocarcinoma expressing MUC1, were of performance status 0 to 1, with no autoimmune disease.

Novel role for decay-accelerating factor in coxsackievirus A21-mediated cell infectivity.

Decay-accelerating factor (DAF) is involved in the cell membrane attachment of many human enteroviruses. Presently, further specific active roles of DAF in mediating productive cell infection and in the pathogenesis of natural enterovirus infection are poorly understood. In an attempt to more fully understand the role of DAF in lytic cell infection we examined the specific interactions of the prototype strain of coxsackievirus A21 (CVA21) with surface-expressed DAF.

Characterization of a CD46 transgenic pig and protection of transgenic kidneys against hyperacute rejection in non-immunosuppressed baboons.

Human membrane cofactor protein (CD46) controls complement activation and when expressed sufficiently as a transgene protects xenografts against complement-mediated rejection, as shown here using non-immunosuppressed baboons and heterotopic CD46 transgenic pig kidney xenografts. This report is of a carefully engineered transgene that enables high-level CD46 expression. A novel CD46 minigene was validated by transfection and production of a transgenic pig line.

CD46 protects pig islets from antibody but not cell-mediated destruction in the mouse.

We have previously reported that islets present in cultured fetal pig pancreas (FPP) are resistant to destruction by Galalpha(1,3)Gal antibodies and compliment, but are susceptible to the 'secondary' antibody response which occurs on transplanting pig islet tissue to Galo/o murine recipients. In a model of antibody-mediated graft rejection, we tested the resistance of porcine islets to antibody. Using FPP from human CD46 transgenic pigs, we now report that the complement regulator, CD46, affords protection from antibody-mediated rejection when mouse anti-pig serum (MAPS) was administered to scid mice bearing PFF grafts from either CD46 transgenic or normal pigs.

Ligand binding determines whether CD46 is internalized by clathrin-coated pits or macropinocytosis.

CD46 is a ubiquitous human cell surface receptor for the complement components C3b and C4b and for various pathogens, including the measles virus and human herpes virus 6. Ligand binding to CD46 affects (i) protection of autologous cells from complement attack by breakdown of complement components, (ii) intracellular signals that affect the regulation of immune cell function, (iii) antigen presentation, and (iv) down-regulation of cell surface CD46. Recent evidence indicates that CD46 signaling can link innate and acquired immune function.

Aspects of cancer immunotherapy.

Cancer immunotherapy has traditionally undergone a 'revolution' every decade, from the use of Bacille Calmette-Guérin by scarification in the 1970s, to interleukin-2 therapies in the 1980s, and monoclonal antibody treatments in the early 1990s. Usually the early reports on the use of such agents were encouraging, but when more patients were studied in multiple centres, the initial promising results could not be confirmed. Now in a new century, we have more reagents and methods available than ever before - indeed, with such a plethora of reagents it is difficult to envisage them being fully and appropriately tested within the next decade, by which time there will be even more reagents to test.

Identification of the streptococcal M protein binding site on membrane cofactor protein (CD46).

Adherence of group A streptococcus (GAS) to keratinocytes is mediated by an interaction between human CD46 (membrane cofactor protein) with streptococcal cell surface M protein. CD46 belongs to a family of proteins that contain structurally related short consensus repeat (SCR) domains and regulate the activation of the complement components C3b and/or C4b. CD46 possesses four SCR domains and the aim of this study was to characterize their interaction with M protein.

A functional interaction between CD46 and DLG4: a role for DLG4 in epithelial polarization.

Using a yeast two-hybrid screen, we identified a physical interaction between CD46 and DLG4. CD46 is a ubiquitous human cell-surface receptor for the complement components C3b and C4b and for measles virus and human herpesvirus 6. DLG4 is a scaffold protein important for neuronal signaling and is homologous to the Drosophila tumor suppressor DLG.