Abstract: Human gene therapy has made substantial progress since the initiation of the first clinical trials 20 years ago. Here, we summarized important applications of gene transfer protocols in the treatment of various human diseases using different viral vectors. Recent successful trials on the treatment of ocular diseases and inherited immune deficiencies are particularly encouraging and have raised hopes that human gene therapy as a standard treatment option will finally become a reality. While immune responses and insertional mutagenesis pose obstacles for this novel form of molecular medicine, continuous progress suggests that a wider range of diseases can be treated with gene therapy in the future. ... Read more

Abstract: Mast cells (MC) are specialized exocytic cells that lie beneath the external surfaces of the body. For many decades, MCs were thought to primarily function as effector cells for IgE mediated allergic diseases. However, recent evidence indicates that MCs also function as important cells in immune surveillance. When activated by pathogens, MCs initiate innate and adaptive immune responses thereby resulting in protection against pathogens. The question remains if MC activation may also function in establishing immune responses against allergens and hence allergic disease. New studies suggest that MCs are not only the effector cell of allergy but may also be the initiator of allergy. ... Read more

Abstract: Ovarian cancer is the leading cause of cancer death among gynecological malignances. Despite the initial successful multimodality therapy with cytoreductive surgery and subsequent combination chemotherapy, most patients with advanced disease will ultimately relapse and become incurable. For this reason novel therapeutic approaches for the treatment of this malignancy are urgently needed. Adoptive transfer of genetically modified autologous tumor-reactive T cells is a promising novel antitumor therapy for many cancers. T cells may be genetically modified ex vivo to express chimeric antigen receptors (CARs), which are artificial T cell receptors targeted to specific tumor antigens. The resulting T cells are thus programmed to recognize tumor cells. Ovarian carcinomas in particular appear to be suited to this therapeutic approach based on the fact that these tumors are relatively immunogenic, inducing an endogenous T cell response. Furthermore, the degree to which this endogenous T cell mediated immune response is evident correlates to long-term patient prognosis following surgery and chemotherapy. To this end, adoptive T cell immunotherapy strategies for the treatment of ovarian carcinomas appear to be particularly promising and are currently being investigated at several centers in both pre-clinical and clinical settings. ... Read more

Abstract: Most uveitics enjoy good vision despite potentially sight-threatening complications including cataract development. In those patients who develop cataracts, successful surgery stems from educated patient selection, careful surgical technique, and aggressive preoperative and postoperative control of inflammation. While commonly accepted in the adult patient population, recent investigations reflect the increased tolerance for primary intraocular lens placement in the pediatric cohort. The role of absolute control of inflammation continues with greater focus on immunomodulatory therapies. However, these agents bear their own side effect and complication profiles. Cataract extraction with intraocular lens implantation in the setting of meticulous control of inflammation can optimize visual outcome in adults and children with uveitis. ... Read more

Abstract: One-third of humans carry Mycobacterium tuberculosis, the etiological agent of tuberculosis (TB) where microbe/host immune response interactions result in persistence or active TB. However, immune mediators associated with human TB remain poorly defined. Through a series of comparative studies of lung immune response of TB cases at the time of diagnosis and patients with other infectious lung diseases and volunteers, we found that TB cases expressed significantly higher levels of mediators that counteract Th1-type and innate immunity critical for containment of M. tuberculosis. Despite the concomitant heightened levels of Th1-type mediators, they are likely rendered ineffectual by high levels of intracellular (e.g., SOCS) and extracellular (e.g., IL-10) immune suppressors. These modulators are a direct response to M. tuberculosis as many suppressive factors declined to the levels of controls by 30 days of anti-TB treatment while most Th1-type and innate immune mediators rose above the pre-treatment levels. Parallel laboratory studies and monitored lung alveolar macrophage effector, nitric oxide synthase-2 (being shown critical for killing M. tuberculosis), support that M. tuberculosis actively promotes down-modulatory mediators to counteract Th1-type/innate immunity as an immunopathological strategy. Our studies highlight the potential application of immune mediators as surrogate markers for TB diagnosis or treatment response. ... Read more

Abstract: In this review, I outline a current view of how T lymphocytes use extracellular signals to decide between activation and tolerance, and how the tolerant state is established and maintained at the molecular level. This decision is made by a series of intracellular proteins that actively oppose the induction of effector genes, and are inactivated by signals from costimulatory and/or growth factor receptors. ... Read more

Abstract: The artificial antigen-presenting cells (AAPCs) described in this review were generated to facilitate the production of virus-specific T-cells for the treatment of infections in patients after bone marrow transplant. These AAPCs consist of murine 3T3 cells genetically modified to express critical human molecules needed for T-cell stimulation, such as the co-stimulatory molecules B7.1, ICAM-1, and LFA-3 and one of a series of 6 common HLA class I alleles. When T-cells were sensitized against cytomegalovirus (CMV) using AAPCs that express a shared HLA allele or using autologous antigen-presenting cells (APCs) loaded with the CMVpp65 antigen, they were activated and expanded to become HLA-restricted CMVpp65-specific T-cells. These T-cells demonstrated functional activity in vitro against CMV by producing IFNγ and inducing CMVpp65-specific cytotoxicity. T-cells sensitized with AAPCs recognized antigenic epitopes presented by each HLA allele known to be immunogenic in Man. Sensitization with AAPCs also permitted expansion of IFNγ+ cytotoxic T-cells against subdominant epitopes that were not effectively recognized by T-cells sensitized with autologous APCs. This panel of AAPCs provides a source of immediately accessible, standardizable, and replenishable "off the shelf" cellular reagents with the potential to make adoptive immunotherapy widely available for the treatment of lethal infections, cancer, and autoimmune diseases. ... Read more

Abstract: The evolution of the immune system has provided a multilevel system that interconnects the innate and adaptive immune systems to serve at least three central purposes: the defense from microbial pathogens, the capacity for discrimination of self- from non-self necessary for the prevention of autoimmune disease, and essential effector roles in wound repair and tissue remodeling. In recent studies, we have elucidated an unsuspected role for a class of naturally occurring autoreactive antibodies from the most primitive tier of B lymphocytes, which regulates fundamental functions of the innate immune system. Our findings also throw light onto long unresolved mysteries regarding the origins of the earliest waves of B lymphocyte development. ... Read more

Abstract: Interleukin-21 (IL-21), a cytokine produced by activated CD4+ T cells, activated natural killer T cells, and T follicular cells, has been reported to play a crucial role in the tissue-damaging T cell response in various organs, such as gut, skin, pancreas, and joints. This pathogenic effect is strictly linked to the ability of IL-21 to enhance the functional activities of multiple immune and non-immune cells. Consistently, studies from various laboratories have shown that blockade of IL-21 limits the progression of T cell-mediated inflammatory diseases in mice. Here we review the present knowledge on the expression and role of IL-21 in T cell-mediated pathologies. ... Read more

Abstract: The activation and clonal expansion of naive T cells by antigen-loaded dendritic cells (DCs) in the lymph nodes is a key event during immune response. This activation involves the formation of a specialized cell-cell contact region, formed between a mature DC and a CD4 T cell, which is called immunological synapse (IS). The IS includes a DC and a T cell side that we call IS(DC) and IS(T cell), respectively. Most studies on the IS have focused on the IS(T cell) and the information gathered on the IS(DC) is sparse. However, lines of emerging evidence indicate that the IS(DC), likewise the IS(T cell), is a signaling and functional region that makes important contribution to T cell activation and the immune response. ... Read more