Clinical and applied immunology reviews最新文献

At present, treatment for human immunodeficiency virus (HIV)-1 infection employs highly active anti-retroviral therapy (HAART), which utilizes a combination of retroviral therapy (RT) and protease inhibitors [1]. Unfortunately, HIV can escape many therapies because of its high mutation rate and the complexity of its pathogenesis. HIV-1 integrates into the cellular genome, which facilitates persistence and acts as a reservoir for reactivation and replication. As an alternative or adjuvant to chemotherapy we have been developing a ribonucleic acid (RNA) based gene therapy approach for the treatment of HIV-1 infection. Dr. Narva Sarver was a visionary and an activist who saw the potential for gene therapy as a long term treatment for HIV-1 infection [2]. She was a strong proponent of RNA based gene therapy, in particular ribozyme gene therapy for HIV-1 treatment. Working in close communication with Dr. Sarver over the past several years we have investigated gene therapy approaches that employ the use of anti-HIV ribozymes to control viral replication in acquired immunodeficiency syndrome (AIDS) patients. This article summarizes our past work, as well as describing new technologies being developed for application in a gene therapy setting.

Deoxyribonucleic acid (DNA) vaccination, also known as genetic immunization, is a novel vaccine technology that has been tested in humans for many current infectious diseases, and has been found to be well-tolerated. The approach has been used to induce protective immunity against infectious pathogens, malignancies, as well as prevent the development of autoimmune disorders in animal models. Moreover, DNA vaccines have been tested for clinical use as both prophylactic and therapeutic agents. For these vaccines, plasmid DNA encoding a polypeptide/protein antigen is introduced into a host where it enters host cells and serves as an epigenetic template for the high efficiency translation of antigen. Although DNA immunogens have been shown to stimulate both the cellular and/or humoral arms of the immune system, improving the potency of these vaccines is clearly important. In this regard, several approaches to improve efficacy are currently being tested and will be discussed in this review. One such approach is to improve the DNA plasmid by introducing codon optimization in the DNA plasmid that improves expression and immunogenicity in animals. A second approach aims to manipulate the host immune response by including immunologic molecular adjuvants as part of the vaccine including T cell costimulatory molecules, cytokines, and chemokines. Using immunologic adjuvants, researchers have tailored the immune response to the DNA vaccine toward a particular Th subtype, allowing for the preferential induction of predominantly cell-mediated or humoral response. In particular, interleukin-15 (IL-15) expands CD8 immune responses in the absence of T cell help, while chemokines attract dendritic cells as well as other professional antigen presenting cells, directly activating T and/or B cells in the periphery. Furthermore, priming with such adjuvanted DNAs and boosting with T cell costimulatory molecules further enhances antigen-specific immune response to the DNA antigen. Combining these approaches may be particularly useful against human immunodeficiency virus (HIV) infection, in which both cell-mediated and humoral immune responses are required to fight infection. Ultimately, clinical evidence of these approaches may influence not just how we approach HIV treatment, but also treatments for other infectious diseases, autoimmunity, and cancer.

Protection from exogenous invaders and elimination of endogenous aberrations are the main contributions of T cells to homeostasis. T cells with Vγ9Vδ2-encoded T-cell receptors (TCRs) have a unique ability to interact with a plethora of phosphoantigens in a major histocompatibility complex (MHC)-unrestricted manner. The biological function of this recognition is largely unclear. However, since Vγ9Vδ2 T cells are potent cytotoxic effectors capable of killing tumor cells and target cells infected with numerous viruses including human immunodeficiency virus (HIV), simian immunodeficiency virus (SIV), herpes viruses and many others, it is likely that they are involved in antitumor and antiviral immunosurveillance. The observations of tumor-infiltrating γδ T cells with cytotoxic properties and profound quantitative and functional changes in γδ T cells associated with various infectious diseases (including those caused by viruses) are compatible with this hypothesis. For example, the most frequent human peripheral blood γδ T-cell subset expressing Vγ9Vδ2 TCRs is functionally disabled and numerically decreased in some HIV-infected persons. The nonresponsiveness of Vγ9Vδ2 T cells is accompanied by their decreased IFNγ and TNFα production. The overall level of γδ T-cell activation at different stages of HIV infection may be clinically relevant. At an initial stage of HIV infection, the extremely potent antiviral cytotoxic activities of Vγ9Vδ2 T cells may limit the viral spread. At later stages of disease, Vγ9Vδ2 T-cell dysfunction may contribute to the loss of resistance to opportunistic pathogens (such as atypical mycobacteria) and neoplasms (e.g., lymphomas) frequently associated with HIV infections. The activity of Vγ9Vδ2 T cells both in vivo and can be regulated by nonpeptidic antigens. These molecules are being assessed as potential therapeutic vaccines in acquired immunodeficiency syndrome (AIDS) and certain cancers susceptible to the Vγ9Vδ2 T-cell attack.

Anti-mitochondrial antibodies (AMA) are a serological hallmark of primary biliary cirrhosis (PBC). The major autoantibody targets are located in the inner mitochondrial membrane, are encoded by nuclear genes and are components of the 2-oxo acid dehydrogenase complexes. Greater than 90% of PBC patients react with one or more of these autoantigens. The major epitopes have been mapped to the lipoic acid binding domain. The apparent hepatic targets of immune destruction, the apical biliary epithelial cells, express proteins that mimic these epitopes. Nevertheless, the role of AMA in biliary pathology is not clear and observed abnormalities may be due to T-cells that respond to similar epitopes. AMAs are often accompanied by autoantibodies to other intracellular components such as the nuclear pore complex, centromeres/kinetochores, and other nuclear antigens. The origin or inciting agent(s) of AMA is not known but epidemiological and immunological evidence implicates environmental agents.

There is increasing use of antibody measurements for diagnosing well-established autoimmune disorders of the nervous system, and in the investigation of other less well characterized diseases. Antibodies against muscle or neuronal ion channels, and against myelin glycolipids are clearly associated with peripheral neurological diseases. Some of these antibodies are also being identified in central nervous system (CNS) disorders, where their pathogenic role has yet to be clearly demonstrated. Antibodies to intracellular antigens, that are co-expressed by certain tumors, are found in patients with paraneoplastic neurological disorders and are very important as tumor markers, but the conditions are probably the result of a T-cell mediated attack. This review will discuss the methods currently in use for measuring these antibodies, their importance in clinical practice, and indicate new developments.

Probiotic lactobacilli are able to transiently survive in the human gastrointestinal tract following oral delivery, where they may signal sentinel cells of the immune system (such as those expressing pattern recognition receptors). Recent evidence suggests that the form of immune signal is strongly strain-dependent, with some well-defined bacterial strains potentiating systemic T helper (Th) 1-type immune activity and favoring cell-mediated immunity (CMI). Clinical studies have shown promising outlets for the use of non-pathogenic lactobacilli as provisioners of pro-Th1 immune signals in anti-allergy and anti-tumor immunotherapy, as well as combating intracellular microbial infections and immunosenescence. The underlying process appears to involve pro-Th1 activating cytokines (IFNα/IFNγ, IL-12, and IL-18) generated following bacterial contact with accessory leukocytes. The utilization of pro-Th1/CMI lactobacilli in present and future clinical immunotherapy is discussed.

Objective: Develop and evaluate assays for the detection of antibodies to soluble liver antigen (SLA). SLA, also known as liver/pancreas antibody, was found to be 100% specific for autoimmune hepatitis (AIH) in a recent study of 2000 sera collected from individuals with various disease conditions and healthy individuals (Wies et al., Lancet 2000; 355:1510). Although SLA antibodies occur in only about 30% of patients with autoimmune hepatitis, they are found in some individuals with AIH who are negative for other autoantibodies.

Methods: Specimens from patients with autoimmune hepatitis, non-autoimmune liver disease, various autoimmune conditions, as well as specimens from healthy individuals were tested by the INOVA QUANTA Lite™ SLA (Soluble Liver Antigen) ELISA. The ELISA test uses a recombinant SLA antigen. The feasibility of simultaneous detection of antibodies to SLA, LKM-1, and M-2 antibodies was also determined using the QuantaPlex™ test system (Luminex).

Results: Site 1 (San Diego): Testing of 132 specimens from normal, healthy individuals with ages ranging from 5 to 69 years old, resulted in a specificity of 100% (132/132). A second panel, consisting of 10 clinically-defined samples obtained from Dr. Lohse (5 positive and 5 negative), was tested and in complete agreement with the results obtained in the Mainz laboratory by an inhibition ELISA assay and western blot analysis. A panel of 18 specimens positive for various autoimmune or disease antibodies, including GBM, LKM-1, ANA, SLE, M-2 and GPA, were all found to be negative on the SLA ELISA. The multiplex assay was able to clearly discriminate and identify SLA, LKM-1, and M-2 positive samples and offers a promising new methodology for evaluation of patients with suspected liver disease.

Site 2 (Mainz): A panel of 200 sera were tested. These included 32 SLA/LP positive AIH sera, 18 SLA/LP negative AIH sera, 100 sera from viral hepatitis patients, 15 sera from patients with non-AIH liver diseases and sera from 35 patients with various disease conditions. 31 of the 32 SLA positive sera were clearly positive and one was equivocal. Excluding the equivocal result, the sensitivity was 100%.

Conclusions: Our data show that with the exclusion of the 1 equivocal result, the SLA ELISA test had 100% specificity and 100% sensitivity. No cross-reactivity was seen with sera positive for other autoimmune makers. Availability of assays for detection of SLA antibodies will provide a new marker to assist in the diagnosis of patients with autoimmune hepatitis. Detection of SLA antibodies is especially valuable for testing the 10–15% of AIH patients who are negative for conventional autoantibodies.