Springer seminars in immunopathology最新文献

Autoimmune disorders are characterized by the destruction of self-tissues by the immune system. Multiple checkpoints are in place to prevent autoreactivity under normal circumstances. Coexpression of activating and inhibitory Fc receptors (FcR) represents such a checkpoint by establishing a threshold for immune cell activation. In many human autoimmune diseases, however, balanced FcR expression is disturbed. Analysis of murine model systems provides strong evidence that aberrant FcR expression can result in uncontrolled immune responses and the initiation of autoimmune disease. This review will summarize this data and explain how this information might be used to better understand human autoimmune diseases and to develop novel therapeutic strategies.

Mucosal secretions of the human gastrointestinal, respiratory, and genital tracts contain significant quantities of IgG. The neonatal Fc receptor for IgG (FcRn) plays a major role in regulating host IgG levels and transporting IgG and associated antigens across polarized epithelial barriers. The FcRn can then recycle the IgG/antigen complex back across the intestinal barrier into the lamina propria for processing by dendritic cells and presentation to CD4(+) T cells in regional organized lymphoid structures. FcRn, through its ability to secrete and absorb IgG, thus integrates luminal antigen encounters with systemic immune compartments and, as such, provides essential host defense and immunoregulatory functions at the mucosal surfaces.

A major challenge in developing an HIV vaccine is to identify immunogens and delivery methods that will elicit balanced humoral and cell mediate immunities against primary isolates of HIV with diverse sequence variations. Since the discovery of using protein coding nucleic acids (mainly DNA but also possible RNA) as a means of immunization in the early 1990s, there has been rapid progress in the creative use of this novel approach for the development of HIV vaccines. Although the initial impetus of using DNA immunization was for the induction of strong cell-mediated immunity, recent studies have greatly expanded our understanding on the potential role of DNA immunization to elicit improved quality of antibody responses. This function is particularly important to the development of HIV vaccines due to the inability of almost every previous attempt to develop broadly reactive neutralizing antibodies against primary HIV-1 isolates. Similar to the efforts of developing cell mediated immunity by using a DNA prime plus viral vector boost approach, the best antibody responses with DNA immunization were achieved when a protein boost component was included as part of the immunization schedule. Current experience has suggested that a combination DNA plus protein vaccination strategy is able to utilize the benefits of DNA and protein vaccines to effectively induce both cell-mediated immunity and antibody responses against invading organisms.

Vaccines have entered into human clinical trials against infectious diseases and as therapies against cancer. The HIV virus establishes a latent infection at a very early stage and the T cell memory of the infected patient is rapidly destroyed. However, results of immunotherapy after DNA and protein immunization show that vaccine-induced immune responses might be present for a long period of time. Patients subjected to therapeutic immunization appear to do well, and to have a small immunological advantage, which, however, will have to be improved. The vaccine therapy should start early, while adequate reservoirs of appropriate T helper cells are available and still inducible. The DNA vaccines induce a relatively long-lived immunological memory, and gene-based immunization is effective in inducing cytotoxic CD8(+) T cells and CD4+ helper cells. Protein vaccines, on the other hand, primarily give T cell help. It thus appears that DNA and protein approaches to HIV immunization complement each other. A surprisingly broad reactivity to peptides from different subtypes of HIV was identified in individuals infected with several subtypes of HIV.

Recombinant vesicular stomatitis virus (rVSV) is currently under evaluation as a human immunodeficiency virus (HIV)-1 vaccine vector. The most compelling reasons to develop rVSV as a vaccine vector include a very low seroprevalence in humans, the ability to infect and robustly express foreign antigens in a broad range of cells, and vigorous growth in continuous cell lines used for vaccine manufacture. Numerous preclinical studies with rVSV vectors expressing antigens from a variety of human pathogens have demonstrated the versatility, flexibility, and potential efficacy of the rVSV vaccine platform. When administered to nonhuman primates (NHPs), rVSV vectors expressing HIV-1 Gag and Env elicited robust HIV-1-specific cellular and humoral immune responses, and animals immunized with rVSV vectors expressing simian immunodeficiency virus (SIV) Gag and HIV Env were protected from AIDS after challenge with a pathogenic SIV/HIV recombinant. However, results from an exploratory neurovirulence study in NHPs indicated that these prototypic rVSV vectors might not be adequately attenuated for widespread use in human populations. To address this safety concern, a variety of different attenuation strategies, designed to produce a range of further attenuated rVSV vectors, are currently under investigation. Additional modifications of further attenuated rVSV vectors to upregulate expression of HIV-1 antigens and coexpress molecular adjuvants are also being developed in an effort to balance immunogenicity and attenuation.

In December 2005, the UNAIDS and WHO reported that the global epidemic known as acquired immunodeficiency syndrome (AIDS) has claimed the lives of more than 25 million adults and children over the past 26 years. These figures included an estimated 3.1 million AIDS-related deaths in 2005. Despite enormous efforts to control the spread of human immunodeficiency virus (HIV) new infection rates are on the rise. An estimated 40.3 million people are now living with HIV, including 4.9 million new infections this past year. Nearly half of new HIV infections are in young people between the ages of 15 and 24. While drug therapies have helped sustain the lives of infected individuals in wealthy regions, they are relatively unavailable to the poorest global regions. This includes sub-Saharan Africa which has approximately 25.8 million infected individuals, more than triple the number of infections of any other region in the world. It is widely believed that the greatest hope for controlling this devastating pandemic is a vaccine. In this review, we will discuss the current state of DNA-based vaccines and how they compare to other vaccination methods currently under investigation. We will also discuss innovative ideas for enhancing DNA vaccine efficacy and the progress being made toward developing an effective vaccine.

The recreational use of legal and illegal drugs has significant effects on immune responses and can potentially modulate susceptibility to infection by a number of pathogens. A number of agents including cannabinoids (marijuana), cocaine opiates, amphetamines, nicotine and alcohol were demonstrated to have potentially adverse effects on the susceptibility to infections, mediated most likely, by adverse effects on immunity. As such, these drugs of abuse could have significant and potentially adverse effects on the vaccination efficacy of a number of vaccines currently on the market and on potential experimental vaccines currently in the pipeline. This review will present an overview on how drugs of abuse potentially impacts immune responses and vaccination efficacy. The emphasis of this review will be the effects of opiate abuse, as exemplified by injecting/intravenous drug users (IDU), on HIV/AIDS and its potential impact on vaccine efficacy trials against this devastating infection/syndrome.

Long-term maintenance of memory T cell response is the hallmark of immune protection and hence the holy grail of most vaccine development studies. Persistent memory cells, developed after either viral infection or vaccination, ensure the generation of an antiviral response upon reexposure to the pathogen. During acute viral infections, as in the case of measles and influenza viruses, strong T cell effector functions, which eradicate the virus and protect patients against reexposure, are achieved by the generation of persistent protective memory cells. However, in chronic infections, T cells drastically lose effector functions before acquiring a memory phenotype. Chronic infections can be categorized into infections where viremia is controlled and protective memory cells are maintained as in the case of EBV and CMV infections, or where the virus persists and memory cells are exhausted and disrupted as in the case of human immunodeficiency virus infection. In this review, we will discuss the different phenotypical and functional characteristics of memory cells subsets, the importance of the role they play during acute and chronic infections, and the mechanisms behind their effectiveness and persistence.

This review highlights some of the most common cytokines currently being tested as adjuvants in HIV-1-DNA vaccine regimens. We discuss their use in both the prophylactic and therapeutic setting. Finally, we describe a novel dendritic cell-targeted vaccine candidate for HIV-1 treatment and prevention called DermaVir and explore the combination of the DermaVir technology with the cytokine adjuvants interleukin-7 and interleukin-15.