Abstract: It is clear that micro-RNAs (miRNAs) are emerging as key players in the control of a multitude of biological processes, from plants to animals, alongside with coding genes. The regulation of miRNA expression is tightly controlled, and often the same rules and regulations that govern coding gene expression apply also to miRNAs. Similar to coding genes, altering the levels and the temporal expression of a specific miRNA clearly affects the proper development and function of the tissue where it is expressed. In this review we discuss seminal studies, which demonstrate the importance of miRNAs in the immune system and a possible link between dysregulated miRNA expression and diseases, such as systemic lupus erythematosus (SLE) and cancer. In addition, we summarize progresses towards targeting miRNAs as therapeutic agents. ... Read more

Abstract: Systemic sclerosis (SSc) is a complex fibrosing autoimmune disease that has variable clinical manifestations and morbidity/mortality secondary to organ damage due to vasculopathy and/or fibrosis. Initial events in the pathogenesis are manifested by fibroproliferative vasculopathy that compromises delivery of blood to critical organs. There is evidence of autoimmunity early in the disease which persists and is accompanied by fibrotic processes that leave large accumulations of collagen and other matrix components in the intima of blood vessels and extracellularly in the connective tissue of organs affected by the disease. It has recently been realized that the lysophospholipids -- lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), which are elevated in sera of SSc patients, are capable of producing many of the abnormalities observed in the vasculature, immune system, and connective tissue of patients with this disease. This article reviews key abnormalities of the vasculature, immune system, and connective tissue in SSc that could be mediated by LPA/S1P. ... Read more

Abstract: Type 1 diabetes (T1D) is an autoimmune disease characterized by the disturbance of pancreatic insulin-producing cells, which results in hyperglycemia. The disease is associated with severe complications that impair the quality of life of individuals. The cause of T1D is unknown. Development of the disease is the result of interactions between immunological, genetic, and environmental factors. Viruses are thought to play an important role in the initiation or acceleration of the disease. This is an important issue since it opens the possibility to develop new preventive and therapeutic strategies to fight the disease. The role of enteroviruses in the development of T1D, in particular type B coxsackieviruses, is supported by epidemiological observations. It has been demonstrated that enterovirus infections were significantly more common in recently diagnosed diabetic patients, compared with control subjects. Enteroviral RNA and/or proteins can be detected in blood samples and intestine biopsies of patients with T1D. The hypothesis of a relationship between enteroviruses and the disease has been strengthened by the presence of enteroviral components or infectious particles in the pancreas of patients with T1D. In this review, arguments in favor of a relationship between enterovirus infections and T1D and the mechanisms of the enteroviral pathogenesis of the disease are presented. ... Read more

Abstract: Transplantation of cells, tissues, and organs from one individual to another can incite the production of antibodies specific for foreign antigens, especially major histocompatibility antigens, in the graft. Antibodies specific for a graft provide an index of immunity and a potential trigger for injury and rejection. However, the index of immunity can sometimes miss antibody-mediated rejection and besides causing injury the antibodies against a graft can also protect a graft from injury by blocking immune recognition, called enhancement, regulating activation of complement, and inducing changes in the graft that resist damage. Reviewed here are potential limitations in the use of antibodies as an index of immunity and the ways antibodies cause and/or prevent injury. ... Read more

Abstract: Cancer vaccines consisting of intact tumor cells genetically modified to secrete the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) have undergone extensive preclinical development. These vaccines induce the massive accumulation of dendritic cells at the intradermal injection site, which engulf, process, and present tumor antigens to activate tumor-specific T cells. Early phase clinical testing demonstrated promising evidence of safety and bioactivity, although initial phase III clinical trials were unsuccessful. Together, the preclinical and clinical data argue for the continued clinical development of these vaccines, integrating them with standard and novel cancer therapeutics that enhance vaccine activity by overcoming immune tolerance and suppression, and/or augmenting co-stimulatory pathways of T cell activation. ... Read more

Abstract: Neonatal exposure to antigen gives rise to a primary response comprising both T helper 1 (Th1) and T helper 2 (Th2) lymphocytes. However, re-encounter with the same antigen yields an indubitably biased response with minimal Th1 but excessive Th2 cells. Since Th1 cells combat microbes while Th2 cells react to allergens, the neonate faces susceptibility to both microbial infections and allergic reactions. The Th1/Th2 imbalance of neonatal immunity stems from a delayed maturation of dendritic cells that yields limited IL-12 cytokine during the neonatal stage. Th1 cells developing under these circumstances up-regulate the IL-13Rα1 chain that physically associates with the IL-4Rα chain, forming a potentially hazardous heteroreceptor. During re-challenge with antigen, IL-4 from Th2 cells utilizes the heteroreceptor to signal the death of Th1 cells, leading to the Th2 bias of neonatal immunity. Our view to overcome Th1 deficiency is to supplement neonatal immunizations with toll-like receptor ligands that could stimulate maturation of dendritic cells and augment IL-12 production to counter IL-13Rα1 up-regulation. This regimen would yield Th1 cells devoid of the heteroreceptor and resistant to IL-4-induced apoptosis. Accordingly, the neonate would have balanced Th1/Th2 immunity and withstand both microbes and allergens. Such approaches could open new avenues for better pediatric vaccines and allergy therapies. ... Read more

Abstract: CD8⁺ CTL responses are critical for eliminating virus infected cells in acute infection and in controlling virus replication during chronic infection. Despite evidence of potent HIV-1-specific CD8⁺ CTL responses during the earliest stage of acute infection leading to replacement of founder virus sequence(s) and resolution of peak viral load, in the majority of infected individuals, these responses are inadequate to prevent the establishment or control of persistent infection. Protective CD8⁺ CTL responses have yet to be achieved by vaccine approaches for HIV-1 or other viruses causing persistent infections, Mycobacterium tuberculosis, malaria, and cancer. Understanding the limitations of CD8⁺ CTL responses to keep pace with the diversity of rapidly evolving virus in the case of HIV-1 and HCV and to overcome the diverse and complex mechanisms persistent pathogens employ to escape immune recognition should lead to more effective prophylactic and therapeutic approaches for these diseases. Recent technological advances including single genome amplification (SGA) of plasma viral RNA along with direct amplicon sequencing to identify virus quasispecies, bioinformatics, and statistical methods for the systematic identification of HLA-class I associated escape mutations, and mathematical models that better define the kinetics of virus replication and decay, have provided significant insight into mechanisms of viral transmission and sequence evolution, virus-host interactions, and HIV-1 pathogenesis. In this review we attempt to integrate recent findings from studies in HIV-1, persistent virus infections, and cancer that predict effective T cell responses and suggest approaches that could shift the balance of control in favor of the host immune response. Here, we highlight factors considered essential for effective HIV-1 vaccine CD8⁺ T cell responses: vaccine antigens, quality, magnitude and breadth, mucosal targeting, and formation of CD8⁺ T cell mucosal memory. ... Read more

Abstract: Vectors based on recombinant adeno-associated virus (AAV) 2/8 hold considerable promise for use in human gene therapy. These vectors are safe, and have minimal immunostimulatory properties. Their combination with efficient, liver-specific promoters allows high-level transgene expression in the hepatocytes of small and large animals. In small animal models, this high level of liver expression results in tolerance to the transgene products. Tolerance to transgene products may also be achievable using these vectors for human gene therapy, but the HLA diversity (and thus variability in T cell recognition of transgene products) and high frequency of prior natural exposure to AAV in human populations impose additional challenges that must be overcome in order for this strategy to succeed. ... Read more

Abstract: Eosinophils have long been observed in the airways of patients with allergic asthma, and in animal models of allergic airway inflammation. Traditionally thought to be an end stage cell that is controlled by the T cell response, more recent findings suggest a more complicated role for these cells. Here we discuss the role of eosinophils in allergic inflammation, and recent findings that suggest an important role in the initiation of allergic airway inflammation. Finally, we discuss some ways in which these cells are being targeted in patients, and promising preclinical findings on novel targets for decreasing the number of these cells in patients with allergic asthma. ... Read more

Abstract: Adult human mesenchymal stem cells (hMSCs) are the focus of a number of clinical applications. The advantage of hMSCs is that they are immuno-modulatory and versatile due to their secreted bioactive molecules that are anti-inflammatory and regenerative. These cells have the potential to orchestrate reparative processes in diseased or injured tissues. Much of the diversity and uniqueness of hMSCs is defined by their response to the milieu of injured tissue. hMSCs are sensitive to their site-specific microenvironment, and it is anticipated that they will deliver the bioactive agents in a site-specific manner quite different from the way pharmaceutical drugs work. This review highlights current concepts of such functions with a focus on the clinical utility of hMSCs in the treatment of lung diseases. ... Read more