Abstract: In the last three decades, we have observed a substantial progress in the organ and cell transplantation. New immune suppressive agents including calcineurin blockers and mTOR inhibitors improved transplantation outcome, but two key problems -- rejection of transplanted organs and graft versus host disease (GVHD) -- continue to be main obstacles after transplantation. Immune response is regulated with coordination of a varying number of cells. T regulatory cells orchestrate other cell responses and eventually limit immune activation and induce immune tolerance. Stimulation of negative costimulatory molecules and adoptive transfer of immunosuppressive cells including regulatory cells are promising therapies that would improve outcome of patients with organ or cell transplantation. ... Read more

Abstract: Our immune system is characterized by remarkable specificity, potency, and memory -- the ability of a single vaccine treatment to provide life-long protection. No pharmacologic treatment for any indication can provide the same level of safety, efficacy, and long-lasting effect that a vaccine can. Thus, researchers and clinicians alike have sought to apply these characteristics to the treatment of cancer. Yet, for the last 125 years, the field has failed to realize this potential. Here, we will review some of the most promising cancer immunotherapeutic approaches in development today, as recent clinical successes signal the beginning of cancer immunotherapy's transition from experimental to established therapy. ... Read more

Abstract: Multiple sclerosis (MS) is the most common inflammatory disease of the central nervous system. The disease is characterized by progressive neurological dysfunction due to demyelination of the nerves, which leads to disability. Currently, no curative therapy is available and patients are subjected to a prolonged course of treatment. Interferon-β (IFNβ) was the first agent to show clinical efficacy in the treatment of MS, and is still the best available therapy. Unfortunately, clinical experience indicates that approximately 40% of the patients do not or only poorly respond to IFNβ treatment. Recent advances revealed the presence of an activated type I IFN pathway in a subset of treatment naïve patients with relapsing remitting MS (RRMS), as shown by the presence of an "IFN signature" and type I IFN bioactivity in the blood of these patients. Evidence exists that quantification of the IFN signature in RRMS is informative as a biomarker to predict the clinical response to IFNβ. In this review we summarize the current evidence of type I IFN activation in RRMS and its clinical relevance. ... Read more

Abstract: Alzheimer's disease (AD) is the most common form of dementia. Its most important pathological hallmarks are profound neuronal loss, presence of intracellular neurofibrillary tangles, and extracellular deposition of beta-amyloid protein (Aβ) as beta-amyloid plaques. One of the most important risk factors for AD is age and with the increase of life-expectancy AD has become the most common form of dementia. The current "Holy Grail" is to be able to diagnose variants of AD before they manifest clinically and before irreparable brain damage is done. To be able to do so, we need robust and reliable biomarkers which reflect the pathogenesis of AD. This is essential because such biomarkers might indicate pathways that could be targeted for interventions aiming at disease prevention or amelioration. Although much attention has been focused on Aβ in this respect, it may not be as attractive a target as thought if current doubts concerning its causative role are substantiated. This review will be in two parts, the first part dealt with the current clinical knowledge and the questions raised by the Aβ cascade hypothesis in the pathogenesis of AD and this second part aims to synthesize our current knowledge and new data suggesting how immunity may contribute to the development of AD and may itself be targeted in future treatments. ... Read more

Abstract: Crohn's disease is an immune-mediated disease that is characterized by chronic intestinal inflammation. Effector CD4+ T-lymphocytes are expanded in Crohn's disease-associated inflammatory lesions and play a critical role in the pathogenesis of this condition. Recently, a novel population of effector T-lymphocytes has been identified, which is clearly separated from the traditional Th1 and Th2 lineages and is characterized by the secretion of IL-17, hence its designation as Th17. The development of this population has been closely linked to IL-23, a member of the IL-12 family of cytokines. Converging lines of evidence support the hypothesis that the IL-23/Th17 axis is of pathogenic relevance for Crohn's disease. Protein and mRNA levels of IL-23, IL-17, and other Th17 effector cytokines, such as IL-21 and IL-22, are elevated in areas with active Crohn's disease-related inflammation, whereas lamina propria mononuclear cells from patients with Crohn's disease secrete increased amounts of IL-17 upon T-cell receptor-specific stimulation. Genome-wide association studies have identified several Crohn's disease-associated polymorphisms in genes that encode for proteins of the IL-23/Th17 pathway. Functional studies have shown that Th17-related effector cytokines induce pro-inflammatory responses that are components of the pathogenetic mechanisms of Crohn's disease, including recruitment of neutrophils via IL-8 induction, upregulation of inflammatory mediators such as TNF-α, IL-1β, and IL-6, and secretion of metalloproteinases by intestinal fibroblasts. Finally, in several animal models of intestinal inflammation, disease severity is ameliorated when the IL-23/Th17 pathway is rendered deficient. These findings point to a critically important role for IL-23/Th17-mediated immune responses in Crohn's disease pathogenesis and may offer unique therapeutic opportunities for patients. ... Read more

Abstract: Costimulation and coinhibition generated by the B7 family and their receptor CD28 family have key roles in regulating T lymphocyte activation and tolerance. These pathways are very attractive therapeutic targets for human cancers including breast cancer. Gene polymorphisms of B7x (B7-H4/B7S1), PD-1 (CD279), and CTLA-4 (CD152) are associated with increased risk of developing breast cancer although the underlying mechanisms are unclear. In human breast cancer microenvironment, up-regulation of coinhibitory B7/CD28 members B7x, B7-H3 (CD276), and PD-L1 (B7-H1/CD274) on tumor cells as well as PD-1 and PD-L1 on tumor-infiltrating immune cells are emerging as immune evasion pathways. Chemotherapy can affect the expression of these molecules, and therefore may dampen the immune response against breast cancer. Immunotherapy targeting T cell coinhibition as monotherapy or combined with standard therapies are in early stages of clinical development, but hold great promise for treatment of human breast cancer. ... Read more

Abstract: Pancreatic cancer is one of the most difficult-to-treat cancers. Despite surgical resection, radiation and/or chemotherapy, greater than 94% of people with pancreatic cancer do not survive beyond 5 years. In fact, median survival after diagnosis of metastatic pancreatic cancer is 4.5 months. The majority of patients are diagnosed with nonresectable, metastatic disease, and chemotherapy only extends their median survival by less than 2 months with only 18% of those treated surviving beyond 1 year. Despite the severity of their disease, most patients exhibit tumor specific cellular immunity to their pancreatic cancer antigens. Obviously their immunity is ineffective in preventing tumor growth. Recent studies have demonstrated that the tumor microenvironment may hold the key to determining the nature of the tumors' ability to escape from immune attack. Preliminary clinical trials have suggested that blocking these escape mechanisms may result in survival benefit to the patients, and phase I and II clinical trials with tumor vaccines have led to some survival benefits. Perhaps combining therapies directed against immune escape mechanisms with tumor vaccines will result in even greater survival benefit for patients with pancreatic cancer. While therapeutic vaccines for pancreatic cancers have been reviewed previously (Plate, 2011), updates on recent preliminary reports of two clinical vaccine trials are worthy of our attention. ... Read more

Abstract: Patients with autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and Sjögren's syndrome have an increased risk of developing B-cell non-Hodgkin's lymphomas but the mechanisms behind this phenomenon remain unknown. By focusing on recent research reports we explore and discuss some of the proposed mechanisms that contribute to this link. The complexity is enormous and can involve genetic and environmental factors, chronic immune stimulation by antigens, and even the treatment for these autoimmune diseases. These mechanisms can be combined in different ways causing great variability in one's predisposition to lymphomagenesis. Knowing more about these pathways is urgent. The more we know about autoimmune diseases the better we can treat our patients effectively and the more we can prevent lymphomas from developing. ... Read more

Abstract: There is considerable debate about the benefits of vitamin D supplementation for multiple sclerosis, allergic asthma, and type 1 diabetes. This has been driven mainly by observational studies linking vitamin D deficiency and insufficiency with increased prevalence of autoimmune and other diseases driven by immune processes. Randomized controlled trials of vitamin D supplementation to treat these (and other) diseases have been disappointing. This review examines the evidence that circulating vitamin D levels provide a surrogate measure of sun exposure and that it is the other molecules and pathways induced by sun exposure, rather than vitamin D-driven processes, that explain many of the benefits often attributed to vitamin D. ... Read more

Abstract: There is a significant association between rheumatoid arthritis (RA) and periodontal disease (PD). Patients with longstanding active RA have been found to have a substantially increased frequency of PD compared with healthy subjects. Further, patients with PD have been shown to have a higher prevalence of RA than patients without periodontitis. Antibodies to Gram-negative, anaerobic periodontal pathogens such as Porphyromonas gingivalis, Prevotella intermedia, Prevotella melaninogenica, and Tannerella forsythia have been detected in the serum and synovial fluid of RA patients. These pathogens have also been identified in the synovial fluid of RA patients, with higher levels of bacterial DNA in RA patients than in controls. This review examines the association between periodontopathic bacteria and the etiology of RA. ... Read more