Abstract：
:The LTB4 pathway is an attractive target for therapeutic drug development. Two broad classes of drugs have been pursued: antagonists of the primary LTB4 receptors (BLT1 and BLT2) and inhibitors of LTA4 Hydrolase (LTA4H), the rate limiting enzyme in the production of LTB4. An initial wave of effort culminated in the 1990s. Over the past 15 years, a second wave of more selective drug candidates, including at least 5 BLT antagonists and 6 LTA4H inhibitors, have reached Phase 2 clinical trials. Despite the extensive efforts to discover and develop LTB4 pathway targeting drugs, only one has reached the market to date. Recently discovered complexities in the pathway and challenges in matching pathway intervention with therapeutic effect could explain the limited clinical success of LTB4 pathway drugs, even though there is a large body of scientific evidence linking LTB4 to human diseases and demonstrating efficacy of these compounds in a wide array of preclinical models. Herein, we describe the clinical programs for the most prominent recent examples from each broad class and discuss the clinical outcomes and their implications for future development of LTB4 pathway drugs.
journal_name
Semin Immunoljournal_title
Seminars in immunologyauthors
Bhatt L,Roinestad K,Van T,Springman EBdoi
10.1016/j.smim.2017.08.007subject
Has Abstractpub_date
2017-10-01 00:00:00pages
65-73eissn
1044-5323issn
1096-3618pii
S1044-5323(16)30133-6journal_volume
33pub_type
杂志文章,评审abstract：:It is known that even the adaptive components of the immune system are based on genetic traits common to all individuals, and that diversity is shaped by the lifelong contacts with different non-self antigens, including those found on infectious pathogens. Besides the individual differences, some of these common trait...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1016/j.smim.2015.03.008
更新日期：2015-03-01 00:00:00
abstract：:CD4+ helper T cells recognize short peptides stably associated with class II MHC molecules displayed on the surface of antigen presenting cells. Very little is known about the sequence of events that lead to the generation of these peptides from protein antigens. It is likely that native proteins must partially unfold...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1006/smim.1995.0039
更新日期：1995-12-01 00:00:00
abstract：:Polymorphic MHC is absent from the trophoblast, therefore, it resists NK as well as CTL-mediated lysis in vitro. Activated gamma / delta TCR positive cells are significantly enriched in the decidua as well as in peripheral blood of healthy pregnant women. Human peripheral gamma / delta lymphocytes preferentially expre...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1006/smim.2000.0318
更新日期：2001-08-01 00:00:00
abstract：:Antigen may be targeted to antigen presenting cells (APC) by conjugating the antigen to monoclonal antibodies directed against surface molecules on APC. By now several laboratories have shown that immunotargeting enhances humoral responses, depending upon the targeted ligand or cell type, with low doses of antigen and...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：
更新日期：1992-08-01 00:00:00
abstract：:T helper (TH) cells can assume different phenotypes characterized by the secretion of distinct effector molecules. Interferon-gamma producing TH1 and IL-4 producing TH2 cells have long been recognized as important mediators of host defense, whereas regulatory T cells are known to suppress T cell responses. Recently, T...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1016/j.smim.2007.10.016
更新日期：2007-12-01 00:00:00
abstract：:V(D)J recombination consists of a DNA cleavage reaction catalysed by RAG1 and RAG2, followed by an end-joining reaction that utilizes the cell's double-strand break repair machinery. Genes essential for the end-joining reaction include: XRCC4 encoding a protein of unknown enzymatic function; XRCC5 and XRCC6 encoding 8...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1006/smim.1997.0070
更新日期：1997-06-01 00:00:00
abstract：:Alarmins are preformed, endogenous molecules that can be promptly released to signal cell or tissue stress or damage. The ubiquitous nuclear molecule high-mobility group box 1 protein (HMGB1) is a prototypical alarmin activating innate immunity. HMGB1 serves a dual alarmin function. The protein can be emitted to alert...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1016/j.smim.2018.02.011
更新日期：2018-08-01 00:00:00
abstract：:The creation of a highly diverse antibody repertoire requires the synergistic activity of a DNA mutator, known as activation-induced deaminase (AID), coupled with an error-prone repair process that recognizes the DNA mismatch catalyzed by AID. Instead of facilitating the canonical error-free response, which generally ...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1016/j.smim.2012.05.005
更新日期：2012-08-01 00:00:00
abstract：:Studies on oral immunotherapy (OIT) have been increasing worldwide. Nevertheless, some concerns exist with this treatment. The rate of long-term sustained unresponsiveness is quite low; moreover, the desensitization or sustained unresponsiveness does not equate to tolerance. Furthermore, adverse reactions are frequent...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1016/j.smim.2017.07.008
更新日期：2017-04-01 00:00:00
abstract：:B cells require signals from multiple sources for their development from precursor cells, and differentiation into effector cells. BAFF has been identified as a critical regulator of B cell development and differentiation. Defects in the production of BAFF and/or expression of its receptors have been associated with a...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1016/j.smim.2006.04.004
更新日期：2006-10-01 00:00:00
abstract：:TCR gamma delta + T cells represent a minority of CD3+ T cells in many species including man. The molecular structure of the TCR gamma and delta loci in man is well understood. The gamma and delta loci contain V, D, J and C gene segments. These segments do not rearrange randomly but in a coordinated, ordered fashion d...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：
更新日期：1991-03-01 00:00:00
abstract：:During lymphocyte development, cell-fate decisions are determined by a myriad of signals produced by the micro- environment of the thymus and the bone marrow. These yet to be fully defined developmental cues regulate stage-specific gene expression, and the extraordinarily well-characterized stages of T and B cell deve...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1006/smim.1998.0153
更新日期：1999-02-01 00:00:00
abstract：:Vaccinations are powerful tools for combating infections. Because of the age-related impairment in immune functions, the currently available vaccines are protecting only a small proportion of the elderly population. We, here, provide an overview of age-related changes in innate and adaptive immunity with particular em...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1016/j.smim.2005.05.005
更新日期：2005-10-01 00:00:00
abstract：:In a panel of wild mice trapped in different geographical regions, the concomitant expression of V beta 17 T cell receptors and I-E histocompatibility molecules is frequent. By Southern blot analysis, eight forms of V beta 17 genes have been distinguished that encode five kinds of V beta 17 domains. Populations of Asi...
journal_title：Seminars in immunology
pub_type： 杂志文章
doi：
更新日期：1992-10-01 00:00:00
abstract：:Poxviruses, unlike some other large DNA viruses, do not undergo a latent stage but rely on the expression of viral proteins to evade host immune responses. Of the many poxviral evasion genes identified, most target cytokines or other innate immune defenses. Resistance to interferons appears to be a priority as there a...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1006/smim.2000.0296
更新日期：2001-02-01 00:00:00
abstract：:The MHC class I antigen presentation pathway enables cells infected with intracellular pathogens to signal the presence of the invader to the immune system. Cytotoxic T lymphocytes are able to eliminate the infected cells through recognition of pathogen-derived peptides presented by MHC class I molecules at the cell s...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1016/j.smim.2015.03.010
更新日期：2015-03-01 00:00:00
abstract：:Neoantigens are antigens encoded by tumor-specific mutated genes. Studies in the past few years have suggested a key role for neoantigens in cancer immunotherapy. Here we review the discoveries of neoantigens in the past two decades and the current advances in neoantigen identification. We also discuss the potential b...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1016/j.smim.2015.11.002
更新日期：2016-02-01 00:00:00
abstract：:Multiple sclerosis (MS) is an idiopathic autoimmune neurodegenerative disease. Like many common diseases, MS has a genetic component; however, as with most complex diseases, the genetic architecture may be influenced by heterogeneity, incomplete penetrance, polygenic inheritance, and environmental factors. This clinic...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1016/j.smim.2009.08.003
更新日期：2009-12-01 00:00:00
abstract：:Obesity is now recognised as a chronic, low-grade inflammatory disease contributing to insulin resistance, type 2 diabetes (T2D) and cardiovascular disease (CVD). Multiple mechanisms leading to the low grade inflammation in this setting have been suggested. Due to the complexity and interconnection of inflammatory and...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1016/j.smim.2016.10.001
更新日期：2016-10-01 00:00:00
abstract：:Minor lymphocyte stimulating (Mls) antigens have profound effects on the murine immune system and have been very important for our current understanding of immune tolerance. It has recently been discovered that these Mls antigens are encoded in an open reading frame located in the 3' long terminal repeat of endogenous...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：
更新日期：1992-10-01 00:00:00
abstract：:It is now well established that the progression of T cell development requires interactions between the surfaces of thymocytes and thymic stromal cells. For example, the maturation of CD4+8+ cells into functional CD4+ or CD8+ cells requires TCR/MHC interactions, which, depending on the specificity of the particular TC...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1006/smim.1994.1028
更新日期：1994-08-01 00:00:00
abstract：:Many human cancers possess a complex chemokine network that may influence the extent and phenotype of the leukocyte infiltrate, angiogenesis, tumor cell growth, survival and migration. Restricted expression of chemokine receptors on leukocytes may allow concise control of cell movement and retention at the tumor site....
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1016/s1044-5323(02)00127-6
更新日期：2003-02-01 00:00:00
abstract：:Bacteria, apoptotic cells and other particulate material are taken up through phagocytosis, a conserved cellular function driven by actin polymerization. As reviewed here, small GTPases of the Rho family, their activators and effectors control the local reorganization of the actin cytoskeleton underneath bound particl...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1006/smim.2001.0331
更新日期：2001-12-01 00:00:00
abstract：:Nanotechnology-based strategies can dramatically impact the treatment, prevention and diagnosis of a wide range of diseases. Despite the unprecedented success achieved with the use of nanomaterials to address unmet biomedical needs and their particular suitability for the effective application of a personalized medici...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1016/j.smim.2017.09.003
更新日期：2017-12-01 00:00:00
abstract：:Mendelian susceptibility to mycobacterial diseases confers predisposition to clinical disease caused by weakly virulent mycobacterial species in otherwise healthy individuals. Since 1996, disease-causing mutations have been found in five autosomal genes (IFNGR1, IFNGR2, STAT1, IL12B, IL12BR1) and one X-linked gene (NE...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1016/j.smim.2006.07.010
更新日期：2006-12-01 00:00:00
abstract：:T helper 17 (Th17) cells have been reported to be responsible for several chronic inflammatory diseases. However, a peculiar feature of human Th17 cells is that they are very rare in the inflammatory sites in comparison with Th1 cells. The first reason for this rarity is the existence of some self-regulatory mechanism...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1016/j.smim.2013.10.011
更新日期：2013-11-15 00:00:00
abstract：:The germinal center is a critical locus in the production of protective immunity, but its function is poorly understood. Studies of mutant forms of CD19 revealed differences in signaling in different compartments inside the germinal center, and structural findings indicate a selective role in the interaction with foll...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1016/j.smim.2007.12.007
更新日期：2008-02-01 00:00:00
abstract：:Interferon epsilon (IFNε) is a type I IFN with unusual patterns of expression and therefore, function. It is constitutively expressed by reproductive tract epithelium and regulated by hormones during estrus cycle, reproduction, and menopause and by exogenous hormones. The IFNe protein is encoded by a gene in the type ...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1016/j.smim.2019.101328
更新日期：2019-06-01 00:00:00
abstract：:In seeking an explanation for the complexity of tissue development, biologists are obliged to explain lineage commitment, the events that dictate whether or not a progenitor cell will differentiate into one cell type or another. Such explanations have been sought across a broad spectrum of biological systems, although...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1006/smim.1999.0180
更新日期：1999-08-01 00:00:00
abstract：:Recent advances have enabled a comprehensive understanding of the genetic architecture of inflammatory bowel disease (IBD) with over 30 identified and replicated disease loci. The pathophysiological consequences of disease gene variants in Crohn disease and ulcerative colitis, the two main subentities of IBD, so far a...
journal_title：Seminars in immunology
pub_type： 杂志文章,评审
doi：10.1016/j.smim.2009.10.001
更新日期：2009-12-01 00:00:00
