International Immunology (INT IMMUNOL)

Publisher: Oxford University Press (OUP)

Journal description

International Immunology publishes a broad range of experimental and theoretical studies in molecular and cellular immunology conducted in laboratories throughout the world.

Current impact factor: 3.18

Impact Factor Rankings

2015 Impact Factor Available summer 2015
2013 / 2014 Impact Factor 3.181
2012 Impact Factor 3.135
2011 Impact Factor 3.415
2010 Impact Factor 3.301
2009 Impact Factor 3.403
2008 Impact Factor 3.181
2007 Impact Factor 3.29
2006 Impact Factor 4.015
2005 Impact Factor 3.317
2004 Impact Factor 3.543
2003 Impact Factor 3.69
2002 Impact Factor 3.595
2001 Impact Factor 3.611
2000 Impact Factor 3.13
1999 Impact Factor 2.897
1998 Impact Factor 3.188
1997 Impact Factor 3.548
1996 Impact Factor 4.485
1995 Impact Factor 4.333
1994 Impact Factor 4.185
1993 Impact Factor 3.954
1992 Impact Factor 3.841

Impact factor over time

Impact factor

Additional details

5-year impact 3.23
Cited half-life 8.40
Immediacy index 0.41
Eigenfactor 0.01
Article influence 1.36
Website International Immunology website
Other titles International immunology online., International immunology
ISSN 0953-8178
OCLC 20567176
Material type Periodical, Internet resource
Document type Journal / Magazine / Newspaper, Internet Resource

Publisher details

Oxford University Press (OUP)

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    • 12 months embargo
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    • Eligible authors may deposit in OpenDepot
    • The publisher will deposit in PubMed Central on behalf of NIH authors
    • Publisher last contacted on 19/02/2015
    • This policy is an exception to the default policies of 'Oxford University Press (OUP)'
  • Classification
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Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: During the last 20 years a deeper understanding of the lymphatic circulatory system, lymph formation, and composition has emerged. This review will examine the current knowledge on the organization of the lymphatic vascular tree, the formation of lymph from the extracellular fluid, lymph circulation and the lymph proteomic composition during physiological and pathological conditions. Formation of the lymph fluid is dependent on pressure gradients in the capillary beds and the composition of the endothelial cell glycocalyx, which acts as a molecular sieve. Fluid propulsion towards the draining node is dependent on the intrinsic pumping mechanism of the lymphangions and their unidirectional valves. The lymph 'omics' composition is dependent on the ultrafiltration of plasma proteins as well as proteins and molecules derived from the metabolic and catabolic activities of each parenchymal organ from which the lymph drains. Altogether, these new insights have brought about a new awareness of the importance of the lymphatic system in human physiology and pathology. © The Japanese Society for Immunology. 2015. All rights reserved. For permissions, please e-mail:
    International Immunology 03/2015; DOI:10.1093/intimm/dxv012
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    ABSTRACT: The specific organ placenta is much more than a filter: it is an organ which protects, feeds, and regulates the grooving of the embryo. Affinity chromatography, ELISA, SDS-PAGE and MALDI mass spectrometry were used. Using ten intact human placentas deprived of blood a quantitative analysis of average relative content (%) of total IgGs (92.7), IgA (2.4), IgM (2.5), kappa-Abs (51.4), lambda-Abs (48.6), IgG1 (47.0), IgG2 (39.5), IgG3 (8.8), and IgG4 (4.3) was carried out for the first time. It was shown for the fist time that placenta contains sIgA (2.5 %). In the classic paradigm, immunoglobulins represent products of clonal B cell populations, each producing antibodies recognizing a single antigen. There is a common belief that IgGs in mammalian biological fluids are monovalent molecules having stable structures and two identical antigen-binding sites. However, similarly to human milk immunoglobulins, placenta antibodies undergo to extensive half-molecule exchange and IgG pool consists of 43.5 ± 15.0% kappa-kappa-IgGs, and 41.6 ± 17.0% of lambda-lambda-IgGs, while 15.0 ± 4.0% of the IgGs contained both kappa- and lambda-□light chains. Kappa-kappa-IgGs and lambda-lambda-IgGs contained respectively (%): IgG1 (47.7 and 34.4), IgG2 (36.3 and 44.5), IgG3 (7.4 and 11.8), and IgG4 (7.5 and 9.1), while chimeric kappa-lambda-IgGs consisted of (%): 43.5 IgG1, 41.0 IgG2, 5.6 IgG3, and 7.9 IgG4. Our data are indicative of the possibility of half-molecule exchange between placenta IgGs of various subclasses, raised against different antigens, which explains a very well known polyspecificity and cross-reactivity of different human IgGs. © The Japanese Society for Immunology. 2015. All rights reserved. For permissions, please e-mail:
    International Immunology 02/2015; DOI:10.1093/intimm/dxv003
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    ABSTRACT: The aim of this study was to evaluate the association between the HLA-G 14bp dele-tion/insertion (Del/Ins) polymorphism and soluble (s) HLA-G production in patients with Crohn's disease (CD). We analyzed also the sHLA-G molecules by ELISA and Western Blot in plasma samples. Among unselected patients, the 14bp Del/Ins polymorphism was not sig-nificantly associated with increased Crohn's disease risk neither for alleles (p=0.371) nor for genotypes (p=0.625). However, a significant association was reported between the 14bp Del/Ins polymorphism and CD, in particular in young-onset CD patients for alleles (p=0.020, OR= 2.438, 95%CI: 1.13-5.25) but not with adult-onset CD patients. A significant associa-tion was reported concerning the genotype Ins/Ins for young-onset CD patients (p=0.029, OR=3.257, 95%CI:1.08-9.77). We observed also a significant increase in sHLA-G dosed by ELISA in CD patients compared to controls (p=0.002). The 14bp Del/Del and 14bp Del/Ins genotypes are the high HLA-G producers. Among sHLA-G(positive) patients, a 43% of subjects present dimers of HLA-G. The presence of dimers seems to be related to the advanced stages of the disease. The 14bp Del/Ins polymorphism is associated with an increased risk of CD particularly in young-onset CD patients and controls sHLA-G plasma levels. Dimers of sHLA-G are frequent in advanced disease stages. The above findings indicate that the genetic 14bp Del/Ins polymorphism in the exon 8 of HLA-G gene is associated with the risk of CD, and suggest a role for sHLA-G as prognostic marker for progressive disease. © The Japanese Society for Immunology. 2015. All rights reserved. For permissions, please e-mail:
    International Immunology 01/2015; DOI:10.1093/intimm/dxv002
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    ABSTRACT: Active vitamin D (1,25D3) blocks the development of experimental autoimmune diseases. However, the molecular and immunobiological mechanisms underlying 1,25D3's anti-inflammatory properties are not fully understood. We employed a murine model of experimental autoimmune encephalomyelitis (EAE) in order to determine the role of NKT cells in 1,25D3-mediated protection from EAE. WT mice or mice lacking all NKT cells (CD1d(-/-)) or invariant NKT cells (Jα18(-/-)) were fed control or 1,25D3 supplemented diets. All mice fed control diet developed severe EAE. 1,25D3 treatment of WT mice protected them from developing EAE. CD1d(-/-) and Jα18(-/-) mice treated with 1,25D3 were not protected to the same extent as WT mice. MOG-specific IL-17 and IFN-γ production was significantly reduced in 1,25D3 WT mice compared to WT but was not decreased in 1,25D3 CD1d(-/-) mice compared to CD1d(-/-) mice. IL-4(-/-) mice were utilized to determine how IL-4 deficiency affects susceptibility to EAE. IL-4(-/-) mice were not protected from developing EAE by α-GalCer or 1,25D3 treatment. Furthermore, 1,25D3 treatment of splenocytes in vitro decreased α-GalCer-induced IL-17 and increased IL-4, IL-5 and IL-10 production. 1,25D3 alters the cytokine profile of iNKT cells in vitro. These studies demonstrate that NKT cells are important mediators of 1,25D3-induced protection from EAE in mice and NKT cell-derived IL-4 may be an important factor in providing this protection. © The Japanese Society for Immunology. 2015. All rights reserved. For permissions, please e-mail:
    International Immunology 01/2015; DOI:10.1093/intimm/dxu147
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    ABSTRACT: Drak2 is a promising therapeutic target to treat organ-specific autoimmune diseases such as type 1 diabetes and multiple sclerosis without causing generalized immune suppression. Inhibition of Drak2 may also prevent graft rejection following organ in various tumor cell lines, which would challenge the prospect of targeting Drak2 for therapeutic treatment. Thus, we examined the susceptibility of Drak2(-/-) mice in several tumor models. We show that Drak2 is not required to prevent tumor formation in a variety of settings. Therefore, Drak2 does not function as an essential tumor suppressor in in vivo tumor models. These data further validate Drak2 as a viable therapeutic target to treat autoimmune disease and graft rejection. Importantly, these data also indicate that while Drak2 may induce apoptosis when overexpressed in cell lines, it is not an essential tumor suppressor. © The Japanese Society for Immunology. 2015. All rights reserved. For permissions, please e-mail:
    International Immunology 01/2015; DOI:10.1093/intimm/dxu146
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    ABSTRACT: The anaemia of chronic disease results from inflammation-mediated up-regulation of the iron-regulatory hormone hepcidin, with the consequent sequestration of iron limiting its availability for erythropoiesis. The inflammatory cytokine interleukin-6 (IL6), a regulator of hepcidin, has been implicated in this process. Recent in vivo and in vitro studies indicate that interleukin-22 (IL-22) is also able to stimulate hepcidin expression. We aimed to determine if IL-22 had a role in causing the hypoferremia associated with the inflammatory response. Wild-type and Il22 knockout mice were subjected to an acute inflammatory stimulus via administration of lipopolysaccharide (LPS) and the response of hepcidin and iron homeostasis analysed. In the absence of IL-22 there was a response of hepcidin, resulting in a reduction in serum iron levels. However, the hypoferremic response to LPS was slightly blunted in mice lacking IL-22, suggesting that, during LPS-mediated inflammation, IL-22 may play a minor role in mediating the hypoferremic response. These results may have implications for the treatment and management of the anaemia of chronic disease. © The Japanese Society for Immunology. 2015. All rights reserved. For permissions, please e-mail:
    International Immunology 01/2015; DOI:10.1093/intimm/dxu144
  • International Immunology 01/2015; 27(1):1-2. DOI:10.1093/intimm/dxu106
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    ABSTRACT: The respiratory syncytial virus (RSV) is responsible for as many as 199,000 annual deaths worldwide. Currently there is no standard treatment for RSV disease, and no vaccine. Sendai virus is an attractive pediatric vaccine candidate because it elicits robust and long-lasting virus-specific B cell and T cell activities in systemic and mucosal tissues. The virus serves as a gene delivery system as well as a Jennerian vaccine against its close cousin, human parainfluenza virus type 1. Here is described the testing of a recombinant SeV (SeVRSV-Fs) that expresses an unconstrained, secreted RSV-F protein as a vaccine against RSV in cotton rats. After a single intranasal immunization of cotton rats with SeVRSV-Fs, RSV-specific binding and neutralizing antibodies were generated. These antibodies exhibited cross-reactivity with both RSV A and B isolates. RSV-F-specific interferon-γ-producing T cells were also activated. The SeVRSV-Fs vaccine conferred complete protection against RSV challenge without enhanced immunopathology. In total, results showed that an SeV recombinant that expresses RSV F in an unconstrained, soluble form can induce humoral and cellular immunity that protects against infection with RSV. © The Japanese Society for Immunology. 2014. All rights reserved. For permissions, please e-mail:
    International Immunology 12/2014; DOI:10.1093/intimm/dxu107
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    ABSTRACT: A canonical pre-TCR/TCR signaling pathway critical for thymic T cell development involves sequential phosphorylation and signaling through Lck, Zap70, Lat, and Slp76. However, we and others have previously reported that genomic deletion of c-Cbl (Cbl) partially or completely reverses the defects in thymic development in mice deficient in Zap70, Slp76, Lat, or Vav1, indicating the presence of alternative pathways normally suppressed by Cbl. To further elucidate pre-TCR/TCR signaling pathways involved in thymic development, we characterized the effect of Cbl inactivation on developmental and signaling defects in mice deficient in proximal signaling molecules Lck and Zap70. Inactivation of Cbl partially reversed defective T cell development in Zap70(-/-) mice and reversed defects in phosphorylation of Erk, Plc-γ1, Vav1, and Akt, in TCR-stimulated Cbl(-/-)Zap70(-/-) thymocytes. Recent reports identified an essential role of Lck in associating with CD4 and CD8 coreceptors and mediating the requirement for MHC restriction in TCR recognition. Since TCR recognition has been shown to be MHC-restricted in Cbl(-/-) mice, it was of interest to determine whether the requirement for Lck remained unmodified by Cbl deletion, Indeed, in contrast to the effect of Cbl inactivation in partially or fully bypassing requirements for other TCR signaling components, inactivation of Cbl did not reverse either defective T cell developmental or defective phosphorylation of TCR signaling molecules in Lck(-/-) mice. Thus, Lck, which plays a unique role in enforcing MHC restriction, is essential for thymic development in presence or absence of Cbl, ensuring MHC restriction of T cells derived from either pathway. Published by Oxford University Press on behalf of The Japanese Society for Immunology 2014.
    International Immunology 12/2014; DOI:10.1093/intimm/dxu105
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    ABSTRACT: If Bcl11b activity is compromised, CD4(+)CD8(+) double-positive (DP) thymocytes produce a greatly increased fraction of innate CD8(+) single-positive (SP) cells highly producing IFN-γ, which are also increased in mice deficient of genes such as Itk, Id3 and NF-κB1 that affect TCR signaling. Of interest, the increase in the former two is due to the bystander effect of IL-4 that is secreted by PLZF-expressing NKT and γδT cells whereas the increase in the latter is cell intrinsic. Bcl11b zinc-finger proteins play key roles in T cell development and T cell-mediated immune response likely through TCR signaling. We examined thymocytes at and after the DP stage in Bcl11b(F/S826G) CD4cre, Bcl11b(F/+) CD4cre, and Bcl11b(+/S826G) mice, carrying the allele that substituted serine for glycine at the position of 826. Here we show that Bcl11b impairment leads to an increase in the population of TCRαβ(high)CD44(high)CD122(high) innate CD8SP thymocytes, together with two different developmental abnormalities: impaired positive and negative selection accompanying a reduction in the number of CD8SP cells, and developmental arrest of NKT cells at multiple steps. The innate CD8SP thymocytes express Eomes and secrete IFN-γ after the stimulation with PMA and ionomycin, and in this case their increase is not due to a bystander effect of IL-4 but cell intrinsic. Those results indicate that Bcl11b regulates development of different thymocyte subsets at multiple stages and prevents the excess of innate CD8SP thymocytes. © The Japanese Society for Immunology. 2014. All rights reserved. For permissions, please e-mail:
    International Immunology 11/2014; DOI:10.1093/intimm/dxu104
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    ABSTRACT: Endometriosis is a significant debilitating gynecological problem affecting women of reproductive age group and post-menopause. Recent reports prompt at the role of endometriotic Mesenchymal Stem Cells (ectopic MSCs) in pathogenesis of endometriosis. To investigate the plausible mechanisms leading to the pathogenic behavior of ectopic MSCs, we compared the immunomodulatory properties of eutopic and ectopic (healthy) MSCs. We analyzed MSC phenotypes, differential gene expression for an array of pattern recognition receptors (PRRs) and pro-inflammatory cytokine release along with markers of migration and angiogenesis among eutopic and ectopic MSCs. Further, alterations in immunosuppressive functions of eutopic and ectopic MSCs were examined by co-culturing them with mitogen-activated allogenic PBMCs. Transcripts of PRRs such as all Toll-like Receptors (TLR 1-10), except TLR8, collectins (CL-L1, CL-P1, CL-K1), NOD-1 and 2 receptors, secreted pro-inflammatory cytokines like IL-6, IFNγ, VEGF, EGF, MCP-1 were significantly upregulated in ectopic MSCs. The anti-inflammatory cytokine TGFβ showed significant downregulation, while IL-10 showed a significant increase in ectopic MSCs. Further, ectopic MSCs showed upregulated expression for markers of migration and angiogenesis such as MMP - 2, 3, 9 and VEGF respectively. We report here that proliferation of PBMCs was less inhibited upon co-culture with ectopic MSCs compared with eutopic MSCs. The findings suggest that ectopic MSCs with increased levels of TLRs, collectins, pro-inflammatory cytokines and markers of migration and angiogenesis, exhibit a distinct immune-phenotype compared to eutopic MSCs. This distinct phenotype may be responsible for the reduced immunosuppressive property of ectopic MSCs and may be associated with the pathogenesis of endometriosis. © The Japanese Society for Immunology. 2014. All rights reserved. For permissions, please e-mail:
    International Immunology 11/2014; DOI:10.1093/intimm/dxu103
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    ABSTRACT: While for a century therapeutics has been dominated by small molecules organic chemicals of ~ 400 daltons absorbable via the gut, this is no longer the case. There are now a plethora of important medicines which are proteins, and injectable which have dramatically improved the therapy of many inflammatory diseases and of cancer. Most of these are monoclonal antibodies, some are receptor Ig Fc fusion proteins, others are cytokines or enzymes. The key to this new aspect of therapeutics has been the filling of unmet needs, and the consequent commercial success, which promoted further research and development. The first 'biologic' for a common disease, rheumatoid arthritis (RA) was a monoclonal antibody to human TNF, infliximab. This was based on our work, which is described in this review, summarising how TNF was defined as a good target in RA, how it was developed is described here, as well as future indications for antiTNF and related agents. Biologics are now the fastest growing sector of therapeutics. © The Japanese Society for Immunology. 2014. All rights reserved. For permissions, please e-mail:
    International Immunology 11/2014; DOI:10.1093/intimm/dxu102
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    ABSTRACT: Primary Sjögren's syndrome (pSS) is a chronic autoimmune disorder of the exocrine glands with associated lymphocytic infiltrates of the affected glands. Dryness of the mouth and eyes results from involvement of the salivary and lacrimal glands. Efficacy of Rituximab (RTX) in pSS is still open to debate. This study delineates the signalling pathway involved in RTX-mediated pro-inflammatory factors down-regulation in a co-culture system of pSS salivary gland epithelial cells (SGEC) with syngeneic pSS B-lymphocytes. In addition, the effects of RTX on the Raf-1/ERK1/2 pathway activation in pSS SGEC co-cultured with syngeneic pSS T-lymphocytes were also investigated. This study demonstrated that RTX may interfere with the ERK1/2 pathway in a syngeneic co-culture of pSS SGEC with pSS B lymphocytes, leading to decreased cytokines production by SGEC. These novel findings reveal that syngeneic co-culture of pSS SGEC with pSS B lymphocytes leads to a down-regulation of Raf-1 in epithelial cells that adversely regulates the activity of the ERK1/2 pathway and determines a subsequent reduction of the pro-inflammatory factors release.
    International Immunology 11/2014; DOI:10.1093/intimm/dxu100
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    ABSTRACT: G protein-coupled receptor 55 (GPR55) is activated by endogenous, plant-derived and synthetic cannabinoids. Recent studies reported a broad tissue distribution for GPR55 and found prominent roles for this receptor in inflammatory pain, gut and bone physiology, as well as cancer. However, little is known about the expression and function of GPR55 in immune cells. To address this question, we performed a detailed characterization of GPR55 in different human innate and adaptive immune populations using polychromatic flow cytometry and we found that monocytes and NK cells expressed remarkable levels of this receptor compared to several cells of adaptive immunity. GPR55 activation by the specific agonist O-1602 boosted IL-12 and TNF-α production, and increased endocytic activity, in LPS-activated monocytes. In addition, it increased CD69 activation marker expression, granzyme B and CD107a-dependent cytotoxicity, IFN-γ and TNF-α production in NK cells activated by both IL-2 and IL-12. These over-stimulatory effects of GPR55 were antagonized by its selective antagonist cannabidiol (CBD). Altogether, our data thus unveil a proinflammatory role for GPR55 in innate immunity that may be important for the design of new immune therapeutic strategies.
    International Immunology 10/2014; DOI:10.1093/intimm/dxu097
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    ABSTRACT: The immune system is inextricably linked with many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), a devastating neuromuscular disorder affecting motor cell function with an average survival of 3 years from symptoms onset. In ALS there is a dynamic interplay between the resident innate immune cells, i.e. microglia and astrocytes, which may become progressively harmful to motor neurons. While innate and adaptive immune responses are associated with progressive neurodegeneration, in the early stages of ALS immune activation pathways are primarily considered to be beneficial promoting neuronal repair of the damaged tissues, though a harmful effect of T cells at this stage of disease has also been observed. In addition, while autoantibodies against neuronal antigens are present in ALS, it is unclear whether these arise as a primary or secondary event to neuronal damage, and whether the autoantibodies are indeed pathogenic. Understanding how the immune system contributes to the fate of motor cells in ALS may shed light on the triggers of disease as well as on the mechanisms contributing to the propagation of the pathology. Immune markers may also act as biomarkers while pathways involved in immune action may be targets of new therapeutic strategies. Here, we review the modalities by which the immune system senses the core pathological process in motor neuron disorders, focussing on tissue-specific immune responses in the neuromuscular junction and in the neuroaxis observed in affected individuals and in animal models of ALS. We elaborate on existing data on the immunological fingerprint of ALS that could be used to identify clues on the disease origin and patterns of progression.
    International Immunology 10/2014; DOI:10.1093/intimm/dxu099
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    ABSTRACT: Allergic contact dermatitis (ACD) is one of typical occupational diseases in industrialized countries. Although various cytokines and chemokines are suggested to be involved in the pathogenesis of ACD, the roles of these molecules remain to be elucidated. CC chemokine receptor 8 (CCR8) is one of such molecules, of which expression is up-regulated in inflammatory sites of ACD patients. In this study, we found that Ccr8(-/-) mice developed severer contact hypersensitivity (CHS) responses to 2,4-dinitrofluorobenzene, a murine model of ACD, compared to wild-type mice. T cells from Ccr8(-/-) mice showed enhanced proliferative recall responses and Th1 and Th17 cell populations were expanded in these mice. However, CHS responses were similar between SCID mice adoptively transferred with Ccr8(-/-) and WT T cells, suggesting that CCR8 in T cells is not responsible for the exacerbation of CHS. Notably, skin-resident dendritic cells (DCs), such as Langerhans cells and dermal DCs, and inflammatory DCs were highly accumulated in lymph nodes (LNs) of Ccr8(-/-) mice after sensitization. Consistent with this, Ccr8(-/-) antigen presenting cells readily migrated from the skin to the draining LNs after sensitization. These observations suggest that CCR8 negatively regulates migration of cutaneous DCs from the skin to the draining LNs in CHS by keeping these cells in the skin.
    International Immunology 10/2014; DOI:10.1093/intimm/dxu098
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    ABSTRACT: Multiple Sclerosis (MS) is a disorder of putative autoimmune origin, where immune cells invade the central nervous system and cause damage by attacking the myelin sheath of nerve cells. The blockade of the integrin very-late-antigen-4 (VLA-4) with the monoclonal antibody natalizumab has become the most effective therapy against MS since its approval in 2004. It is assumed that the inhibition of VLA-4-mediated immune cell adhesion to the endothelium of the blood-brain-barrier alleviates pathogenic processes of MS and, therefore, reduces disease severity and -burden. Not all approaches to treat additional immune-mediated disorders (e.g. Rasmussen Encephalitis and Neuromyelitis Optica) with natalizumab have been successful, but allowed researchers to gain additional insight into mechanisms of specific immune cell subsets' blood-brain-barrier migration in the human system. While the long-term efficacy and general tolerability of natalizumab in MS are clear, the over 400 cases of natalizumab-associated progressive multifocal leukoencephalopathy have been of great concern and methods of risk stratification in patients have become a major area of research. Modern risk stratification includes established factors such as treatment duration, previous immune-suppressive therapy, and anti-JC virus antibody seropositivity, but also experimental factors such as anti-JC virus antibody titers and levels of L-selectin. Today, anti-VLA-4 therapy is reserved for patients with highly active relapsing-remitting MS and patients are monitored closely for early signs of potential progressive multifocal leukoencephalopathy.
    International Immunology 10/2014; DOI:10.1093/intimm/dxu096
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    ABSTRACT: The human immune system evolves continuously during development from the embryo into the adult, reflecting the ever-changing environment and demands of our body. This ability of our immune system to sense external cues and adapt as we develop is just as important in the early tolerogenic environment of the fetus, as it is in the constantly pathogen-challenged adult. Dendritic cells (DCs), the professional antigen-sensing and antigen-presenting components of the immune system, play a crucial role in this process where they act as sentinels, both initiating and regulating immune responses. Here we provide an overview of the human immune system in the developing fetus and the adult, with a focus on DC ontogeny and function during these discrete but intimately linked life stages.
    International Immunology 10/2014; DOI:10.1093/intimm/dxu091
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    ABSTRACT: Despite extensive investigation over the past three decades, cancer immunotherapy has produced limited success, with few agents achieving approval by the Food and Drug Administration and even the most effective helping only a minority of patients, primarily with melanoma or renal cancer. In recent years immune checkpoints that maintain physiologic self-tolerance have been implicated in the downregulation of antitumor immunity. Efforts to restore latent antitumor immunity have focused on antibody-based interventions targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on T lymphocytes, and its principal ligand (PD-L1) on tumor cells. Ipilimumab, an antibody targeting CTLA-4, appears to restore tumor immunity at the priming phase whereas anti-PD- 1/PD-L1 antibodies restore immune function in the tumor microenvironment. Although ipilimumab can produce durable long-term responses in patients with advanced melanoma, it is associated with significant immune-related toxicities. By contrast, antibodies targeting either PD-1 or PD-L1 have produced significant antitumor activity with considerably less toxicity. Activity was seen in patients with melanoma and renal cancer, as well as those with non-small cell lung, bladder and head and neck cancers, tumors not previously felt to be sensitive to immunotherapy. The tolerability of PD-1-pathway blockers and their unique mechanism of action have made them ideal backbones for combination regimen development. Combination approaches involving cytotoxic chemotherapy, anti-angiogenic agents, alternative immune-checkpoint inhibitors, immunostimulatory cytokines and cancer vaccines, are currently under clinical investigation. Current efforts focus on registration trials of single agents and combinations in various diseases and disease settings and identifying predictive biomarkers of response.
    International Immunology 10/2014; DOI:10.1093/intimm/dxu095