Xenobiotics, chimerism and the induction of tolerance following organ transplantation

The successful results seen after organ transplantation are largely attributable to the potency and specificity of modern immunosuppressive agents. Although drug-free unresponsiveness to graft alloantigens has not been routinely achieved in clinical practice, recent appreciation of the importance of cell chimerism, which develops after the migration from donor to host of leukocytes contained in solid organ grafts, has introduced a concept which may explain the mechanism of graft tolerance. Recent evidence has indicated that immunosuppressive drugs may have a common potential to induce graft tolerance, even though they act through diverse mechanisms, and that this potential may be mediated by a permissive effect on the migration and survival of donor-derived leukocytes. This review briefly examines the mechanisms by which immunosuppressive drugs function and analyses the different methods which these agents might use to induce chimerism associated with graft tolerance. Furthermore, we describe ongoing clinical studies in which the chimerism produced after solid organ transplantation is augmented with donor bone marrow in an attempt to facilitate the induction of tolerance

Identification of donor-derived dendritic cell progenitors in bone marrow of spontaneously tolerant liver allograft recipients

Multilineage donor-derived hematopoietic cell chimerism is a persistent feature of spontaneously tolerant mouse liver allograft recipients. We have shown previously that normal liver-derived precursors of “chimeric” dendritic cells (DC) propagated in vitro migrate in vivo to T-dependent areas of allogeneic lymphoid tissue, where they or their progeny appear to persist indefinitely. In this study, granu-locyte-macrophage colony-stimulating factor (GM-CSF)+interleukin-4 (IL-4) were used to propagate DC progenitors from freshly isolated mouse bone marrow. The progenitor cells gave rise in 7-10 days to potent antigen-presenting cells (APC) that stimulated naive allogeneic T cells in primary mixed leukocyte cultures (MLC). The culture method, together with the reverse transcriptase-polymerase chain reaction (RT-PCR) for the detection of donor and recipient strain major histocompatibility complex (MHC) class II mRNA was used to test whether donor-derived DC could be propagated from the bone marrow of unmodified, orthotopic liver allograft recipients. Freshly isolated bone marrow from these transplanted animals contained small numbers of donor cells and responded to GM-CSF+IL-4 stimulation. In addition to cells expressing recipient (BIO) phenotype (H-2Kb+; Iab+), a minor population of donor (BlO.BR)-derived cells (H-2Kk+; Iak) were also propagated from liver graft recipients euthanized two weeks posttransplant. DC sorted from these cultures exhibited stimulatory activity for recipient strain T cells consistent with a low level (<1%) of donor DC propagation. The immunologic role of donor-derived DC progenitors in liver allograft recipients and its relation to the induction and maintenance of donor-specific unresponsiveness remains to be determined. © 1995 by Williams & Wilkins

Instrumental and Constructivist Conceptualizations of Ethnicity: Implications for Latin American Social Movements Research

This is the author accepted manuscript. The final version is available from Instituto de Estudios Internacionales de la Universidad de Chile via the DOI in this record.Within the realm of comparative politics ethnicity has been conceptualized as both a fixed category individuals are born into, as well as a relatively fluid identity that can be made politically salient by different actors. The latter perspective corresponds with instrumental and constructivist conceptualizations of ethnicity that seeks first and foremost to answer the question: ‘Under which circumstances will ethnicity become activated and affect citizens’ political behavior?’ Beginning in the 1990s, Latin American social movements began to ‘play the ethnic card’, which culminated with the first indigenous candidate ever to win a presidential election in the region in 2005. Applying research designs based on instrumental and constructivist conceptualizations of ethnicity could significantly advance the study of Latin American social movements

Public Support for Economic and Military Coercion and Audience Costs

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.I specify the role public support for economic and military coercion and reactions to executive inconsistencies play in generating and/or weakening approval for executives. In times of international crises, these factors may compete against each other when it comes to determining public approval. To examine this claim, I conducted a survey experiment on a representative sample of adults to determine when audiences will support economic or military coercion, and how this willingness to support specific coercive action affects their evaluation of the executive’s handling of international crises. I find that public policy preferences can have a stronger effect than a preference for having a leader behave consistently. Specifically, I find that, (1) executive inconsistency is not punished when a leader backs down from a military commitment in a non-threatening crisis, (2) executive inconsistencies are not only punished in military disputes but also in cases of economic coercion (punishment is in fact more prominent in sanctions cases), and (3) executive inconsistency can be punished both in major and lesser conflicts.This work was supported by the National Science Foundation (SES-1123291). Any opinions, findings, and conclusions or recommendations expressed in this material do not necessarily reflect the views of the National Science Foundation

TLR7-mediated skin inflammation remotely triggers chemokine expression and leukocyte accumulation in the brain

Background: The relationship between the brain and the immune system has become increasingly topical as, although it is immune-specialised, the CNS is not free from the influences of the immune system. Recent data indicate that peripheral immune stimulation can significantly affect the CNS. But the mechanisms underpinning this relationship remain unclear. The standard approach to understanding this relationship has relied on systemic immune activation using bacterial components, finding that immune mediators, such as cytokines, can have a significant effect on brain function and behaviour. More rarely have studies used disease models that are representative of human disorders. Methods: Here we use a well-characterised animal model of psoriasis-like skin inflammation—imiquimod—to investigate the effects of tissue-specific peripheral inflammation on the brain. We used full genome array, flow cytometry analysis of immune cell infiltration, doublecortin staining for neural precursor cells and a behavioural read-out exploiting natural burrowing behaviour. Results: We found that a number of genes are upregulated in the brain following treatment, amongst which is a subset of inflammatory chemokines (CCL3, CCL5, CCL9, CXCL10, CXCL13, CXCL16 and CCR5). Strikingly, this model induced the infiltration of a number of immune cell subsets into the brain parenchyma, including T cells, NK cells and myeloid cells, along with a reduction in neurogenesis and a suppression of burrowing activity. Conclusions: These findings demonstrate that cutaneous, peripheral immune stimulation is associated with significant leukocyte infiltration into the brain and suggest that chemokines may be amongst the key mediators driving this response

Anti-Allergic Cromones Inhibit Histamine and Eicosanoid Release from Activated Human and Murine Mast Cells by Releasing Annexin A1

PMCID: PMC3601088This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Fungal iron availability during deep seated candidiasis is defined by a complex interplay involving systemic and local events

Peer reviewedPublisher PD

Anti-müllerian hormone is not associated with cardiometabolic risk factors in adolescent females

&lt;p&gt;Objectives: Epidemiological evidence for associations of Anti-Müllerian hormone (AMH) with cardiometabolic risk factors is lacking. Existing evidence comes from small studies in select adult populations, and findings are conflicting. We aimed to assess whether AMH is associated with cardiometabolic risk factors in a general population of adolescent females.&lt;/p&gt; &lt;p&gt;Methods: AMH, fasting insulin, glucose, HDLc, LDLc, triglycerides and C-reactive protein (CRP) were measured at a mean age 15.5 years in 1,308 female participants in the Avon Longitudinal Study of Parents and Children (ALSPAC). Multivariable linear regression was used to examine associations of AMH with these cardiometabolic outcomes.&lt;/p&gt; &lt;p&gt;Results: AMH values ranged from 0.16–35.84 ng/ml and median AMH was 3.57 ng/ml (IQR: 2.41, 5.49). For females classified as post-pubertal (n = 848) at the time of assessment median (IQR) AMH was 3.81 ng/ml (2.55, 5.82) compared with 3.25 ng/ml (2.23, 5.05) in those classed as early pubertal (n = 460, P≤0.001). After adjusting for birth weight, gestational age, pubertal stage, age, ethnicity, socioeconomic position, adiposity and use of hormonal contraceptives, there were no associations with any of the cardiometabolic outcomes. For example fasting insulin changed by 0% per doubling of AMH (95%CI: −3%,+2%) p = 0.70, with identical results if HOMA-IR was used. Results were similar after additional adjustment for smoking, physical activity and age at menarche, after exclusion of 3% of females with the highest AMH values, after excluding those that had not started menarche and after excluding those using hormonal contraceptives.&lt;/p&gt; &lt;p&gt;Conclusion: Our results suggest that in healthy adolescent females, AMH is not associated with cardiometabolic risk factors.&lt;/p&gt

The microaerophilic microbiota of de-novo paediatric inflammatory bowel disease: the BISCUIT study

&lt;p&gt;Introduction: Children presenting for the first time with inflammatory bowel disease (IBD) offer a unique opportunity to study aetiological agents before the confounders of treatment. Microaerophilic bacteria can exploit the ecological niche of the intestinal epithelium; Helicobacter and Campylobacter are previously implicated in IBD pathogenesis. We set out to study these and other microaerophilic bacteria in de-novo paediatric IBD.&lt;/p&gt; &lt;p&gt;Patients and Methods: 100 children undergoing colonoscopy were recruited including 44 treatment naïve de-novo IBD patients and 42 with normal colons. Colonic biopsies were subjected to microaerophilic culture with Gram-negative isolates then identified by sequencing. Biopsies were also PCR screened for the specific microaerophilic bacterial groups: Helicobacteraceae, Campylobacteraceae and Sutterella wadsworthensis.&lt;/p&gt; &lt;p&gt;Results: 129 Gram-negative microaerophilic bacterial isolates were identified from 10 genera. The most frequently cultured was S. wadsworthensis (32 distinct isolates). Unusual Campylobacter were isolated from 8 subjects (including 3 C. concisus, 1 C. curvus, 1 C. lari, 1 C. rectus, 3 C. showae). No Helicobacter were cultured. When comparing IBD vs. normal colon control by PCR the prevalence figures were not significantly different (Helicobacter 11% vs. 12%, p = 1.00; Campylobacter 75% vs. 76%, p = 1.00; S. wadsworthensis 82% vs. 71%, p = 0.312).&lt;/p&gt; &lt;p&gt;Conclusions: This study offers a comprehensive overview of the microaerophilic microbiota of the paediatric colon including at IBD onset. Campylobacter appear to be surprisingly common, are not more strongly associated with IBD and can be isolated from around 8% of paediatric colonic biopsies. S. wadsworthensis appears to be a common commensal. Helicobacter species are relatively rare in the paediatric colon.&lt;/p&gt

The ‘ultimate insurance’ or an ‘irrelevance’ for national security needs? Partisanship, foreign policy attitudes, and the gender gap in British public opinion towards nuclear weapons

This is the author accepted manuscript. The final version is available from Cambridge University Press via the DOI in this recordOnly two European countries – France and the UK, both NATO members – have nuclear weapons, and leading politicians have called for the UK and EU to maintain close military and security links post-Brexit. In the context of the Trident renewal debate and the UK government's recently published integrated defence and security review, this article uses data from the new UK Security Survey to analyse attitudes towards the possession of nuclear weapons among the British public. It assesses three key theorical strands in the wider scholarly literature on public opinion and states’ use of military force: domestic political attitudes, foreign policy predispositions, and the ‘gender gap’. We find that all three theoretical perspectives contribute to the underpinnings of contemporary public opinion towards nuclear weapons. Support for the retention of Britain's nuclear deterrent is associated with being a Conservative Party supporter, favouring Brexit, endorsing superior military power worldwide as an important foreign policy goal, wanting to protect the transatlantic relationship, and with being male. The article makes a distinctive contribution to the growing subfield of research on public opinion and foreign policy, while the findings advance wider empirical understanding of contemporary citizen engagement in a key dimension of security policy.Economic and Social Research Council (ESRC)University of Exete