Clinical tolerance in allogeneic hematopoietic stem cell transplantation

Allogeneic hematopoietic stem cell transplantation (HSCT) has been a curative therapeutic option for a wide range of immune hematologic malignant and non-malignant disorders including genetic diseases and inborn errors. Once in the host, allogeneic transplanted cells have not only to ensure myeloid repopulation and immunological reconstitution but also to acquire tolerance to host human leukocyte antigens via central or peripheral mechanisms. Peripheral tolerance after allogeneic HSCT depends on several regulatory mechanisms aimed at blocking alloimmune reactivity while preserving immune responses to pathogens and tumor antigens. Patients transplanted with HSCT represent an ideal model system in humans to identify and characterize the key cellular and molecular players underlying these mechanisms. The knowledge gained from these studies has allowed the development of novel therapeutic strategies aimed at inducing long-term peripheral tolerance, which can be applicable not only in allogeneic HSCT but also in autoimmune diseases and solid-organ transplantation. In the present review, we describe Type 1 regulatory T cells, initially discovered and characterized in chimeric patients transplanted with human leukocyte antigen-mismatched HSCT, and how their presence correlates to tolerance induction and maintenance. Furthermore, we summarize different cell therapy approaches with regulatory T cells, designed to facilitate tolerance induction, minimizing pharmaceutical interventions.     

Comparative study of the viscoelastic mechanical behavior of agarose and poly(ethylene glycol) hydrogels

This study presents a comparative investigation into differences in the mechanical properties between two hydrogels commonly used in cartilage tissue engineering [agarose vs. poly(ethylene glycol) (PEG)], but which are formed through distinctly different crosslinking mechanisms (physical vs. covalent, respectively). The effects of hydrogel chemistry, precursor concentration, platen type (nonporous vs. porous) used in compression bioreactors, and degradation (for PEG) on the swelling properties and static and dynamic mechanical properties were examined. An increase in precursor concentration resulted in decreased equilibrium mass swelling ratios but increased equilibrium moduli and storage moduli for both hydrogels (p < 0.05). Agarose displayed large stress relaxations and a frequency dependence indicating its viscoelastic properties. Contrarily, PEG hydrogels displayed largely elastic behavior with minimal stress relaxation and frequency dependence. In biodegradable PEG hydrogels, the largely elastic behavior was retained during degradation. The type of platen did not affect static mechanical properties, but porous platens led to a reduced storage modulus for both hydrogels implicating fluid flow. In summary, agarose and PEG exhibit vastly different mechanical behaviors; a finding largely attributed to differences in their chemistries and fluid movement. Taken together, these design choices (hydrogel chemistry/structure, loading conditions) will likely have a profound effect on the tissue engineering outcome.     

Dual function of Langerhans cells in skin TSLP-promoted TFH differentiation in mouse atopic dermatitis

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Novel NOBOX loss-of-function mutations account for 6.2% of cases in a large primary ovarian insufficiency cohort

Primary ovarian insufficiency (POI) is a disorder associated with female infertility, which affects approximately 1% of women under 40 years of age. A genetic component has been suggested as one possible cause of the majority of cases of nonsyndromic forms. Newborn Ovary Homeobox (NOBOX) is an ovary-specific gene, playing a critical role in ovary in mice, as its absence leads to sterility mimicking a POI. In this study, we sequenced NOBOX in a cohort of 178 women with idiopathic POI. Among 19 identified variations, we described one nonsense (c.907C>T/p.R303X) and four missense (c.271G>T/p.G91W, c.349C>T/p.R117W, c.1025G>C/p.S342T, and c.1048G>T/p.V350L) NOBOX heterozygous mutations in 12 patients. We reproduced each of the five mutations and tested their effects on the signaling activity in transfected cells. We demonstrated that these mutations compromised the ability of the proteins to bind to and transactivate the well-known growth differentiation factor 9 (GDF9) promoter. The pattern of our findings suggests that the genetic mechanism in humans responsible for POI in women involves haploinsufficiency rather than dominant negative gene action. The identification, characterization, and the very high 6.2% prevalence of these new mutations in POI patients suggest considering NOBOX as the first autosomal candidate gene involved in this syndrome.     

Polyopisthocotylean monogeneans from carangid fishes off Queensland,Australia and New Caledonia,with a description of <Emphasis Type="Italic">Heteromicrocotyloides megaspinosus</Emphasis> sp. nov.

Gills of carangid fishes in Australian waters are dominated by a diversity of polyopisthocotylean monogeneans. This study updates current knowledge of polyopisthocotyleans from carangid hosts in waters along the Queensland coast of Australia and also off New Caledonia. The discovery of Protomicrocotyle celebesensis Yamaguti, 1953 is the first record for the genus in Australian waters and represents a new geographic location for the species, extending its distribution from Sulawesi, Indonesia and Hawaii to Australia. Furthermore, Caranx ignobilis and Carangoides fulvoguttatus are reported as new host records for P. celebesensis. Carangoides gymnostethus is recorded as a new host for Heteromicrocotyla australiensis Rohde, 1977 from a new geographic location, namely Lizard Island, Queensland. Heteromicrocotyloides mirabilis Rohde, 1977 is reported from the gills of C. fulvoguttatus off Lizard Island, Queensland representing a new geographic record. Heteromicrocotyloides megaspinosus sp. nov. is described from the gills of C. fulvoguttatus from Lizard Island, Queensland and New Caledonia. The new species is distinguished from H. mirabilis by the larger number and size of spines in the male genital corona. Gonoplasius carangis was collected from Pseudocaranx dentex at Heron Island, Queensland. Gonoplasius longirostri is synonymised with G. carangis due to overlap in measurements and similar morphology. The number of ‘dorsal pits’ in this taxon may not be a useful character because they can be cryptic and hard to see. Most hosts from which these two Gonoplasius species have been collected previously have been synonymised as Pseudocaranx dentex except Caranx ascensionis which is now considered to be C. lugubris. Our report of G. carangis from P. dentex at Heron Island, Queensland is a new geographic record.     

Global molecular epidemiology of the O15:K52:H1 extraintestinal pathogenic Escherichia coli clonal group: evidence of distribution beyond Europe

Escherichia coli O15:K52:H1 is a significant extraintestinal pathogen in Europe (G. Prats et al., J. Clin. Microbiol. 38:201-209, 2000). To search for evidence of this clonal group outside of Europe, 75 non-European E. coli isolates of serogroup O15 were compared with five members of the O15:K52:H1 clonal group from Barcelona, Spain, according to genomic background, virulence genotypes, and antimicrobial resistance profiles. Amplification phylotyping showed that 16 (21%) of the 75 non-European O15 isolates corresponded with the O15:K52:H1 clonal group. The 16 non-European O15:K52:H1 clonal group members represented diverse geographic locales. They were isolated almost exclusively from humans with extraintestinal infections and accounted for 50% of all O15 isolates from five human clinical collections studied. Most non-European clonal group members exhibited a consensus virulence factor profile that included the F16 or F7-2 papA alleles (P fimbrial structural subunit), papG allele II (P fimbrial adhesin), iha (putative adhesin siderophore), and iutA (aerobactin receptor). This resembles the virulence profiles of (i) European representatives of the O15:K52:H1 clonal group and (ii) phylogenetically related "clonal group A," a recently recognized significant contributor to trimethoprim-sulfamethoxazole resistance in the United States (A. R. Manges et al., N. Engl. J. Med. 345:1007-1013, 2001). Antimicrobial resistance profiles were variable, and resistance was inconsistently transferred by conjugation. These findings indicate that the O15:K52:H1 clonal group is broadly distributed beyond Europe, exhibits previously unrecognized phenotypic and genotypic diversity, and contributes significantly to extraintestinal infections in humans.     

The Ariadne principles: how to handle multimorbidity in primary care consultations

Multimorbidity is a health issue mostly dealt with in primary care practice. As a result of their generalist and patient-centered approach, long-lasting relationships with patients, and responsibility for continuity and coordination of care, family physicians are particularly well placed to manage patients with multimorbidity. However, conflicts arising from the application of multiple disease oriented guidelines and the burden of diseases and treatments often make consultations challenging. To provide orientation in decision making in multimorbidity during primary care consultations, we developed guiding principles and named them after the Greek mythological figure Ariadne. For this purpose, we convened a two-day expert workshop accompanied by an international symposium in October 2012 in Frankfurt, Germany. Against the background of the current state of knowledge presented and discussed at the symposium, 19 experts from North America, Europe, and Australia identified the key issues of concern in the management of multimorbidity in primary care in panel and small group sessions and agreed upon making use of formal and informal consensus methods. The proposed preliminary principles were refined during a multistage feedback process and discussed using a case example. The sharing of realistic treatment goals by physicians and patients is at the core of the Ariadne principles. These result from i) a thorough interaction assessment of the patient’s conditions, treatments, constitution, and context; ii) the prioritization of health problems that take into account the patient’s preferences – his or her most and least desired outcomes; and iii) individualized management realizes the best options of care in diagnostics, treatment, and prevention to achieve the goals. Goal attainment is followed-up in accordance with a re-assessment in planned visits. The occurrence of new or changed conditions, such as an increase in severity, or a changed context may trigger the (re-)start of the process. Further work is needed on the implementation of the formulated principles, but they were recognized and appreciated as important by family physicians and primary care researchers.Please see related article: http://www.biomedcentral.com/1741-7015/12/222.