Daratumumab is an anti-CD38 monoclonal antibody with lytic activity against multiple myeloma (MM) cells, including ADCC (antibody-dependent cellular cytotoxicity) and CDC (complement-dependent ...cytotoxicity). Owing to a marked heterogeneity of response to daratumumab therapy in MM, we investigated determinants of the sensitivity of MM cells toward daratumumab-mediated ADCC and CDC. In bone marrow samples from 144 MM patients, we observed no difference in daratumumab-mediated lysis between newly diagnosed or relapsed/refractory patients. However, we discovered, next to an expected effect of effector (natural killer cells/monocytes) to target (MM cells) ratio on ADCC, a significant association between CD38 expression and daratumumab-mediated ADCC (127 patients), as well as CDC (56 patients). Similarly, experiments with isogenic MM cell lines expressing different levels of CD38 revealed that the level of CD38 expression is an important determinant of daratumumab-mediated ADCC and CDC. Importantly, all-trans retinoic acid (ATRA) increased CD38 expression levels but also reduced expression of the complement-inhibitory proteins CD55 and CD59 in both cell lines and primary MM samples. This resulted in a significant enhancement of the activity of daratumumab in vitro and in a humanized MM mouse model as well. Our results provide the preclinical rationale for further evaluation of daratumumab combined with ATRA in MM patients.
IgG antibodies can organize into ordered hexamers on cell surfaces after binding their antigen. These hexamers bind the first component of complement C1 inducing complement-dependent target cell ...killing. Here, we translated this natural concept into a novel technology platform (HexaBody technology) for therapeutic antibody potentiation. We identified mutations that enhanced hexamer formation and complement activation by IgG1 antibodies against a range of targets on cells from hematological and solid tumor indications. IgG1 backbones with preferred mutations E345K or E430G conveyed a strong ability to induce conditional complement-dependent cytotoxicity (CDC) of cell lines and chronic lymphocytic leukemia (CLL) patient tumor cells, while retaining regular pharmacokinetics and biopharmaceutical developability. Both mutations potently enhanced CDC- and antibody-dependent cellular cytotoxicity (ADCC) of a type II CD20 antibody that was ineffective in complement activation, while retaining its ability to induce apoptosis. The identified IgG1 Fc backbones provide a novel platform for the generation of therapeutics with enhanced effector functions that only become activated upon binding to target cell-expressed antigen.
Systematic review on cashew nut allergy van der Valk, J. P. M.; J. Dubois, A. E.; Gerth van Wijk, R. ...
Allergy,
June 2014, Letnik:
69, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Recent studies on cashew nut allergy suggest that the prevalence of cashew nut allergy is increasing. Cashew nut consumption by allergic patients can cause severe reactions, including anaphylaxis. ...This review summarizes current knowledge on cashew nut allergy to facilitate timely clinical recognition and to promote awareness of this emerging food allergy amongst clinicians. The goal of this study is to present a systematic review focused on the clinical aspects of allergy to cashew nut including the characteristics of cashew nut, the prevalence, allergenic components, cross‐reactivity, diagnosis and management of cashew nut allergy. The literature search yielded 255 articles of which 40 met our selection criteria and were considered to be relevant for this review. The 40 articles included one prospective study, six retrospective studies and seven case reports. The remaining 26 papers were not directly related to cashew nut allergy. The literature suggests that the prevalence of cashew nut allergy is increasing, although the level of evidence for this is low. A minimal amount of cashew nut allergen may cause a severe allergic reaction, suggesting high potency comparable with other tree nuts and peanuts. Cashew allergy is clearly an underestimated important healthcare problem, especially in children.
In 2005 four outstanding multiple burials were discovered near Eulau, Germany. The 4,600-year-old graves contained groups of adults and children buried facing each other. Skeletal and artifactual ...evidence and the simultaneous interment of the individuals suggest the supposed families fell victim to a violent event. In a multidisciplinary approach, archaeological, anthropological, geochemical (radiogenic isotopes), and molecular genetic (ancient DNA) methods were applied to these unique burials. Using autosomal, mitochondrial, and Y-chromosomal markers, we identified genetic kinship among the individuals. A direct child-parent relationship was detected in one burial, providing the oldest molecular genetic evidence of a nuclear family. Strontium isotope analyses point to different origins for males and children versus females. By this approach, we gain insight into a Late Stone Age society, which appears to have been exogamous and patrilocal, and in which genetic kinship seems to be a focal point of social organization.
Complement activation by antibodies bound to pathogens, tumors, and self antigens is a critical feature of natural immune defense, a number of disease processes, and immunotherapies. How antibodies ...activate the complement cascade, however, is poorly understood. We found that specific noncovalent interactions between Fc segments of immunoglobulin G (IgG) antibodies resulted in the formation of ordered antibody hexamers after antigen binding on cells. These hexamers recruited and activated C1, the first component of complement, thereby triggering the complement cascade. The interactions between neighboring Fc segments could be manipulated to block, reconstitute, and enhance complement activation and killing of target cells, using all four human IgG subclasses. We offer a general model for understanding antibody-mediated complement activation and the design of antibody therapeutics with enhanced efficacy.
Instruments have been developed and validated for the measurement of health-related quality of life in patients with food allergy. This guideline has been prepared by the European Academy of Allergy ...and Clinical Immunology's (EAACI) Guidelines for Food Allergy and Anaphylaxis Group. It draws on a systematic review of the literature on quality of life instruments for food allergy and the Appraisal of Guidelines for Research & Evaluation (AGREE II) guideline development process. Guidance is provided on the use of such instruments in research, and the current limitations of their use in clinical practice are described. Gaps in current knowledge as well as areas of future interest are also discussed. This document is relevant to healthcare workers dealing with food-allergic patients, scientists engaging in food allergy research and policy makers involved in regulatory aspects concerning food allergy and safety.
IgG antibodies play a central role in protection against pathogens by their ability to alert and activate the innate immune system. Here, we show that IgGs assemble into oligomers on antigenic ...surfaces through an ordered, Fc domain-mediated process that can be modulated by protein engineering. Using high-speed atomic force microscopy, we unraveled the molecular events of IgG oligomer formation on surfaces. IgG molecules were recruited from solution although assembly of monovalently binding molecules also occurred through lateral diffusion. Monomers were observed to assemble into hexamers with all intermediates detected, but in which only hexamers bound C1. Functional characterization of oligomers on cells also demonstrated that C1 binding to IgG hexamers was a prerequisite for maximal activation, whereas tetramers, trimers, and dimers were mostly inactive. We present a dynamic IgG oligomerization model, which provides a framework for exploiting the macromolecular assembly of IgGs on surfaces for tool, immunotherapy, and vaccine design.
Large-scale losses of seagrass beds have been reported for decades and lead to numerous restoration programs. From worldwide scientific literature and 20 years of seagrass restoration research in the ...Wadden Sea, we review and evaluate the traditional guidelines and propose new guidelines for seagrass restoration.
Habitat and donor selection are crucial: large differences in survival were found among habitats and among donor populations. The need to preferably transplant in historically confirmed seagrass habitats, and to collect donor material from comparable habitats, were underlined by our results. The importance of sufficient genetic variation of donor material and prevention of genetic isolation by distance was reviewed. The spreading of risks among transplantation sites, which differed in habitat characteristics (or among replicate sites), was positively evaluated. The importance of ecosystem engineering was shown in two ways: seagrass self-facilitation and facilitation by shellfish reefs. Seagrass self-facilitative properties may require a large transplantation scale or additional measures.
In 3D topological insulators achieving a genuine bulk-insulating state is an important research topic. Recently, the material system (Bi,Sb)2(Te,Se)3 (BSTS) has been proposed as a topological ...insulator with high resistivity and a low carrier concentration (Ren et al 2011 Phys. Rev. B 84 165311). Here we present a study to further refine the bulk-insulating properties of BSTS. We have synthesized BSTS single crystals with compositions around x = 0.5 and y = 1.3. Resistance and Hall effect measurements show high resistivity and record low bulk carrier density for the composition Bi Sb Te Se . The analysis of the resistance measured for crystals with different thicknesses within a parallel resistor model shows that the surface contribution to the electrical transport amounts to 97% when the sample thickness is reduced to 1 m. The magnetoconductance of exfoliated BSTS nanoflakes shows 2D weak antilocalization with as expected for transport dominated by topological surface states.
Background
Breastfeeding may have immune modulatory effects that influence the development of childhood allergic sensitization and atopic diseases. We aimed to examine the associations of ...breastfeeding with childhood allergic sensitization, inhalant or food allergy and eczema, and whether any association was affected by disease‐related modification of the exposure or modified by maternal history of allergy, eczema, or asthma.
Methods
This study among 5828 children was performed in a population‐based prospective cohort from fetal life onwards. We collected information on duration (<2 months, 2‐4 months, 4‐6 months, and ≥6 months) and exclusiveness (nonexclusive vs exclusive for 4 months) of breastfeeding in infancy by postal questionnaires. At age 10 years, inhalant allergic sensitization and food‐allergic sensitization were measured by skin prick tests, and physician‐diagnosed inhalant and food allergy by a postal questionnaire. Data on parental‐reported eczema were available from birth until age 10 years.
Results
We observed no association of breastfeeding with any allergic sensitization, physician‐diagnosed allergy, or combination of these outcomes. Shorter breastfeeding duration was associated with an overall increased risk of eczema (P‐value for trend <.05). Nonexclusively breastfed children had an overall increased risk of eczema (adjusted odds ratio 95% confidence interval: 1.11 1.01, 1.23), compared with children exclusively breastfed for 4 months. Risk period‐specific sensitivity analyses, additional adjustment for ointment use for eczema at age 2 months, and cross‐lagged modeling showed no consistent results for disease‐related modification of the exposure. Results were not modified by maternal history of allergy, eczema, or asthma (lowest P‐value for interaction=.13).
Conclusion
Shorter duration or nonexclusiveness of breastfeeding is associated with a weak overall increased risk of eczema but not allergic sensitization or physician‐diagnosed allergy at age 10 years.
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