Effects of pectin methyl-esterification on intestinal microbiota and its immunomodulatory properties in naive mice.

Pectins are dietary fibers that are attributed with several beneficial immunomodulatory effects. Depending on the degree of esterification (DE), pectins can be classified as high methoxyl pectin (HMP) or low methoxyl pectin (LMP). The aim of this study was to investigate the effects of pectin methyl-esterification on intestinal microbiota and its immunomodulatory properties in naive mice. Supplementation of the diet with LMP or HMP induced changes in the composition of the intestinal microbiota in mice toward Bacteroides, which was mainly promoted by HMP. Metabolome analysis of stool samples from pectin-fed mice showed a different effect of the two types of pectin on the levels of short-chain fatty acids and bile acids, which was consistent with highly efficient in vivo fermentation of LMP. Analysis of serum antibody levels showed a significant increase in IgG and IgA levels by both pectins, while FACS analysis revealed a decrease of infiltrating inflammatory cells in the intestinal lamina propria by HMP. Our study revealed that the structural properties of the investigated pectins determine fermentability, effects on microbial composition, metabolite production, and modulation of immune responses. Consumption of HMP preferentially altered the gut microbiota and suppressed pro-inflammatory immune responses, suggesting a beneficial role in inflammatory diseases.

Epithelial-immune cell interactions in allergic diseases.

Epithelial/immune interactions are characterized by the different properties of the various epithelial tissues, the mediators involved, and the varying immune cells that initiate, sustain, or abrogate allergic diseases on the surface. The intestinal mucosa, respiratory mucosa, and regular skin feature structural differences according to their primary function and surroundings. In the context of these specialized functions, the active role of the epithelium in shaping immune responses is increasingly recognizable. Crosstalk between epithelial and immune cells plays an important role in maintaining homeostatic conditions. While cells of the myeloid cell lineage, mainly macrophages, are the dominating immune cell population in the skin and the respiratory tract, lymphocytes comprise most intraepithelial immune cells in the intestine under healthy conditions. Common to all surface epithelia is the fact that innate immune cells represent the first line of immunosurveillance that either directly defeats invading pathogens or initiates and coordinates more effective successive immune responses involving adaptive immune cells and effector cells. Pharmacological approaches for the treatment of allergic and chronic inflammatory diseases involving epithelial barriers target immunological mediators downstream of the epithelium (such as IL-4, IL-5, IL-13, and IgE). The next generation of therapeutics involves upstream events of the inflammatory cascade, such as epithelial-derived alarmins and related mediators.

Patient Satisfaction with the Hybrid Telemedicine Model for Ophthalmology.

Background: The purpose of this research was to compare patient satisfaction between hybrid ophthalmology telemedicine and standard-of-care in-person visits. A retrospective, cross-sectional, case-control analysis of patient satisfaction based on survey data was used. Methods: Responses to the National Research Council Health Patient Survey were retrieved for randomly sampled hybrid ophthalmology telemedicine and in-person visits between March 11, 2020 and December 31, 2021 at a hospital-based eye clinic in Boston, Massachusetts. The primary outcome was based on the question "How likely would you be to recommend this provider to your family and friends?" (0-10 scale) with a score of 9 or 10 coded as satisfied. Two-sample t-tests, Pearson's chi-square tests, and bivariate logistic regressions were used to compare patient satisfaction scores between the hybrid and in-person cohorts. Demographic data, including age, sex, language, and self-reported race and ethnicity, were used as potential predictors of patient satisfaction in a multivariable logistic regression model. Results: There were 49 surveys from hybrid visits and 3,390 surveys from in-person visits. Hybrid visit patients reported high satisfaction scores without significant differences compared to in-person visit patients (hybrid 79% satisfied, in-person 82% satisfied, p = 0.728). Age was significantly associated with satisfaction in the hybrid cohort with the 65+ age group reporting lower satisfaction (below 65 years 100% satisfied, 65+ years 60% satisfied, p = 0.003). No association with age was observed in the in-person cohort. Conclusions: The hybrid ophthalmology telemedicine model can provide effective care without sacrificing patient satisfaction. Older patients may benefit from targeted interventions in future telemedicine models.

Demographic and socioeconomic disparities in the hybrid ophthalmology telemedicine model.

IMPORTANCE: As telemedicine use expands, it is important to evaluate demographic and socioeconomic disparities among patients receiving ophthalmic care through new hybrid telemedicine models. OBJECTIVE: To evaluate whether there are demographic and socioeconomic disparities in the delivery of the hybrid telemedicine model. DESIGN: Retrospective, cross-sectional, case-control analysis of patient encounters from April to December 2020. SETTING: A single, academic, hospital-based eye clinic in Boston, Massachusetts. METHODS: Electronic medical records of all patient encounters from April to December 2020 were reviewed and categorized into hybrid, virtual-only, and standard in-person visits. Patient-level data for all visits were extracted including age, sex, race/ethnicity, primary language, Area Deprivation Index (ADI), insurance type, and marital status. Visit-level data for all hybrid visits were also extracted from the medical record including the visit dates and patient adherence. Demographics for the cohort of patients with at least one no-show visit were compared with demographics for the cohort of patients who only had completed visits. The primary study outcomes were the differences in demographic characteristics between the hybrid visit show and no-show groups. The secondary outcomes included demographic characteristics of patients who did not complete their hybrid visit versus a time-matched cohort of patients who did not complete their standard in-person visit. Continuous variables for patient characteristics were compared with independent samples t-tests and categorical variables were compared using Pearson chi-square tests. Multivariate logistic regression was used to examine the differences between the cohorts. Variables with missing values other than suppressed ADI values were imputed using multiple imputations by chained equations. RESULTS: Of a total of 1025 patients who were scheduled for a hybrid visit, 145 (14.1%) patients failed to complete their visit. Primary language and insurance were found to be statistically different between patients who completed and did not complete their hybrid visits. More English speakers and fewer Haitian Creole speakers completed their hybrid visits (p = 0.007) while more patients with private insurance and fewer patients with Medicaid completed their hybrid telemedicine visits (p = 0.026). No associations were found between hybrid telemedicine visit adherence and age, sex, race/ethnicity, marital status, or ADI. When the 145 patients who failed to complete their hybrid visits were compared to a time-matched cohort of patients who failed to complete their standard in-person visit, we found that patients who missed hybrid visits were similar to those who missed standard in-person visits except for patients insured by Medicare. These patients were more likely to miss a hybrid visit than a standard in-person visit (Odds Ratio 2.199, 95% confidence interval 1.136-4.259, p = 0.019). No associations were found between patient nonadherence with hybrid telemedicine versus with standard in-person visits based on age, sex, primary language, race/ethnicity, marital status, or ADI. CONCLUSION: The hybrid telemedicine model was associated with insurance and language-based disparities. Patients with non-English primary language and Medicaid recipients were more likely to miss a hybrid visit than their counterparts. Our findings support developing deliberate interventions to ensure hybrid telemedicine care is delivered equitably to all patients.

Outcomes of a Hybrid Ophthalmology Telemedicine Model for Outpatient Eye Care During COVID-19.

Importance: The hybrid ophthalmology telemedicine model asynchronously pairs an imaging appointment by a technician with a subsequent virtual appointment by a clinician. Although it has been mentioned in several studies as an alternative to standard in-person care during the COVID-19 pandemic, outcomes of this alternative clinical care model remain to be evaluated. Objective: To investigate the outcomes associated with the hybrid ophthalmology telemedicine model during the COVID-19 pandemic for nonurgent and nonprocedural ophthalmological care. Design, Setting, and Participants: Retrospective, cross-sectional study of all hybrid visits scheduled during the year 2020 in a single academic, hospital-based eye clinic in Boston, Massachusetts. All hybrid ophthalmology telemedicine visits completed in the year 2020 by opthalmologists and optometrists were included. Data were analyzed from January to December 2020. Exposures: Hybrid telemedicine clinical encounters. Main Outcomes and Measures: Four outcome metrics were calculated: (1) need for subsequent procedure visit, (2) medication change, (3) nonurgent, and (4) urgent consultation with another eye clinician. Adverse outcomes were defined as irreversible vision loss and the need for additional in-person evaluation to reach a management decision. Results: From April 9 to December 30, 2020, 889 patients (506 female patients [56.9%]; mean [SD] age, 62.1 [14.5] years; age range, 13-98 years) completed 940 hybrid visits. The most common visit indications were glaucoma (424 visits [45.1%]) and retinal diseases (499 visits [53.1%]). A total of 25 visits (2.7%) led to a procedure, 22 visits (2.3%) led to a change in medication, and 44 visits (4.7%) were referred for nonurgent consultation with another subspecialty with no instances of urgent referrals. Sixteen patients (1.7%) were referred to the on-call clinician for a same-day emergency in-person visit or recommended for a subsequent standard in-person visit to reach a management decision. There were no cases of irreversible vision loss following a hybrid visit. Conclusions and Relevance: These findings suggest that with the appropriate patient selection and clinical setting, the hybrid ophthalmology telemedicine model may be a good alternative to standard in-person visits, particularly for patients with glaucoma and retinal diseases.

Interleukin-17A and interleukin-22 production by conventional and non-conventional lymphocytes in three different end-stage lung diseases.

Objectives: The contribution of adaptive vs. innate lymphocytes to IL-17A and IL-22 secretion at the end stage of chronic lung diseases remains largely unexplored. In order to uncover tissue- and disease-specific secretion patterns, we compared production patterns of IL-17A and IL-22 in three different human end-stage lung disease entities. Methods: Production of IL-17A, IL-22 and associated cytokines was assessed in supernatants of re-stimulated lymphocytes by multiplex assays and multicolour flow cytometry of conventional T cells, iNKT cells, γδ T cells and innate lymphoid cells in bronchial lymph node and lung tissue from patients with emphysema (n = 19), idiopathic pulmonary fibrosis (n = 14) and cystic fibrosis (n = 23), as well as lung donors (n = 17). Results: We detected secretion of IL-17A and IL-22 by CD4+ T cells, CD8+ T cells, innate lymphoid cells, γδ T cells and iNKT cells in all end-stage lung disease entities. Our analyses revealed disease-specific contributions of individual lymphocyte subpopulations to cytokine secretion patterns. We furthermore found the high levels of microbial detection in CF samples to associate with a more pronounced IL-17A signature upon antigen-specific and unspecific re-stimulation compared to other disease entities and lung donors. Conclusion: Our results show that both adaptive and innate lymphocyte populations contribute to IL-17A-dependent pathologies in different end-stage lung disease entities, where they establish an IL-17A-rich microenvironment. Microbial colonisation patterns and cytokine secretion upon microbial re-stimulation suggest that pathogens drive IL-17A secretion patterns in end-stage lung disease.

Turning off the alarm - Targeting alarmins and other epithelial mediators of allergic inflammation with biologics.

Besides the major players IL-4, IL-13, IL-5, and IgE as targets for biologics, other mediators have been identified that are secreted by epithelial cells and act upstream in the cascade of allergic inflammation. Such are the alarmin IL-33 as well as TSLP and IL-5. The role of each cytokine in sensitization and effector phase of allergic inflammation and how development of biologics is ongoing in order to inhibit this pathomechanism will be described in the following article.

Does the Food Ingredient Pectin Provide a Risk for Patients Allergic to Non-Specific Lipid-Transfer Proteins?

Pectin, a dietary fiber, is a polysaccharide that is widely used in food industry as a gelling agent. In addition, prebiotic and beneficial immunomodulatory effects of pectin have been demonstrated, leading to increased importance as food supplement. However, as cases of anaphylactic reactions after consumption of pectin-supplemented foods have been reported, the present study aims to evaluate the allergy risk of pectin. This is of particular importance since most of the pectin used in the food industry is extracted from citrus or apple pomace. Both contain several allergens such as non-specific lipid transfer proteins (nsLTPs), known to induce severe allergic reactions, which could impair the use of pectins in nsLTP allergic patients. Therefore, the present study for the first time was performed to analyze residual nsLTP content in two commercial pectins using different detection methods. Results showed the analytical sensitivity was diminished by the pectin structure. Finally, spiking of pectin with allergenic peach nsLTP Pru p 3 led to the conclusion that the potential residual allergen content in both pectins is below the threshold to induce anaphylactic reactions in nsLTP-allergic patients. This data suggests that consumption of the investigated commercial pectin products provides no risk for inducing severe reactions in nsLTP-allergic patients.

IL-17A from innate and adaptive lymphocytes contributes to inflammation and damage in cystic fibrosis lung disease.

BACKGROUND: Elevated levels of interleukin (IL)-17A were detected in the airways of patients with cystic fibrosis (CF), but its cellular sources and role in the pathogenesis of CF lung disease remain poorly understood. The aim of this study was to determine the sources of IL-17A and its role in airway inflammation and lung damage in CF. METHODS: We performed flow cytometry to identify IL-17A-producing cells in lungs and peripheral blood from CF patients and ß-epithelial Na+ channel transgenic (Scnn1b-Tg) mice with CF-like lung disease, and determined the effects of genetic deletion of Il17a and Rag1 on the pulmonary phenotype of Scnn1b-Tg mice. RESULTS: T-helper 17 cells, CD3+CD8+ T-cells, γδ T-cells, invariant natural killer T-cells and innate lymphoid cells contribute to IL-17A secretion in lung tissue, lymph nodes and peripheral blood of patients with CF. Scnn1b-Tg mice displayed increased pulmonary expression of Il17a and elevated IL-17A-producing innate and adaptive lymphocytes with a major contribution by γδ T-cells. Lack of IL-17A, but not the recombination activating protein RAG1, reduced neutrophilic airway inflammation in Scnn1b-Tg mice. Genetic deletion of Il17a or Rag1 had no effect on mucus obstruction, but reduced structural lung damage and revealed an IL-17A-dependent macrophage activation in Scnn1b-Tg mice. CONCLUSIONS: We identify innate and adaptive sources of IL-17A in CF lung disease. Our data demonstrate that IL-17A contributes to airway neutrophilia, macrophage activation and structural lung damage in CF-like lung disease in mice. These results suggest IL-17A as a novel target for anti-inflammatory therapy of CF lung disease.

Mimicking Antigen-Driven Asthma in Rodent Models-How Close Can We Get?

Asthma is a heterogeneous disease with increasing prevalence worldwide characterized by chronic airway inflammation, increased mucus secretion and bronchial hyperresponsiveness. The phenotypic heterogeneity among asthmatic patients is accompanied by different endotypes, mainly Type 2 or non-Type 2. To investigate the pathomechanism of this complex disease many animal models have been developed, each trying to mimic specific aspects of the human disease. Rodents have classically been employed in animal models of asthma. The present review provides an overview of currently used Type 2 vs. non-Type 2 rodent asthma models, both acute and chronic. It further assesses the methods used to simulate disease development and exacerbations as well as to quantify allergic airway inflammation, including lung physiologic, cellular and molecular immunologic responses. Furthermore, the employment of genetically modified animals, which provide an in-depth understanding of the role of a variety of molecules, signaling pathways and receptors implicated in the development of this disease as well as humanized models of allergic inflammation, which have been recently developed to overcome differences between the rodent and human immune systems, are discussed. Nevertheless, differences between mice and humans should be carefully considered and limits of extrapolation should be wisely taken into account when translating experimental results into clinical use.

Constitutive TNF-α signaling in neonates is essential for the development of tissue-resident leukocyte profiles at barrier sites.

Newborn infants have a high disposition to develop systemic inflammatory response syndromes (SIRSs) upon inflammatory or infectious challenges. Moreover, there is a considerable trafficking of hematopoietic cells to tissues already under noninflammatory conditions. These age-specific characteristics suggest a hitherto unappreciated crucial role of the vascular endothelium during the neonatal period. Here, we demonstrate that healthy neonates showed already strong endothelial baseline activation, which was mediated by a constitutively increased production of TNF-α. In mice, pharmacological inhibition of TNF-α directly after birth prevented subsequent fatal SIRS but completely abrogated the recruitment of leukocytes to sites of infection. Importantly, in healthy neonates, blocking TNF-α at birth disrupted the physiologic leukocyte trafficking, which resulted in persistently altered leukocyte profiles at barrier sites. Collectively, these data suggest that constitutive TNF-α-mediated sterile endothelial activation in newborn infants contributes to the increased risk of developing SIRS but is needed to ensure the postnatal recruitment of leukocytes to organs and interfaces.-Bickes, M. S., Pirr, S., Heinemann, A. S., Fehlhaber, B., Halle, S., Völlger, L., Willers, M., Richter, M., Böhne, C., Albrecht, M., Langer, M., Pfeifer, S., Jonigk, D., Vieten, G., Ure, B., von Kaisenberg, C., Förster, R., von Köckritz-Blickwede, M., Hansen, G., Viemann, D. Constitutive TNF-α signaling in neonates is essential for the development of tissue-resident leukocyte profiles at barrier sites.

Mouse Models for Food Allergies: Where Do We Stand?

Food allergies are a steadily increasing health and economic problem. Immunologically, food allergic reactions are caused by pathological, allergen-specific Th2 responses resulting in IgE-mediated mast cell degranulation and associated inflammatory reactions. Clinically, food allergies are characterized by local inflammation of the mouth mucosa, the face, the throat, the gastrointestinal tract, are frequently paralleled by skin reactions, and can result in life-threatening anaphylactic reactions. To better understand food allergies and establish novel treatment options, mouse models are indispensable. This review discusses the available mouse food allergy models, dividing them into four categories: (1) adjuvant-free mouse models, (2) mouse models relying on adjuvants to establish allergen-specific Th2 responses, (3) mouse models using genetically-modified mouse strains to allow for easier sensitization, and (4) humanized mouse models in which different immunodeficient mouse strains are reconstituted with human immune or stem cells to investigate humanized immune responses. While most of the available mouse models can reproducibly portray the immunological parameters of food allergy (Th2 immune responses, IgE production and mast cell activation/expansion), so far, the recreation of the clinical parameters has proven more difficult. Therefore, up to now none of the available mouse models can reproduce the complete human pathology.

Suppression of Th17-polarized airway inflammation by rapamycin.

Because Th17-polarized airway inflammation correlates with poor control in bronchial asthma and is a feature of numerous other difficult-to-treat inflammatory lung diseases, new therapeutic approaches for this type of airway inflammation are necessary. We assessed different licensed anti-inflammatory agents with known or expected efficacy against Th17-polarization in mouse models of Th17-dependent airway inflammation. Upon intravenous transfer of in vitro derived Th17 cells and intranasal challenge with the corresponding antigen, we established acute and chronic murine models of Th17-polarised airway inflammation. Consecutively, we assessed the efficacy of methylprednisolone, roflumilast, azithromycin, AM80 and rapamycin against acute or chronic Th17-dependent airway inflammation. Quantifiers for Th17-associated inflammation comprised: bronchoalveolar lavage (BAL) differential cell counts, allergen-specific cytokine and immunoglobulin secretion, as well as flow cytometric phenotyping of pulmonary inflammatory cells. Only rapamycin proved effective against acute Th17-dependent airway inflammation, accompanied by increased plasmacytoid dendritic cells (pDCs) and reduced neutrophils as well as reduced CXCL-1 levels in BAL. Chronic Th17-dependent airway inflammation was unaltered by rapamycin treatment. None of the other agents showed efficacy in our models. Our results demonstrate that Th17-dependent airway inflammation is difficult to treat with known agents. However, we identify rapamycin as an agent with inhibitory potential against acute Th17-polarized airway inflammation.

IL-27 Is Essential for Suppression of Experimental Allergic Asthma by the TLR7/8 Agonist R848 (Resiquimod).

Different models of experimental allergic asthma have shown that the TLR7/8 agonist resiquimod (R848) is a potential inhibitor of type 2 helper cell-driven inflammatory responses. However, the mechanisms mediating its therapeutic effects are not fully understood. Using a model of experimental allergic asthma, we show that induction of IL-27 by R848 is critical for the observed ameliorative effects. R848 significantly inhibited all hallmarks of experimental allergic asthma, including airway hyperreactivity, eosinophilic airway inflammation, mucus hypersecretion, and Ag-specific Ig production. Whereas R848 significantly reduced IL-5, IL-13, and IL-17, it induced IFN-γ and IL-27. Neutralization of IL-27 completely reversed the therapeutic effect of R848 in the experimental asthma model, demonstrating dependence of R848-mediated suppression on IL-27. In vitro, R848 induced production of IL-27 by murine alveolar macrophages and dendritic cells and enhanced expression of programmed death-ligand 1, whose expression on monocytes and dendritic cells has been shown to regulate peripheral tolerance in both murine and human studies. Moreover, in vitro IL-27 enhanced secretion of IFN-γ whereas it inhibited IL-5 and IL-13, demonstrating its direct effect on attenuating Th2 responses. Taken together, our study proves that R848-mediated suppression of experimental asthma is dependent on IL-27. These data provide evidence of a central role of IL-27 for the control of Th2-mediated allergic diseases.

Superior Suppressive Capacity of Skin Tregs Compared with Lung Tregs in a Model of Epicutaneous Priming.

We have previously shown that T helper type 2 (Th2)-polarized airway inflammation can facilitate priming to new antigens in the lungs, which we called "collateral priming". To investigate whether allergic skin inflammation can also facilitate priming toward new antigens, we developed an allergic skin inflammation model based on an allergic lung inflammation model. Mice were sensitized intraperitoneally toward the primary antigen, ovalbumin. Challenge was subsequently performed intranasally or epicutaneously with ovalbumin and a secondary antigen, keyhole limpet hemocyanin (KLH). Re-challenge consisted of local application of either antigen alone. Analysis of KLH-specific antibody responses, KLH-specific cytokines, and local inflammation demonstrated tolerance induction toward the secondary antigen in the skin, whereas in the lung priming had occurred. Flow-cytometric analysis revealed increased numbers of regulatory T cells (Tregs), increased cytotoxic T lymphocyte antigen-4 (CTLA-4) expression, and an enhanced suppressive capacity of Tregs from skin-draining lymph nodes when compared with Tregs from the lung-draining lymph nodes. Furthermore, depletion of Tregs resulted in restoration of collateral priming in the skin. These results demonstrate crucial local differences between the Treg function in the skin and lung to repetitive antigen exposure, which can decisively influence the immune response toward new antigens.

Comparison of bone marrow versus peripheral blood allogeneic hematopoietic stem cell transplantation for hematological malignancies in adults - a systematic review and meta-analysis.

It is still under debate whether bone marrow (BM) or peripheral blood (PB) should be the preferred stem cell source in adult patients undergoing allogeneic stem cell transplantation for hematological malignancies. After systematic literature search we identified nine randomised controlled trials comparing BM and PB as stem cell source from 2341 total hits. Meta-analysis involving 1521 patients showed a statistically significant reduction in overall and extensive chronic GvHD for patients transplanted with BM (HR 0.72; 95% CI 0.61 to 0.85 and HR 0.69; 95% CI 0.54 to 0.9), but no difference in overall and disease-free survival. In the related donor setting, data from two of eight studies demonstrated a significant increase of relapse incidence for BM (HR 2.73; 95% CI 1.47 to 5.08). This systematic review demonstrates that the current clinical standard to use peripheral blood stem cells instead of bone marrow for allo-SCT is not inferior with regard to the primary outcome overall survival.

Bone marrow versus peripheral blood allogeneic haematopoietic stem cell transplantation for haematological malignancies in adults.

BACKGROUND: Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is an established treatment option for many malignant and non-malignant disorders. In the past two decades, peripheral blood stem cells replaced bone marrow as stem cell source due to faster engraftment and practicability. Previous meta-analyses analysed patients treated from 1990 to 2002 and demonstrated no impact of the stem cell source on overall survival, but a greater risk for graft-versus-host disease (GvHD) in peripheral blood transplants. As transplant indications and conditioning regimens continue to change, whether the choice of the stem cell source has an impact on transplant outcomes remains to be determined. OBJECTIVES: To assess the effect of bone marrow versus peripheral blood stem cell transplantation in adult patients with haematological malignancies with regard to overall survival, incidence of relapse and non-relapse mortality, disease-free survival, transplant-related mortality, incidence of GvHD and time to engraftment. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 1), MEDLINE (from 1948 to February 2014), trial registries and conference proceedings. The search was conducted in October 2011 and was last updated in February 2014. We did not apply any language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing bone marrow and peripheral blood allogeneic stem cell transplantation in adults with haematological malignancies. DATA COLLECTION AND ANALYSIS: Two review authors screened abstracts and extracted and analysed data independently. We contacted study authors for additional information. We used the standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We included nine RCTs that met the pre-defined selection criteria, involving a total of 1521 participants. Quality of data reporting was heterogeneous among the studies. Overall, the risk of bias in the included studies was low.For the primary outcome overall survival, our analysis demonstrated comparable results between bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) (six studies, 1330 participants; hazard ratio (HR) 1.07; 95% CI 0.91 to 1.25; P value = 0.43; high-quality evidence).Disease-free survival (six studies, 1225 participants; HR 1.04; 95% CI 0.89 to 1.21; P value = 0.6; moderate-quality of evidence) and non-relapse or transplant-related mortality (three studies, 758 participants; HR 0.98; 95% CI 0.76 to 1.28; P = 0.91; high-quality evidence) were also comparable between transplantation arms.In the related-donor setting, data from two of eight studies with 211 participants (21%) indicated a higher relapse incidence in participants transplanted with bone marrow stem cells rather than peripheral blood stem cells (HR 2.73; 95% CI 1.47 to 5.08; P value = 0.001). There was no clear evidence of a difference in relapse incidence between transplantation groups in unrelated donors (HR 1.07; 95% CI 0.78 to 1.47; P value = 0.66). The difference between the donor-related and -unrelated subgroups (P-value = 0.008) was considered to be statistically significant.BMT was associated with lower rates of overall and extensive chronic GvHD than PBSCT (overall chronic GvHD: four studies, 1121 participants; HR 0.72; 95% CI 0.61 to 0.85; P value = 0.0001, extensive chronic GvHD: four studies, 765 participants; HR 0.69; 95% CI 0.54 to 0.9; P value = 0.006; moderate-quality evidence for both outcomes). The incidence of acute GvHD grades II to IV was not lower (six studies, 1330 participants; HR 1.03; 95% CI 0.89 to 1.21; P value = 0.67; moderate-quality evidence), but there was a trend for a lower incidence of grades III and IV acute GvHD with BMT than with PBSCT (three studies, 925 participants; HR 0.75; 95% CI 0.55 to 1.02; P value = 0.07; moderate-quality evidence).Times to neutrophil and platelet engraftment were longer with BMT than with PBSCT (neutrophil: five studies, 662 participants; HR 1.96; 95% CI 1.64 to 2.35; P value < 0.00001; platelet: four studies, 333 participants; HR 2.17; 95% CI 1.69 to 2.78; P value < 0.00001). AUTHORS' CONCLUSIONS: This systematic review  found high-quality evidence that overall survival following allo-HSCT using the current clinical standard stem cell source - peripheral blood stem cells - was similar to that following allo-HSCT using bone marrow stem cells in adults with haematological malignancies. We found moderate-quality evidence that PBSCT was associated with faster engraftment of neutrophils and platelets, but a higher risk of GvHD (in terms of more overall and extensive chronic GvHD). There was an imprecise effect on relapse and on severe (grades III to IV) acute GvHD. Quality of life, which is severely affected by GvHD, was not evaluated.Against the background of transplantation practices that have clearly changed over the past 10 to 15 years, our aim was to provide current data on the best stem cell source for allo-HSCT, by including the results of recently conducted trials. Our review includes participants recruited up to 2009, a proportion of whom were older, had received reduced-intensity conditioning regimens or had been transplanted with stem cells from unrelated donors. However, only one, large, study included relatively recently treated participants. Nevertheless, our findings are comparable to those of previous meta-analyses suggesting that our results hold true for today's practice.

Delineating the role of histamine-1- and -4-receptors in a mouse model of Th2-dependent antigen-specific skin inflammation.

BACKGROUND: Histamine drives pruritus in allergic skin diseases which clinically constitutes a most disruptive symptom. Skin pathology in allergic skin diseases is crucially influenced by different T-helper subsets. However, the contribution of different histamine-receptors to T-helper cell dependent skin pathology has not been definitively answered. Models which can specifically address the functional role of T-helper subsets and the mediators involved are therefore valuable to gain further insights into molecular pathways which contribute to allergic skin disease. They might also be helpful to probe amendable therapeutic interventions such as histamine-receptor antagonism. OBJECTIVE: Establishing an adoptive transfer model for antigen-specific Th cells, we aimed to delineate the role of histamine H1- and H4-receptors in Th2-dependent skin inflammation. METHODS: In-vitro differentiated and OVA primed Th2 cells were adoptively transferred into congenic recipient mice. In vivo treatment with specific histamine H1- and H4-receptor antagonists was performed to analyze the contribution of these histamine-receptors to Th2-dependent skin pathology in our model. Analysis four days after epicutaneous challenge comprised skin histology, flow cytometric detection of transferred T-helper cells and analysis of antigen-cytokine profiles in skin-draining lymph nodes. RESULTS: Use of specific H1- and H4-receptor antagonists revealed a crucial role for H1- and H4-receptors for Th2 migration and cytokine secretion in a Th2-driven model of skin inflammation. While H1- and H4-receptor antagonists both reduced Th2 recruitment to the site of challenge, local cytokine responses in skin-draining lymph nodes were only reduced by the combined application of H1- and H4-receptor antagonists and mast cell counts remained altogether unchanged by either H1R-, H4R- or combined antagonism. CONCLUSION: Our model demonstrates a role for H1- and H4-receptors in Th2 cell infiltration and cytokine secretion in allergic skin diseases and suggests further studies to evaluate these findings for therapeutic approaches.