Donor Macrophages Modulate Rejection After Heart Transplantation.

BACKGROUND: Cellular rejection after heart transplantation imparts significant morbidity and mortality. Current immunosuppressive strategies are imperfect, target recipient T cells, and have adverse effects. The innate immune response plays an essential role in the recruitment and activation of T cells. Targeting the donor innate immune response would represent the earliest interventional opportunity within the immune response cascade. There is limited knowledge about donor immune cell types and functions in the setting of cardiac transplantation, and no current therapeutics exist for targeting these cell populations. METHODS: Using genetic lineage tracing, cell ablation, and conditional gene deletion, we examined donor mononuclear phagocyte diversity and macrophage function during acute cellular rejection of transplanted hearts in mice. We performed single-cell RNA sequencing on donor and recipient macrophages and monocytes at multiple time points after transplantation. On the basis of our imaging and single-cell RNA sequencing data, we evaluated the functional relevance of donor CCR2+ (C-C chemokine receptor 2) and CCR2- macrophages using selective cell ablation strategies in donor grafts before transplant. Last, we performed functional validation that donor macrophages signal through MYD88 (myeloid differentiation primary response protein 88) to facilitate cellular rejection. RESULTS: Donor macrophages persisted in the rejecting transplanted heart and coexisted with recipient monocyte-derived macrophages. Single-cell RNA sequencing identified donor CCR2+ and CCR2- macrophage populations and revealed remarkable diversity among recipient monocytes, macrophages, and dendritic cells. Temporal analysis demonstrated that donor CCR2+ and CCR2- macrophages were transcriptionally distinct, underwent significant morphologic changes, and displayed unique activation signatures after transplantation. Although selective depletion of donor CCR2- macrophages reduced allograft survival, depletion of donor CCR2+ macrophages prolonged allograft survival. Pathway analysis revealed that donor CCR2+ macrophages are activated through MYD88/nuclear factor kappa light chain enhancer of activated B cells signaling. Deletion of MYD88 in donor macrophages resulted in reduced antigen-presenting cell recruitment, reduced ability of antigen-presenting cells to present antigen to T cells, decreased emergence of allograft-reactive T cells, and extended allograft survival. CONCLUSIONS: Distinct populations of donor and recipient macrophages coexist within the transplanted heart. Donor CCR2+ macrophages are key mediators of allograft rejection, and deletion of MYD88 signaling in donor macrophages is sufficient to suppress rejection and extend allograft survival. This highlights the therapeutic potential of donor heart-based interventions.

Role of donor macrophages after heart and lung transplantation.

Since the 1960s, heart and lung transplantation has remained the optimal therapy for patients with end-stage disease, extending and improving quality of life for thousands of individuals annually. Expanding donor organ availability and immunologic compatibility is a priority to help meet the clinical demand for organ transplant. While effective, current immunosuppression is imperfect as it lacks specificity and imposes unintended adverse effects such as opportunistic infections and malignancy that limit the health and longevity of transplant recipients. In this review, we focus on donor macrophages as a new target to achieve allograft tolerance. Donor organ-directed therapies have the potential to improve allograft survival while minimizing patient harm related to global suppression of recipient immune responses. Topics highlighted include the role of ontogenically distinct donor macrophage populations in ischemia-reperfusion injury and rejection, including their interaction with allograft-infiltrating recipient immune cells and potential therapeutic approaches. Ultimately, a better understanding of how donor intrinsic immunity influences allograft acceptance and survival will provide new opportunities to improve the outcomes of transplant recipients.

Clinical factors and high-resolution manometry predicting response to surgery for achalasia in children.

BACKGROUND: Esophageal achalasia is an uncommon condition in children. Although many interventions exist for the management of this disorder, esophageal (Heller) myotomy offers one of the most durable treatments. Our institution sought to review patients undergoing Heller myotomy concentrating on preoperative clinical factors that might predict postoperative outcomes. MATERIALS AND METHODS: All patients from January 1, 2007, to December 31, 2016, who underwent surgical treatment for achalasia at our tertiary pediatric hospital were identified and included in the study cohort. Electronic medical records for these patients were reviewed for clinical presentation variables, nonsurgical preoperative treatment, surgical approach, clinical response to surgery, need for postoperative treatment for ongoing symptoms, and high-resolution manometry (HRM) data. RESULTS: Twenty-six patients were included in the study, and all underwent myotomy with partial fundoplication (median age: 14.4 y [interquartile range 11.6-15.5]). At a median follow-up of 9.75 mo (interquartile range 3.5-21 mo), 16 (61.5%) patients reported good resolution of their dysphagia symptoms with surgery alone. Two patients (7.7%) had perforation of the gastrointestinal tract requiring surgical intervention. Eight patients (30.8%) required additional treatment for achalasia, with 5 (19.2%) of these undergoing additional surgery or endoscopic treatment. Patients who had preoperative dilation did not have good resolution of their dysphagia (n = 2; P = 0.037). Two of four patients undergoing postoperative dilation had preoperative dilation. None of these patients underwent preoperative manometry. There was a statistically significant difference in the ages of patients who required postoperative intervention and those who did not (14.1 versus 15.2 y old, respectively; P = 0.043). In patients who reported improvement of gastroesophageal reflux disease/reflux type symptoms after Heller myotomy, lower esophageal residual pressure (29.1 versus 18.7 mmHg; P = 0.018) on preoperative HRM was significantly higher than in those who did not report improvement after surgery. Higher upper esophageal mean pressure (66.6 versus 47.8 mmHg; P = 0.05) also predicted good gastroesophageal reflux disease/reflux symptom response in a similar manner. CONCLUSIONS: Current analysis suggests that preoperative dilation should be used cautiously and older patients may have a better response to surgery without need for postoperative treatment. In addition, preoperative HRM can aid in counseling patients in the risk of ongoing symptoms after surgery and may aid in determining if a fundoplication should be completed at the index procedure. Further research is needed to delineate these factors. LEVEL OF EVIDENCE: Level III.

Cosmetic outcome of skin adhesives versus transcutaneous sutures in laparoscopic port-site wounds: a prospective randomized controlled trial.

BACKGROUND: In an elective laparoscopic surgery, the cosmetic outcome becomes increasingly important. We conducted a study to evaluate the cosmetic outcome 3 months after a laparoscopic procedure and compared skin adhesive (SA) versus transcutaneous suture (TS). METHODS: A randomized, controlled, prospective study was conducted at a single study centre in Hamburg, Germany. Seventy-seven patients undergoing laparoscopic surgery with two lower abdominal port sites met the study requirements. It was decided randomly which port site would be closed with SA. The opposite site was closed with TS. Wounds were assessed after 7-12 days and after 3 months. Cosmetic outcome was measured by a visual analogue scale (VAS) completed by the patient, by the Hollander wound evaluation scale (HWES) and by the judgement of blinded investigators. RESULTS: Seventy-seven subjects were randomized. Complete data from the 3-month follow-up visit were available from 56 patients (72.7 %). The VAS scale ranged from 0 to 100 mm with "0" representing the best possible cosmetic outcome. Median satisfaction was 2 mm in the TS group and 3 mm in the SA group. The mean was high in both groups 4.6 (s = 13.1) versus 3.8 mm (s = 4.6). The outcome was neither clinically nor statistically significant. Cosmetic outcome was assessed by an investigator, and the HWES showed no difference. In regard to complications, no difference was found between SA and TS, either. CONCLUSIONS: In conclusion this study demonstrated that closure of laparoscopic port-site wounds leads to equivalent outcomes whether SAs or TSs are used. Complications are rare in both methods. Thus, SAs seem to be a valid alternative to sutures in laparoscopic surgery. Registration site: www.clinicaltrials.gov . REGISTRATION NUMBER: NCT02179723.

Germany's disease management program: improving outcomes in congestive heart failure.

Hospital admissions among patients with congestive heart failure (CHF) are a major contributor to health care costs. A comprehensive disease management program for CHF was developed for private and statutory health insurance companies in order to improve health outcomes and reduce rehospitalization rates and costs. The program comprises care calls, written training material, telemetric monitoring, and health reports. Currently, 909 members from six insurance companies are enrolled. Routine evaluation, based on medical data warehouse software, demonstrates benefits in terms of improved health outcomes and processes of care. Economical evaluation of claims data indicates significant cost savings in a pre/post study design.

Association of hormone replacement therapy with bronchial hyper-responsiveness.

Postmenopausal hormone replacement therapy (HRT) has been linked to asthma in women, however, with inconsistent conclusions. This study examined the association of HRT with bronchial hyper-responsiveness (BHR). Eighty-five postmenopausal women completed a women-specific questionnaire and underwent methacholine challenge testing according to the protocol of the European community respiratory health survey. Associations of HRT use with BHR (based on a 20% fall in FEV1), mild BHR (10% fall in FEV1) or dichotomized dose-response slopes were analyzed by logistic regression, controlling for age, education, smoking and overweight. The 27 HRT users were less likely to show BHR compared to the 58 non-users (11% vs. 41%), multiply adjusted odds ratio (95% confidence interval) 0.12 (0.03, 0.55). Results for dose-response slopes were similar, while mild BHR showed no association with HRT use. These results point to a relaxing effect of estrogens on bronchial smooth muscle.

Exposure to pets and allergies in children.

Currently, there is ongoing discussion regarding potential protective effects of exposure to pets during early childhood on the development of atopic disorders in children later in life. We used data from three consecutive cross-sectional surveys to study the relationship between contact with dogs, cats and other pets, and allergic diseases in schoolchildren 5-14 years of age. In three study areas of the former East Germany, 7,611 questionnaires were received from 5,360 different children who were examined between 1992 and 1999 as school entrants, or third- or sixth-graders. Allergic sensitization to common aeroallergens (birch, grass, mite, cat) was assessed by specific serum immunoglobulin E (IgE) concentrations [using radioallergosorbent testing (RAST)] for 85% of the children. After adjustment for possible confounders, inverse associations were found between contact with dogs in the first year of life and lifetime prevalences of asthma [odds ratio (OR) = 0.68; 95% confidence interval (CI): 0.43-1.08], hay fever (OR = 0.61; 95% CI: 0.39-0.95), eczema (OR = 0.76; 95% CI: 0.61-0.94), itchy rash (OR = 0.76; 95% CI: 0.61-0.94), and pollen sensitization (RAST >/= 4: OR = 0.56; 95% CI: 0.38-0.82). These effects were more pronounced for children with atopic parents. Similar associations were observed for current contact with dogs. We identified no clear relationships for the other pets (cats, rodents, birds), with the exception that children currently exposed to cats were more likely to be sensitized against cats. In conclusion, this study supports the hypothesis of a potential protective mechanism related to dog exposure in early life, especially for children of atopic parents. However, this association was found only for dogs and not for cats.

Improved air quality in reunified Germany and decreases in respiratory symptoms.

BACKGROUND: Previous research on air pollution effects has found associations with chronic adverse health effects even at the relatively low levels of ambient particulates currently measured in most urban areas. METHODS: We assessed the impact of declines of total suspended particulates and sulfur dioxide in eastern Germany after reunification on the prevalence of nonallergic respiratory disorders in children. In the 1990s, particle mass (total suspended particulates) and sulfur dioxide declined, whereas number concentrations of nucleation-mode particles (10-30 nm) increased. In three study areas, questionnaires for 7,632 children between 5 and 14 years of age were collected in three phases: 1992-1993, 1995-1996, and 1998-1999. RESULTS: Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for a 50-microg/m3 increment in total suspended particulates were 3.0 (CI = 1.7-5.3) for bronchitis, 2.6 (CI = 1.0-6.6) for sinusitis, and 1.9 (CI = 1.2-3.1) for frequent colds. The effect sizes for a 100-microg/m3 increment in sulfur dioxide were similar. The effect estimates for ambient total suspended particulates and sulfur dioxide were stronger among children not exposed to gas stove emissions, visible molds or dampness, cats, or environmental tobacco smoke. CONCLUSIONS: The decreasing prevalence of nonallergic respiratory symptoms, along with improvements in ambient particle mass and sulfur dioxide (but not in nucleation-mode particles), indicates the reversibility of adverse health effects in children. This adds further evidence of a causal association between combustion-related air pollutants and childhood respiratory symptoms.