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Allergen immunotherapy, also called desensitisation, is a strategic process by which the immune system is gradually "trained" to tolerate increasing amounts of an allergen, which it previously would have reacted to. In the UK, it is estimated that approximately 20% of the population suffers with at least one allergic disease. The potential to modify the disease process is no longer out of our reach for certain allergies, with the hope of improved quality of life. Immunotherapy can be offered as a treatment for IgE mediated allergic disease such as allergic rhinoconjunctivitis, immediate type food allergies, bee and wasp anaphylaxis, and can have a synergistic effect on asthma and eczema. However, it would be incorrect to consider this treatment as a panacea, as there remain pitfalls, gaps in equity of treatment, and uncertainty with longer-term efficacy of the newer food desensitisation treatments. This review focuses on our current clinical understanding and indications for immunotherapy for children and young people, delivery and monitoring within the UK, and the future scope of immunotherapy. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine whether a multicomponent intervention focused on early peanut introduction was associated with a lower peanut allergy incidence in young children. METHODS: The study cohort comprised all children born January 1, 2013 through December 31, 2018 receiving care at a large health care organization. Intervention activities occurred over 16 months and included provider educational programs, electronic health record tools, and new patient instructions. We used an interrupted time series design to assess whether peanut allergy incidence differed across 3 time periods (preintervention, interim, postintervention) among high- and lowrisk children. The primary outcome was incident peanut allergy by age 24 months, defined as peanut allergy in the allergy field or active problem list plus a positive supportive test. Severe eczema and/or egg allergy presence defined highrisk. Because the study was conducted as part of routine care, it was not feasible to measure what counseling clinicians provided, or how and when parents fed their children peanutcontaining foods. RESULTS: In a cohort of 22,571 children, the percent with peanut allergy by age 24 months was 17.3% (116 of 671) among high-risk and 0.8% (181 of 21,900) among low-risk children. In multivariate analyses, the adjusted peanut allergy rate per 100 person-years was not significantly different across study periods among high-risk (9.6 preintervention, 11.7 interim, and 9.9 postintervention, P = .70) or low-risk (0.5 preintervention, 0.7 interim, and 0.5 postintervention, P = .17) children. CONCLUSIONS: In a community-based setting, the incidence of peanut allergy did not decline following a multicomponent intervention focused on early peanut introduction. [ABSTRACT FROM AUTHOR]

CpG oligodeoxynucleotide (CpG-ODN; CpG, in short) has been employed as an adjuvant in allergen specific immunotherapy (AIT) to treat allergic diseases. The underlying mechanism needs to be further explained. The aim of this study is to examine the mechanism by which CpG and dust mite extracts (DME, a specific antigen) alleviate experimental airway allergy. DME was used as the specific allergen to establish an airway allergy mouse model. The mice were directly exposed to DME and CpG through nasal instillations (the CpG.DME therapy). The response of DCs and allergic responses in the airways were assessed using immunological approaches. The airway allergy reaction was effectively suppressed by CpG.DME therapy. The administration of CpG or DME alone did not have any significant suppressive effects on the airway allergic response. Direct exposure to CpG.DME induced type 1 DCs (DC1s) and plasmacytoid DCs (pDCs), while CpG alone induced DC1s and DME alone induced DC2s in the airway tissues. Both DC1s and pDCs were required for the induction of type 1 regulatory T cells in the airway tissues by CpG.DME therapy. Depletion of either pDCs or DC1s abolished the induction of Tr1 cells, and abolished the suppressive effects on airway allergic response by the CpG.DME therapy. Direct exposure to CpG.DME induces DC1s and pDCs in the airway tissues. DC1s in synergy with pDCs induce type 1 regulatory T cells. The CpG.DME therapy is effective in suppressing allergic responses in mice with airway allergy. [ABSTRACT FROM AUTHOR]

In recent years, paediatric ABO incompatible (ABOi) living donor liver transplant (LT) has shown promising outcomes and can potentially eliminate organ shortage. This study aims to report paediatric ABOi LT experience, including short- and long-term outcomes. It is a single-centre retrospective study. Out of 108 LTs, 20 were done in children. We compared the outcomes between ABOi (n = 20) and non-ABOi (n = 220) paediatric living donor liver transplantation (LDLT) performed during the study period. All the children received pre-LT desensitization therapy comprising rituximab and plasmapheresis targeting pre-LT isohemagglutinin (IHA) titres of ≤1:16. Out of 239 paediatric LDLTs from 2017 to 2022, 19 children (11 females) underwent 20 ABOi LTs (including one retransplant with an ABOi domino allograft) at a median age of 12 (12, 51) months, with the majority being biliary atresia (60%). The median change in CD19 cell%, CD20 cell%, and IHA titres after rituximab from day −14 to day −1 (before LT) was satisfactory. In the first 3 months following LT, acute cellular rejection, culture-proven sepsis, and biliary and vascular complications were seen in 10%, 20%, 20%, and 15%, respectively. None of the ABOi LT recipients developed antibody-mediated rejection. ABOi LT recipients, as compared to non-ABOi LT recipients, had a higher incidence of bile leaks and prolonged hospital stay, with the rest of the complications, including biliary strictures and long-term outcomes, being comparable. At a median follow-up of 21 (14, 33) months, 4 children expired (21%). ABOi LT in children shows excellent outcomes and can be performed safely with prior desensitization when a compatible liver is unavailable. [Display omitted] [ABSTRACT FROM AUTHOR]

ABO-incompatible living donor liver transplantation (ABOi-LDLT) is on the rise as a viable option in countries with limited access to deceased donor grafts. While reported outcomes of ABOi-LT in children are similar to ABO- Compatible liver transplant (ABOc-LT), most children beyond 1–2 years of age will need desensitization to overcome the immunological barrier of incompatible blood groups. The current standard protocol for desensitization is Rituximab that targets B lymphocytes and is given 2–3 weeks prior to LT. However, this timeline may not be feasible in children requiring emergency LT for acute liver failure (ALF) or acute-on-chronic liver failure (ACLF). In this emergency situation of ABOi-LT, a safe multipronged approach may be an acceptable alternative solution. We report a child with acute Wilson's disease with rapidly deteriorating liver function who underwent a successful ABOi-LDLT using a rapid desensitization protocol. [ABSTRACT FROM AUTHOR]

The conjugation of chitopentaose (CHP) on β-lactoglobulin (βLg) via Maillard reaction was used to desensitize βLg. The stable βLg-CHP conjugate (βC-4) was formed at 4 h incubation, which contains 5 CHP attached molecules and a conjugated degree of 42 %. The conjugation promoted the thermal stability and emulsifying properties of βLg, and inhibited the immunoglobulin E (IgE) combining capacity by decreasing the content of β-sheet in βLg. Moreover, βLg-CHP conjugates were imparted with anti-oxidant properties and anti-inflammatory activities. Further, the combined action of inhibited IgE combining capacity and anti-inflammatory activities improved the allergy desensitization in βLg sensitized mice. The results showed that overexpressed IgE and inflammatory factors, unbalanced Th1-/Th2- immune cytokines were significantly attenuated after βLg was conjugated with CHP, avoiding the inflammatory lesions in spleen and colon. Additionally, the adverse changes in gut microbiota were alleviated in βC-4 group with a decrease of Bacteroidetes and increase of Firmicutes at phylum level and the probiotic bacteria of Lactobacillaceae was significantly improved at the family level. Thus, the conjugation of CHP can desensitize allergic reaction caused by βLg. [ABSTRACT FROM AUTHOR]

Pretransplant desensitization protocols, including plasmapheresis, intravenous immunoglobulin, induction antibody therapy, and intensive maintenance immunosuppression, are generally employed in kidney transplant recipients who have positive status for donor-specific anti-HLA antibody (DSA). To avoid serious infectious complications, the authors designed a novel low-dose protocol in Thai patients undergoing DSA+ living-related kidney transplantation (LRKT). A retrospective cohort study of the patients who underwent DSA+ LRKT was conducted. The novel protocol consisted of 3 to 5 sessions of pretransplant double-filtration plasmapheresis (DFPP) with or without low-dose intravenous immunoglobulin together with low-dose anti-thymocyte globulin (ATG) induction (1-1.5 mg/kg/d for 3-4 days) and low-dose tacrolimus (Tac) (trough level 5-10 ng/mL), mycophenolate, and prednisolone. The study included 17 patients. The lymphocyte crossmatch via complement-dependent cytotoxicity was negative in 12 patients and positive for B cell immunoglobulin M in 5 patients. The novel desensitization protocol resulted in a decrease of at least 50% of DSA mean fluorescence intensity from baseline (from 4320 ± 549 before DFPP to 1601 ± 350 before transplantation, P <.005) and successful kidney transplantation with good allograft function in all cases. Early DSA rebound was observed in 3 patients after transplantation, and kidney biopsy revealed subclinical antibody-mediated rejection in 1 patient and diffuse C4d staining without cell infiltration in 2 patients. There were good long-term outcomes in patient and graft survival (100% and 94.1%, respectively). Only 1 allograft loss occurred because of nonadherence. The majority of patients have stable allograft function with serum creatinine less than 1.5 mg/dL. However, infections, including CMV and other organisms, were commonly observed. Desensitization protocol with DFPP, low-dose ATG, and Tac provides excellent outcomes in living donor kidney transplantation in highly sensitized Asian populations. • Pretransplant double-filtration plasmapheresis with or without intravenous immunoglobulin, low-dose anti-thymocyte globulin, and tacrolimus reduce risk for rejection and provide long-term successful kidney transplantation in donor-specific anti-HLA antibody–positive (DSA+) Asian populations. • Transient DSA rebound early after transplantation may be found with or without rejection. • Cytomegalovirus (CMV) reactivation was common, and oral valganciclovir prophylaxis was strongly recommended in this group of patients. • The authors observed more infectious complications in the group of patients who did not receive CMV prophylaxis and developed CMV viremia. [ABSTRACT FROM AUTHOR]

Introduction of rituximab in the desensitization protocols for ABO-incompatible (ABOI) kidney transplantation (KTX) has afforded excellent results. However, the acceptability of minimal dosage of rituximab in these protocols remains to be defined. Sixty-three patients who underwent ABOI KTX were included in this study. The desensitization protocol consisted of plasmapheresis, tacrolimus, mycophenolate mofetil, methylprednisolone, intravenous immunoglobulin, basiliximab, and low-dose rituximab (100 mg/body). We evaluated the efficacy, safety, and long-term outcome of this protocol (group R, n = 39) and compared them with those of patients who underwent splenectomy (group S, n = 24). Graft and patient survival at 10 years after KTX were comparable between the groups (94.4% [group R] vs 95.4% [group S] and 94.6% [group R] vs 95.8% [group S], respectively). The incidence of acute antibody-mediated rejection (AAMR) was similar in the 2 groups (10.2% vs 12.5%). There were no significant differences in the incidence of chronic active antibody-mediated rejection. Of the patients, 7 developed AAMR and 3 of these patients (1 in group R and 2 in group S) lost their grafts. There were no significant differences in the incidence of chronic active antibody-mediated rejection. The incidence of postoperative cytomegalovirus infection in group R was significantly lower than that in group S. Furthermore, the incidence of postoperative late-onset neutropenia was low in group R. A low-dose rituximab regimen for ABOI KTX is acceptable for preventing AAMR with a low incidence of delayed adverse events. • Low-dose rituximab regimen for ABO-incompatible kidney transplantation afforded excellent long-term graft and patient survival. • The incidence of rejection associated with ABO-incompatible kidney transplantation was comparable to that associated with the conventional splenectomy regimen. • The incidence of postoperative cytomegalovirus infection associated with ABO-incompatible kidney transplantation was significantly lower than that associated with the conventional splenectomy regimen. • A low incidence of postoperative late-onset neutropenia was observed. [ABSTRACT FROM AUTHOR]

Antigen-specific immunotherapies (ASIT) present compelling potential for introducing precision to the treatment of autoimmune diseases where nonspecific, global immunosuppression is currently the only treatment option. Central to ASIT design is the delivery of autoantigen, which parallels allergy desensitization approaches. Clinical success in tolerizing allergen-specific responses spans longer than a century, but autoimmune ASITs have yet to see an FDA-approved breakthrough. Allergens and autoantigens differ substantially in physicochemical properties, and these discrepancies influence the nature of their interactions with the immune system. Approved allergen-specific immunotherapies are typically administered as water soluble, neutrally charged protein fractions from 10 to 70 kDa. Conversely, autoantigens are native proteins that exhibit wide-ranging sizes, solubilities, and charges that render them susceptible to immunogenicity. To translate the success of allergen hyposensitization to ASIT, delivery strategies may be necessary to effectively format autoantigens, guide biodistribution, and engage appropriate immune mechanisms. Unlabelled Image • Antigen-specific immunotherapy (ASIT) seeks to introduce precision to autoimmune disease treatments. • Autoimmune ASIT principles parallel those of allergen desensitization regimens, but none have been FDA-approved to date. • Allergens and autoantigens differ substantially in physicochemical properties including size, solubility, and charge. • Drug delivery and biomaterial design strategies are likely necessary to overcome detrimental autoantigen properties. [ABSTRACT FROM AUTHOR]

Cow's milk protein allergy (CMPA) is caused by a reproducible immune-mediated response to milk proteins and tends to present during the first few months of life. This response can vary significantly from an immediate reaction within 2 hours of ingestion to a more delayed reaction, which can occur anywhere between 2 and 72 hours later. A delay in diagnosis can cause significant child and parental distress, while overdiagnosis can lead to an unnecessary elimination diet. CMPA can be confused with lactose intolerance which is a non-immune mediated response as a result of lactase enzyme deficiency. We review the diagnosis and management of CMPA in this article along with future directions. [ABSTRACT FROM AUTHOR]

Eye Movement Desensitization and Reprocessing (EMDR) has been well established as an effective treatment for post-traumatic stress disorder (PTSD). However, PTSD has been re-categorized as part of trauma and stressor-related disorders instead of anxiety disorders. We conducted the first meta-analysis on Randomized Controlled Trials to evaluate the effectiveness of EMDR on reducing symptoms of anxiety disorders. A manual and systematic search using various databases and reference lists of systematic review articles published up to December 2018 was conducted. The symptoms of anxiety, phobia, panic, traumatic feelings and behaviors/somatic symptoms were examined. Hedges' g effect sizes were computed, and random effect models were used for all analyses. A total of 17 trials with 647 participants were included in this meta-analysis. EMDR was associated with a significant reduction of anxiety (g = −0.71; 95% CI: −0.96 to −0.47), panic (g = −0.62; 95% CI: −1.10 to −0.14), phobia (g = −0.45; 95% CI: −0.81 to −0.08), behavioural/somatic symptoms (g = −0.40; 95% CI: −0.63 to −0.12), but not traumatic feelings (g = −0.48; 95% CI: −1.14 to −0.18). Subgroup analysis revealed greater effects of EMDR if compared to passive control. However, the effects were not significantly different based on the duration, number of therapy sessions, or the number of weekly sessions. Our meta-analysis indicates that EMDR is efficacious for reducing symptoms of anxiety, panic, phobia, and behavioural/somatic symptoms. Further research is needed to explore EMDR's long term efficacy on anxiety disorders. [ABSTRACT FROM AUTHOR]

Background: To review the results of renal transplantation after promulgation of the Human Organ Transplant Act in Taiwan in 1987, we conducted a retrospective study in the first 1000 cases performed in our hospital. Prognostic factors for graft survival were assessed with emphasis on the impact of donor-specific antibody (DSA).Methods: Between January 1988 and April 2014, there were 1000 cases of renal transplantation performed in our hospital. Excluding 30 patients of ABO-incompatible transplantation, we reviewed 970 cases of ABO-compatible renal transplantation to analyze the prognostic factors for graft survival. The patients were grouped according to the dates of operations before (the Early group: 503 cases) and after (the Late group: 467 cases) the introduction of detection and desensitization of alloantibody in our hospital in 2004.Results: The overall 5-year graft survival rate were 82.6%, which was significantly lower in the Early group (79.2%) than the Late group (86.3%) (p = 0.0012). The 1-year rejection-free survival was significantly lower in the Early group (78.3%) than the Late group (91.2%) (p = 0.0165). The difference between the two groups became insignificant when the time of observation extended beyond 12 months. In a multivariate regression model, we identified significant factors for poor graft survival, including HLA mismatches, delayed graft function with or without recovery, and antibody-mediate rejection (AMR).Conclusion: HLA mismatches, delayed graft function with or without recovery, and AMR were significant factors for poor graft survival. Detection and desensitization of DSA currently might be inadequate to improve the long-term outcome of renal transplantation. [ABSTRACT FROM AUTHOR]

Desensitization, the process of reducing anti-human leukocyte antigen (HLA) antibodies in sensitized patients awaiting heart transplantation (HT), has unclear efficacy in pediatric HT candidates. Pediatric HT candidates listed at our institution between January 1, 2013 and June 30, 2018 were retrospectively evaluated. Sensitization was defined as the calculated panel reactive antibody (cPRA) ≥ 10% with ≥ 1 a strong positive antibody. The desensitization response was defined as a ≥ 25% reduction in the mean fluorescence intensity (MFI) for ≥ 90% of the strong positive antibodies on follow-up panel reactive antibody (PRA) testing before waitlist removal, HT, or death (data available for 13 patients). The HT candidates were categorized as sensitized receiving desensitization therapy (ST, n = 14), sensitized not receiving therapy (SNT, n = 18), or non-sensitized (n = 55). A desensitization response was observed in 8 (62%) of the ST upon repeat PRA testing, with the ST responders receiving more doses of intravenous immunoglobulin (IVIG) (8 vs 2, p < 0.05). The anti-HLA class I antibodies were particularly resistant for non-responders (p = 1.9 × 10−4). The combination of homograft and ventricular assist device was more sensitizing than either alone (p = 3.1 × 10−4). However, these sensitization risk factors did not impact the desensitization response. The ST was associated with a higher likelihood of remaining listed and a longer waitlist time without substantially impacting the HT rate, waitlist mortality, or early post-HT outcomes. Most ST patients had a favorable response to desensitization, with a dose-dependent response observed for IVIG. The anti-HLA class likely impacts the ST response, whereas traditional sensitization risk factors had no impact on the response. [ABSTRACT FROM AUTHOR]

Donor-specific human leukocyte antigen (HLA) antibodies (DSA) are being recognized as a risk factor of acute rejection and chronic lung allograft dysfunction (CLAD). Re-transplantation (re-LTx) is the only treatment for CLAD, but the outcome could be limited especially in the sensitized patients. Some desensitization protocols were reportedly verified in a single center study basis, but yet to be standardized in DSA-positive lung transplantation (LTx). Herein, we report a case of successful lung re-LTx along with perioperative desensitization for a DQ DSA-positive recipient. A 10-year-old-man underwent living-donor single lobar LTx for pulmonary graft-versus-host disease after bone marrow transplant. Three years later, he developed antibody-mediated rejection due to de novo DSA. The mean fluorescence intensity of DQ4 exceeded 12000 which was persistent even after antibody targeted therapy, resulting in the development of bronchiolitis obliterans syndrome. He needed a mechanical ventilator, and temporary use of Extra-Corporeal Membrane Oxygenation. Following two-year waiting time, he eventually acquired an organ offer from a brain-dead donor and underwent re-LTx. The virtual crossmatch revealed the patient's preformed antibody to DQ4 was donor-specific, and flow cytometry crossmatch test for B cell was also positive. Thus, we performed two sessions of plasma exchanges (PLEX) with 1.5 volume of fresh frozen plasma preoperatively, and five sessions postoperatively. Subsequently, intravenous immune globulin (1 g/kg) and antithymocyte globulin (3mg/kg) was also given. Target trough level of tacrolimus was set in a usual manner. Mean fluorescence intensities for the DSAs were monitored at several times (pre PLEX, post all perioperative desensitization, and two months after re-LTx) and confirmed to be going down (DQ4; 12580, 7578, 6344). He developed a single episode of mild acute cellular rejection, but his postoperative course was almost uneventful and he is doing well 4 months after re-LTx and returns to his normal daily life. Although this case possessed multiple immunological risks including re-LTx and positive DQ-DSA, perioperative desensitization with the combination of multiple PLEXs, IVIG and antithymocyte globulin was effective. Careful monitoring of DSA is planned in the long term. [ABSTRACT FROM AUTHOR]

The Toronto Lung Transplant Program uses a desensitization protocol that includes intraoperative therapeutic plasma exchange (iTPE) for virtual crossmatch (VXM) positive lung transplants (LTx), which improves access to LTx for sensitized candidates while successfully mitigating immunologic risk. Concern for peri-operative bleeding has reduced broader adoption of this protocol. We conducted a retrospective cohort study to quantify the impact of iTPE on peri-operative bleeding. All first-time LTx recipients from 2014-2019 who received iTPE were compared to those who did not. Logistic regression was used to determine the association between iTPE and high peri-operative transfusion requirements (>5 packed red blood cell (pRBC) units within 24 hours of transplant start), adjusted for disease type, LTx type, and extracorporeal membrane oxygenation (ECMO)/cardiopulmonary bypass (CPB) use. The margins command (Stata/SE15.1) was used to determine the impact of iTPE on the predicted probability of high peri-operative transfusion requirements. The incidence of hemothorax (need for re-operation within 7 days of LTx) was compared between the 2 groups using Chi square test. 142 patients (16%) received iTPE and 755 patients (84%) did not. iTPE was associated with an increased odds of high peri-operative transfusion requirements (OR 1.6, 95% CI: 0.9-2.8, p=0.08), but was not associated with an increased incidence of hemothorax (5% in both groups, p=0.99). The predicted probabilities of high peri-operative transfusion requirements for a double LTx for restrictive lung disease based on iTPE and ECMO/CPB use are shown in Table 1. This study demonstrates that the use of iTPE in LTx may increase peri-operative bleeding, but not to a clinically meaningful degree. The addition of iTPE allows sensitized candidates to undergo LTx safely without changing the most probable peri-operative transfusion requirements (even for LTx performed on ECMO or CPB), or increasing the risk of hemothorax. [ABSTRACT FROM AUTHOR]

Frizzleds (FZDs) are receptors for secreted lipoglycoproteins of the Wingless/Int-1(WNT)family, initiating an important signal transduction network in multicellular organisms. FZDs are G protein-coupled receptors (GPCRs), which are well known to be regulated by phosphorylation, leading to specific downstream signaling or receptor desensitization. The role and underlying mechanisms of FZD phosphorylation remain largely unexplored. Here, we investigated the phosphorylation of human FZD6. Using MS analysis and a phospho-state- and -site-specific antibody, we found that Ser-648, located in the FZD6 C terminus, is efficiently phosphorylated by casein kinase 1 ϵ (CK1ϵ) and that this phosphorylation requires the scaffolding protein Dishevelled (DVL). In an overexpression system, DVL1, -2, and -3 promoted CK1ϵ-mediated FZD6 phosphorylation on Ser-648. This DVL activity required an intact DEP domain and FZD-mediated recruitment of this domain to the cell membrane. Substitution of the CK1ϵ-targeted phosphomotif reduced FZD6 surface expression, suggesting that Ser-648 phosphorylation controls membrane trafficking of FZD6. Phospho- Ser-648 FZD6 immunoreactivity in human fallopian tube epithelium was predominantly apical, associated with cilia in a subset of epithelial cells, compared with the total FZD6 protein expression, suggesting that FZD6 phosphorylation contributes to asymmetric localization of receptor function within the cell and to epithelial polarity. Given the key role of FZD6 in planar cell polarity, our results raise the possibility that asymmetric phosphorylation of FZD6 rather than asymmetric protein distribution accounts for polarized receptor signaling. [ABSTRACT FROM AUTHOR]

Human α 1D -adrenoceptors (α 1D -ARs) are a group of the seven transmembrane-spanning proteins that mediate many of the physiological and pathophysiological actions of adrenaline and noradrenaline. Although it is known that α 1D -ARs are phosphoproteins, their specific phosphorylation sites and the kinases involved in their phosphorylation remain largely unknown. Using a combination of in silico analysis, mass spectrometry and site directed mutagenesis, we identified distinct α 1D -AR phosphorylation patterns during noradrenaline- or phorbol ester-mediated desensitizations. We found that the G protein coupled receptor kinase, GRK2, and conventional protein kinases C isoforms α/β, phosphorylate α 1D -AR during these processes. Furthermore, we showed that the phosphorylated residues are located in the receptor's third intracellular loop (S300, S323, T328, S331, S332, S334) and carboxyl region (S441, T442, T477, S486, S492, T507, S515, S516, S518, S543) and are conserved among orthologues but are not conserved among the other human α 1 -adrenoceptor subtypes. Additionally, we found that phosphorylation in either the third intracellular loop or carboxyl tail was sufficient to regulate calcium signaling desensitization. By contrast, mutations in either of these two domains significantly altered mitogen activated protein kinase (ERK) pathway and receptor internalization, suggesting that they have differential regulatory mechanisms. Our data provide new insights into the functional repercussions of these posttranslational modifications in signaling outcomes and desensitization. [ABSTRACT FROM AUTHOR]

Vaccines typically come with adjuvants that trigger the innate immune system in order to prepare best possible inflammatory conditions as to allow the adaptive immune system to become activated, generally for the induction of antibodies. The oldest approved and most abundant immunological adjuvants are salts of aluminium, which are also frequently used in animal models of immunisation and allergy desensitization. In rodents, the intraperitoneal administration of aluminium adjuvants is commonly performed and considered safe. In the current investigation, we show that intraperitoneal administration of aluminium adjuvants is associated with a dose-dependent hypothermic reaction within 10 min of the injection. The body temperature of mice dropped as much as 4 °C, and the clinical symptoms included apathy, hunched posture, and piloerection. The temperature normalised and other clinical manifestations disappeared within 60–80 min of the intraperitoneal aluminium injection, which caused strong infiltration of neutrophil and eosinophil granulocytes into the peritoneal cavity, a clinical manifestations typically associated with inflammasome activation. However, the observed reactions to aluminium adjuvants were independent of NALP3, caspase-1, and interleukin-1β, but dependent on histamine. Hence, aluminium adjuvants may have potential local and systemic side effects, which warrants further investigations into the nature of these side effects, but also into the possible implications on health in man. [ABSTRACT FROM AUTHOR]

Background: Iron deficiency anemia is a disease that can significantly compromise a patient's quality of life. Desensitization is a safe and effective treatment option for iron-deficient anemic patients who require intravenous iron despite their hypersensitivity to iron. This report describes a safe desensitization protocol for patients with iron hypersensitivity who require iron treatment for their clinical improvement. Case presentation: Two patients of 20 and 46-year-old diagnosed with secondary iron deficiency anemia hipermenorreas and a clinical history of fail treatment with oral iron, who presented a reaction of the anaphylactic type while they receive iron parenteral sucrose. Therefore, the patients were treated with the desensitization protocol applied for patients with hypersensitivity to iron. Conclusion: Iron deficiency anemia is a disease that can significantly compromise the quality of life of patients. The desensitization protocol for patients with hypersensitivity to iron is a safe and effective treatment option for patients with a history of allergy to intravenous iron. This case report shows the usefulness to use the desensitization protocol for patients with hypersensitivity to iron. [ABSTRACT FROM AUTHOR]

Various additives, including food colorants (FCs), are used in the food industry to make food appealing to consumers and to add variety. Despite the widespread usage of FCs, adverse reactions related to their consumption, including reactions triggered by immune (immediate and delayed-type hypersensitivity) and non-immune (intolerance) mechanisms, are considered rare. There is a discrepancy between the perception of patients and parents (7.4%) and the reported prevalence of adverse reactions to additives (0.01–0.23%), which is higher in atopic individuals (2–7%). Documented reactions are mild, involving mainly the skin, and, rarely, anaphylaxis. A major problem in diagnosing reactions to FCs is identification of the offending agent(s), which is based on careful dietary history taking. Allergy testing is usually unrevealing, except for reaction to some natural colorants. Treatment consists of avoidance of the offending colorant as no successful desensitization procedures have been reported. [ABSTRACT FROM AUTHOR]

Background The waiting time for re-transplantation for sensitized patients is greatly prolonged, given the lack of transplants that are available for this group and additional immunologic barriers. We report the case of a successful re-transplantation in a patient with very high levels of panel reactive antibodies ([PRA] >85%). Methods A 45-year-old woman had repetitive rejections after simultaneous pancreas-kidney transplantation, with consequent loss of function of both transplanted organs. Because of a symptomatic episode of kidney rejection, additional removal of the transplanted kidney was performed 6 years later. Because our patient had a very high PRA level, she was enrolled in a desensitization protocol. The regimen was based on an initial single dose of rituximab, followed by repetitive plasmapheresis/immune-absorption sessions and intravenous substitution of immunoglobulin. Eight cycles were required, until a cross-match test was negative (PRA level <50%). The protocol included prednisolone and weight-adapted thymoglobulin. The basic immunosuppressive medication consisted of prednisolone, tacrolimus, and mycophenolate mofetil. The patient's postoperative course was uneventful. Results Preoperative treatment is essential for sensitized patients. There are no prospective, randomized trials comparing all suggested desensitization protocols. The main tenets of every approach are plasmapheresis and intravenous substitution of immunoglobulin, which appear to have a strong immunomodulatory effect. In the case of re-transplantation, the clinical surgeon not only faces special technical and surgical challenges but also must confront immunologic barriers. Conclusions Pancreas-kidney transplantation in patients with high PRA levels is feasible and can be performed successfully with novel desensitization protocols. [ABSTRACT FROM AUTHOR]

Allergen-specific sublingual immunotherapy (SLIT) is well known as an effective and non-invasive route to induce allergy desensitization. The goal of this study was to investigate whether a TAT-fused recombinant allergen could enhance SLIT efficacy. BALB/c mice sensitized to the main allergen (Che a 3) of Chenopodium album pollen were treated sublingually either with rChe a 3 (100 μg/dose) or rTAT-Che a 3 (100 μg/dose), two times per week for eight weeks. SLIT with rTAT-Che a 3 led to significantly greater allergen-specific IgG2a than rChe a 3; however, neither rTAT-Che a 3 nor rChe a 3 affected allergen-specific IgE or IgG1 antibody levels. In addition, interleukin 4 (IL-4) levels in re-stimulated splenocytes from the rTAT-Che a 3 mice were significantly lower than in those from the rChe a 3 mice, while interferon-γ (IFN-γ) was significantly greater in the rChe a 3 mice than in the rTAT-Che a 3 mice. Furthermore, sublingual administration of rTAT-Che a 3 induced significantly greater TGF-β secretion in re-stimulated splenocytes than administration of rChe a 3. Accordingly, SLIT with rTAT-Che a 3 led to significantly greater expression of TGF-β- and Foxp3-specific mRNAs in the splenocytes than in those from the rChe a 3 mice. Our findings demonstrate that TAT-fused rChe a 3 suppressed the allergic response through preferential enhancement of systemic regulatory T-cell (Treg)-mediated immunity responses, likely by facilitating allergen capture and presentation by sublingual Langerhans-like dendritic cells. [ABSTRACT FROM AUTHOR]

Preformed HLA antibodies are associated with an increased occurrence of complications post transplantation. The role of HLA-DP antibodies and HLA-DP antigen expression on myocytes has not been well studied in the past. A 64-year-old female with prior history of breast cancer treated with lumpectomy & radiation, ischemic cardiomyopathy with LVEF 10%, two prior pregnancies and no prior blood transfusion was evaluated for LVAD/cardiac transplant for her advanced heart failure. Her initial cPRA (calculated panel-reactive antibody) was determined to be 0%; semi-quantitative assessment of HLA-DP antibodies was below the positive threshold of 10,000 MFI. She underwent LVAD implantation as a bridge to transplant, and in the post-op period, she required multiple blood and platelet transfusions due to recurrent bleeding. Ten days post LVAD, her Class I cPRA rose to 70%, Class II cPRA 48%, with very strong DP antibodies against the 84DEAV epitope detected. Following her rise in cPRA, desensitization was performed using plasmapheresis, IVIG and Rituximab. She was listed for heart transplant. Almost 5 months from LVAD implantation, she received a donor offer. A donor-specific DP10 antibody at an MFI of ∼20,000 was seen at the time of offer, and physical crossmatches were performed. CDC crossmatch for both T-cell (HLA Class I) and B-cell (HLA Class II) were negative; flow-cytometry crossmatch for T-cell was negative, as expected. However, B-cell flow-crossmatch was positive. Due to her clinical condition, the potential risk of transplantation was deemed acceptable and she underwent successful transplantation, receiving plasmapheresis on POD1. On POD 7, her DP10 DSA was 16,000 MFI. Five more rounds of plasma exchange with alternating IVIG administration were performed. Her graft function remained normal, and her POD 7 biopsy showed no evidence of cellular nor antibody mediated rejection. At 16-weeks post-op, her DP10 MFI values had dropped to ∼3,000. Her LHC at 1 year showed normal coronaries. This is a case of a successful transplantation in a recipient with very high HLA-DP donor specific antibodies. The presence of DSA to HLA-DP is not necessarily a contraindication to heart transplant. The case further raises questions on the clinical impact of detectable DP antibodies in potential heart transplant patients, and if desensitization is necessary in similar scenarios. [ABSTRACT FROM AUTHOR]

Apelin acts via the G protein-coupled apelin receptor (APJ) to mediate effects on cardiovascular and fluid homeostasis. G protein-coupled receptor (GPCR) trafficking has an important role in the regulation of receptor signalling pathways and cellular functions, however in the case of APJ the mechanisms and proteins involved in apelin-induced trafficking are not well understood. We generated a stable HEK-293 cell line expressing N-terminus HA-tagged mouse (m) APJ, and used a semi-automated imaging protocol to quantitate APJ trafficking and ERK1/2 activation following stimulation with [Pyr 1 ]apelin-13. The mechanisms of [Pyr 1 ]apelin-13-induced internalization and desensitization were explored using dominant-negative mutant (DNM) cDNA constructs of G protein-coupled receptor kinase 2 (GRK2), β-arrestin1, EPS15 and dynamin. The di-phosphorylated ERK1/2 (ppERK1/2) response to [Pyr 1 ]apelin-13 desensitized during sustained stimulation, due to upstream APJ-specific adaptive changes. Furthermore, [Pyr 1 ]apelin-13 stimulation caused internalization of mAPJ via clathrin coated vesicles (CCVs) and also caused a rapid reduction in cell surface and whole cell HA-mAPJ. Our data suggest that upon continuous agonist exposure GRK2-mediated phosphorylation targets APJ to CCVs that are internalized from the cell surface in a β-arrestin1-independent, EPS15- and dynamin-dependent manner. Internalization does not appear to contribute to the desensitization of APJ-mediated ppERK1/2 activation in these cells. [ABSTRACT FROM AUTHOR]

Background/purpose: Intravenous immunoglobulin (IVIG) plays a central role in the treatment of antibody-mediated rejection (AMR) of renal allografts, but the treatment outcomes for late AMR (>6 months after transplantation) are poor.Methods: We performed a retrospective study to assess the response patterns of IVIG-based (2 g/kg) desensitization for late AMR. Patients who received desensitization after the pathological diagnosis of late AMR positive for complement component C4d were grouped as the Desensitized Group and compared to a historical Control Group with complement component C4d positivity in retrospective stainings.Results: The 10-year graft survival of the Desensitized Group (73.9%, n = 35) was significantly better than that of the historical Control Group (35.0%, n = 40) without desensitization. In the Desensitized Group, a subgroup of patients (D2 Subgroup, n = 11), who responded to desensitization initially but deteriorated later, was identified to benefit from repeated cycles of desensitization at 31.1 ± 20.9 months. Patients receiving only one cycle of desensitization were further grouped into D1-good (n = 10) and D1-poor (n = 14) based on their long-term renal function. The D2 Subgroup patients did not exhibit significant improvements in renal function compared to the D1-poor patients, until 30 months after IVIG-based desensitization, suggesting desensitization therapy has a working window of approximately 24 months.Conclusion: Repeated cycles of IVIG-based desensitization help stabilize long-term renal function in patients with persistent AMR. [ABSTRACT FROM AUTHOR]

Food allergy is an important public health concern, affecting 10% of infants, 5–6% of children and 2% of adults in westernized countries. Current management involves food avoidance, education of patients and carers in the emergency management of allergic reactions and in some cases provision of an adrenaline autoinjector. Oral immunotherapy (OIT) has recently been explored as a potential treatment for food allergy. This review will discuss mechanisms of oral tolerance and summarize clinical and immunologic effects of OIT. [ABSTRACT FROM AUTHOR]

Food allergy (FA) in children is common, affecting about 6% of children in the UK, and is thought to be increasing in prevalence. Presentation varies widely with age, causative food, type of FA (IgE-mediated or non-IgE mediated) and severity. Assessment of suspected FA includes a detailed clinical history and dietary history and appropriate confirmatory allergy testing. The traditional management of complete dietary exclusion of the causative and related foods is evolving to one of limiting exclusion and early reintroduction. Novel treatments under investigation are mechanisms to prevent FA and oral desensitisation in selected cases in an attempt to cure FA. This article aims to give advice to the generalist about how to assess and initiate appropriate investigation a child presenting with possible food allergy. [ABSTRACT FROM AUTHOR]

Background/purpose: Desensitization regimens including use of intravenous immune globulin and rituximab have been reported to overcome renal transplant hyperacute rejection. A retrospective case-control study was performed to assess the results and complications of renal transplantation with desensitization therapy for donor-specific antibody (DSA) in a transplant center in Asia, where donor exchange was usually not allowed.Methods: Between January 2007 and December 2013, 22 patients with DSA received live-donor renal transplantation after desensitization (DSA group). During the same period, the DSA group was compared to the NSA group (152 renal transplants) who had no specific antibody to the donors (66 from deceased donors and 86 from living relatives). Rejection, renal function, graft and patient survival rates, infection, and cancer incidence were reviewed and analyzed from medical records.Results: The DSA group (46.8%) had significantly higher acute rejection rates than the NSA group (13.7%) at the 1-year follow-up. The estimated renal function, 5-year graft, and patient survival rates were comparable between the groups. The DSA group (19.6%) had significantly higher 5-year de novo cancer incidence than the NSA group (8.5%; p = 0.028); three patients of the DSA group developed urothelial carcinoma 17.0 ± 3.0 months after transplantation. By using stepwise Cox regression analysis, desensitization therapy was identified as the sole independent risk factor for post-transplant urothelial carcinoma.Conclusion: When compared to renal transplantation without DSA, desensitization therapy for DSA resulted in equivalent renal transplant outcome but potentially increased risk of urothelial carcinoma after transplantation. [ABSTRACT FROM AUTHOR]

Objectıves Even though allergen immunotherapy is an effective treatment method that has been used on rhinitis, asthma and venom anaphylaxis for over 100 years, systemic reactions (SRs) limit the use of this treatment method. We classified SRs associated with subcutaneous immunotherapy (SCIT) according to the World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System. Risk factors for the SRs were assessed. Methods In this study 67,758 injections to 1350 children with allergic rhinitis and/or asthma were analyzed throughout January 1999–December 2014. Results A total of 51 systemic reactions were observed in 39 patients (0.075% per injection, %3 per patient). Mean age of SRs observed patients was 13 ± 2.6 years (range 9.5–16 years) and 64.1% were male, 35.9% were female. 51.3% of SRs were grade 1, 38.5% grade 2, 7.7% grade 3 and 2.6% grade 4. SRs were early onset in 41% of the patients and delayed onset in 59%. 76.9% of SRs were seen during maintenance therapy and 56.4% during peak pollen season. In 28.2% of cases previous local reactions and in 30.8% previous grade 1 reactions were determined. There was no fatal outcome from any of the SRs. Conclusion SCIT related SRs are generally of mild severity. Although only 10% of the SRs were grade 3 or 4, there is a still a small risk of severe reactions. 76.9% of SRs were observed during maintenance therapy. Delayed-onset SRs rate in our study is 59%. So both clinicians and parents should be alert about the delayed reactions after SCIT. [ABSTRACT FROM AUTHOR]

Sensitization describes the acquired ability of the immune system to react to foreign human leukocyte antigens (HLA) by producing antibodies and developing memory cells. In the field of transplantation, recipient preformed HLA antibodies due to previous sensitization have been identified - beneath ABO incompatibility - as a major factor for acute graft rejection. Several reasons for sensitization have largely been studied, such as previous blood transfusions, pregnancies or former transplants. Recent studies indicate that the use of assist devices (e.g. ECMO) or cadaveric skin allotransplantation providing temporary coverage in burn patients may lead to additional sensitization. As vascularized composite allotransplantation (VCA) has become a rapidly advancing therapeutic option for reconstruction of complex tissue defects in burns, it seems even more important to become familiar with immunological principles and to be cautiously aware of both sources of sensitization and therapeutic concepts in burns avoiding sensitization. This may also include emergency VCAs in burn patients as potential strategy for early definitive reconstruction avoiding procedures triggering HLA antibody formation. We hereby provide an overview on current evidence in the field of pre- and peritransplant sensitization, followed by posttransplant strategies of desensitization and their potential impact on future treatments of burn patients. [ABSTRACT FROM AUTHOR]

Objective: We have recently reported that a new regimen of short-term oral immunotherapy (OIT) with the Cry j1-galactomannan conjugate for Japanese cedar pollinosis (JCP) is effective to the improvement in the symptoms and medication use during the pollen season and relatively safe. The effect of OIT on quality of life (QOL) of JCP patients has not been assessed. Therefore, we evaluated for the first time the effect of OIT on QOL during the Japanese cedar/cypress pollen season.Methods: A prospective, randomized, open-label trial was conducted over a period of 4 months. Participants were randomly divided into two groups. The OIT and control groups comprised 23 and 24 subjects, respectively. The build-up phase was initiated 1 month before the expected pollen season. The maintenance phase was continued for 51 days during the peak of the cedar pollen season. The QOL score in the Japan Rhinoconjunctivitis Quality of Life Questionnaire (JRQLQ) No. 1 and visual analog scale (VAS) throughout the pollen season were evaluated.Results: Participants receiving OIT showed significant improvements in the total QOL score and VAS throughout the pollen season compared with the control group. In addition, the mean total QOL score and VAS correlated in both groups during the pollen season.Conclusion: The new regimen of short-term OIT using the Cry j1-galactomannan conjugate results in meaningful improvements in QOL of JCP patients. Our findings suggest that short-term OIT using allergen-galactomannan conjugates, as well as sublingual and subcutaneous immunotherapy, improves QOL of patients with pollinosis. The study was registered in UMIN-CTR (UMIN000013408) as the name of "a prospective, randomized, open study of oral Cry j1-galactomannan conjugate immunotherapy for Japanese cedar pollen allergy". [ABSTRACT FROM AUTHOR]

Central GABA A receptors mediate GABAergic phasic and tonic inhibition. While synaptic αβγ GABA A receptors primarily mediate phasic inhibition, extrasynaptic αβδ receptors play an important role in mediating tonic inhibition. Etomidate is a general anesthetic that produces its effects by enhancing GABA A receptor activity. We previously showed that etomidate modulates the gating of oocyte-expressed αβγ and αβδ receptors with similar overall allosteric impact, but different pharmacological patterns. In αβγ receptors, etomidate enhances apparent GABA sensitivity (reduces GABA EC 50 ), modestly increases maximal GABA efficacy, and slows current deactivation without affecting desensitization (Zhong et al., 2008). In αβδ receptors characterized by low GABA efficacy, etomidate dramatically increases responses to both low and maximal GABA. The effects of etomidate on desensitization and deactivation of αβδ receptors are unknown. To investigate the kinetic effects of etomidate on α1β3δ receptors of defined subunit arrangement, we expressed concatenated trimer (β3-α1-δ) and dimer (β3-α1) GABA A receptor subunit assemblies in human embryonic kidney (HEK)293T cells and recorded whole-cell voltage-clamp currents during rapid external solution exchanges. As expected, etomidate substantially increased maximal GABA-induced currents and prolonged deactivation. Moreover, desensitization was significantly decreased by etomidate. During prolonged GABA applications, etomidate enhanced steady-state currents more than peak currents. Thus, etomidate enhances tonic GABAergic inhibition through extrasynaptic αβδ receptors by both augmenting gating and reducing desensitization. [ABSTRACT FROM AUTHOR]

Food allergy is a major public health problem affecting nearly 10 % of children in most industrialized countries. Unfortunately, there are no effective therapies for food allergy, relegating patients to simply avoid the offending foods and treat reactions that occur on accidental exposure. Recently however, studies suggest that food immunotherapy may provide a promising new approach to food allergy, particularly using the oral form of immunotherapy (OIT). Enthusiasm for this approach though must be tempered because of the significant allergic reactions that often occur with OIT that tends to limit its use to patients with less severe disease. On the other hand, recent studies suggest that concomitant treatment of patients with omalizumab (anti-IgE monoclonal antibody) during the updosing phase of OIT may greatly reduce the allergic reactions associated with OIT, even in high-risk patients. This combined method may provide a novel approach to successfully and rapidly treat a large fraction of patients with high-risk food allergy. [ABSTRACT FROM AUTHOR]

Problem Overview With cardiovascular disease being the leading cause of morbidity and mortality in the United States, cholesterol-lowering medications have become a prominent focus of medical management and cardiovascular risk reduction, including the use of statins making them the most widely prescribed class of medications in the United States and are the cornerstone of management of hyperlipidemia. This case report describes a 29-year-old female with probable familial hypercholesterolemia (FH) who had allergic reactions to statin therapy on two separate occasions. She required statin therapy based on her elevated carotid intima media thickness test, historic LDL-C ≥190mg/dL, elevated Lp(a), and family history significant for premature coronary heart disease. In this report, we document a case of successful oral desensitization to rosuvastatin and propose a replicable statin desensitization protocol. Major Management The patient was admitted for rosuvastatin desensitization following predetermined protocols, utilizing an interdisciplinary team, and monitored for 24 hours following completion of administration prior to discharge. She successfully completed desensitization to rosuvastatin 10mg by mouth daily without anaphylactic reaction. She continued to tolerate rosuvastatin 10mg daily through most recent follow-up, and with this addition, significant improvement in lipid levels was achieved. Conclusion This case report presented a patient with probable FH who was previously intolerant to other statin therapies that underwent successful desensitization to rosuvastatin with subsequent achievement of therapy goals. [ABSTRACT FROM AUTHOR]

Purpose: We examined the clinical data of patients treated with oxaliplatin to determine the risk factors of oxaliplatin-related hypersensitivity reaction (HSR). In addition, we evaluated the efficacy of rechallenging patients with HSRs with oxaliplatin using prophylactic agents or desensitization procedures. Methods: This study consisted of 162 patients with colorectal cancer (88 men and 74 women) who were treated consecutively at the outpatient chemotherapy department at University Hospital, Kyoto Prefectural University of Medicine. Patients underwent chemotherapy, including oxaliplatin, between March 2006 and June 2012. We analyzed the patients' clinical backgrounds (eg, age, sex, performance status, disease stage, and allergic history) to uncover any connections to the development of HSR to oxaliplatin. In addition, we rechallenged 10 patients who had oxaliplatin-related HSR using prophylactic agents or desensitization procedures. Findings: Of 162 patients, 28 (17.2%) developed oxaliplatin-related HSRs (16, 2, 9 and 1 patient had grade 1, 2, 3, and 4 HSRs, respectively). The total cumulative dose of oxaliplatin at the onset of the HSR was 301 to 1126 mg/m² (median, 582 mg/m²), and the first reactions developed in these patients after 5 to 17 infusions of oxaliplatin (median, 8 infusions). Logistic regression analysis indicated that sex (male: odds ratio = 3.624; 95% CI, 1.181-11.122; P = 0.024) and eosinophil count in peripheral blood (odds ratio = 35.118; 95% CI, 1.058-1166.007; P = 0.046) were independent variables for oxaliplatin-related HSRs. Rechallenging patients with prophylactic agents was successful in 2 (28.6%) of 7 patients who successfully completed their treatment. On the other hand, all 3 patients rechallenged with oxaliplatin using a desensitization protocol successfully completed their treatment without new HSRs. Implications: In this retrospective study, we observed that being male and having higher counts of peripheral eosinophil could be predictors for HSR to oxaliplatin. In addition, this study confirms that oxaliplatin desensitization protocol allows patients who developed HSRs to continue with their treatment. However, the optimum desensitization protocol for oxaliplatin administration in terms of tolerability and efficacy needs to be defined. [ABSTRACT FROM AUTHOR]

Melamine–formaldehyde resins (MF resins) were selected for the fabrication of three typical nitramine explosives (cyclotrimethylenetrinitramine, RDX; cyclotetramethylenetetranitramine, HMX; and hexanitrohexaazaisowurtzitane, CL-20) based microcapsules, the polymer coating shell could be prepared via a facile in situ polymerization of melamine and formaldehyde on the surface of explosive crystals. Structural characterizations and thermal properties of the core–shell composites were systematically studied by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), fourier-transform infrared (FT-IR) spectra and differential scanning calorimeter (DSC). The SEM and XPS results indicated that these three energetic cores were mostly well coated. XRD and FTIR analyses showed the combined characteristics of explosives and MF resins, and revealing that the polymorph of CL-20 maintained the optimal ε form during the whole preparing process. After coating, the endothermic polymorphic phase transition as well as the exothermic thermal decomposition temperature of the explosives was visibly increased, attributing to the outstanding heat resistance of MF resin shell. The impact sensitivity of the resultant microcapsules could be reduced from 2 to 3 times, depending on energetic material, after coating by 3 wt% MF resins. [ABSTRACT FROM AUTHOR]

Background Because of the development of various desensitization strategies, ABO-incompatible (ABOi) living donor liver transplantation (LDLT) has become a feasible option for patients with end-stage liver disease. However, there has been no united desensitization protocol for ABOi LDLT. We analyzed the outcomes after establishment of simplified protocol without splenectomy, intravenous immunoglobulin, and local infusion therapy. Methods We analyzed 19 ABOi LDLT cases that had been performed between January 2012 and December 2013, without splenectomy and local infusion. We used a single dose of rituximab (375 mg/m 2 ) 10 days before transplantation and several series of plasma exchange according to the recipients' iso-agglutinin titer–to–target titer ratio of 1:32. Results Nineteen recipients received ABOi LTs from living donors. The mean initial immunoglobulin (Ig) M and IgG anti-ABO titers were 76.63 ± 78.81 (range, 8∼256) and 162.53 ± 464.1 (0∼2048). We performed preoperative plasma exchange to 16 recipients (mean number of sessions, 3.58; range, 1–10). After surgery, 9 patients received plasma exchange (mean, 1.84; range 1∼14). One death occurred as the result of pneumonia (5.3%). There were 4 cases of acute rejections (21.1%), and all of them were treated successfully with steroid pulse or thymoglobulin. Antibody-mediated rejection and graft failure did not occur. Six cases of postoperative complications (31.6%) occurred, including 3 cases of infections. There were 2 cases of biliary anastomotic stricture (10.5%) and 1 case of portal vein stenosis (5.3%). Conclusions ABOi LDLT with the use of simplified protocol can be safely performed without increased risk of antibody-mediated rejection and other complications. [ABSTRACT FROM AUTHOR]

The tetrameric kainate receptors can be assembled from a combination of five different subunit subtypes. While GluK1–3 subunits can form homomeric receptors, GluK4 and GluK5 require a heteromeric partner to assemble, traffic to the membrane surface, and produce a functional channel. Previous studies have shown that incorporation of a GluK4 or GluK5 subunit changes both receptor pharmacology and channel kinetics. We directly compared the functional characteristics of recombinant receptors containing either GluK4 or GluK5 in combination with the GluK1 or GluK2 subunit. In addition, we took advantage of mutations within the agonist binding sites of GluK1, GluK2, or GluK5 to isolate the response of the wild-type partner within the heteromeric receptor. Our results suggest that GluK1 and GluK2 differ primarily in their pharmacological properties, but that GluK4 and GluK5 have distinct functional characteristics. In particular, while binding of agonist to only the GluK5 subunit appears to activate the channel to a non-desensitizing state, binding to GluK4 does produce some desensitization. This suggests that GluK4 and GluK5 differ fundamentally in their contribution to receptor desensitization. In addition, mutation of the agonist binding site of GluK5 results in a heteromeric receptor with a glutamate sensitivity similar to homomeric GluK1 or GluK2 receptors, but which requires higher agonist concentrations to produce desensitization. This suggests that onset of desensitization in heteromeric receptors is determined more by the number of subunits bound to agonist than by the identity of those subunits. The distinct, concentration-dependent properties observed with heteromeric receptors in response to glutamate or kainate are consistent with a model in which either subunit can activate the channel, but in which occupancy of both subunits within a dimer is needed to allow desensitization of GluK2/K5 receptors. [ABSTRACT FROM AUTHOR]

GABA B receptors assemble from GABA B1 and GABA B2 subunits. GABA B2 additionally associates with auxiliary KCTD subunits (named after their K + channel tetramerization-domain). GABA B receptors couple to heterotrimeric G-proteins and activate inwardly-rectifying K + channels through the βγ subunits released from the G-protein. Receptor-activated K + currents desensitize in the sustained presence of agonist to avoid excessive effects on neuronal activity. Desensitization of K + currents integrates distinct mechanistic underpinnings. GABA B receptor activity reduces protein kinase-A activity, which reduces phosphorylation of serine-892 in GABA B2 and promotes receptor degradation. This form of desensitization operates on the time scale of several minutes to hours. A faster form of desensitization is induced by the auxiliary subunit KCTD12, which interferes with channel activation by binding to the G-protein βγ subunits. Here we show that the two mechanisms of desensitization influence each other. Serine-892 phosphorylation in heterologous cells rearranges KCTD12 at the receptor and slows KCTD12-induced desensitization. Likewise, protein kinase-A activation in hippocampal neurons slows fast desensitization of GABA B receptor-activated K + currents while protein kinase-A inhibition accelerates fast desensitization. Protein kinase-A fails to regulate fast desensitization in KCTD12 knock-out mice or knock-in mice with a serine-892 to alanine mutation, thus demonstrating that serine-892 phosphorylation regulates KCTD12-induced desensitization in vivo. Fast current desensitization is accelerated in hippocampal neurons carrying the serine-892 to alanine mutation, showing that tonic serine-892 phosphorylation normally limits KCTD12-induced desensitization. Tonic serine-892 phosphorylation is in turn promoted by assembly of receptors with KCTD12. This cross-regulation of serine-892 phosphorylation and KCTD12 activity sharpens the response during repeated receptor activation. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Among many immunotherapeutic approaches, oral immunotherapy (OIT) is thought to be an effective route for desensitization against a variety of allergens. However, there is little evidence that OIT is effective for airway allergic diseases such as pollen allergy. Thus, in the present study, we assessed the safety, efficacy and immune response of OIT using the Cry j1–galactomannan conjugate for Japanese cedar pollen allergy. Methods: An open trial was conducted over a period of 4 months. The OIT group comprised of 23 subjects. Treatment was initiated 1 month before the estimated pollen season and continued for 1 month. The control group (the pharmacological treatment group without OIT) comprised of 11 subjects. The symptoms and medication score, levels of allergen-specific serum antibodies, cellular components of lymphocytes and cytokine production from peripheral blood mononuclear cells (PBMCs) were evaluated throughout the pollen season. Results: The participants receiving OIT treatment showed significant improvements in total symptom scores and symptom–medication scores during the pollen season compared with the control group. The levels of allergen-specific serum IgG4 and IL-10 production in PBMCs were significantly increased in the OIT group compared with that in the control group. Importantly, no severe adverse effects were observed in the participants receiving OIT treatment. Conclusion: Short-term OIT using the Cry j1–galactomannan conjugate is effective, relatively safe and induces tolerant immune responses such as increased allergen-specific serum IgG4 and IL-10 production in PBMCs. These results suggest that OIT using allergen–galactomannan conjugates may provide a rapid, effective, and safe immunotherapy regimen for cedar pollen allergy. [Copyright &y& Elsevier]

The single antigen flow bead (SAFB) assay greatly improves the identification of antigenic specificity of anti-HLA alloantibodies. However, it may underestimate or miss high titer antibodies due to the prozone phenomenon caused by a competition between the fluorescent anti-lgG conjugate and serum complement, for the alloanti-body. We explored this effect in our cohort of transplant candidates and transplanted recipients. Among a total of 292 and 269 patients with at least three different sera tested with class I and/or II SAFB assays respectively, we identified 9 patients (6 in class I and 3 in class II) who displayed a profound drop (>75%) followed by a sub-sequent rise (>100%), in strong (mean fluorescence intensity >8000) antibody levels, across an 18-month peri-od. We postulated that such abrupt fluctuations were not explainable by naturally occurring transient desensitization. Sera were analysed with the SAFB assay using EDTA-treated serum and direct complement Clq staining, and with complement-dependent cytotoxicity and flow cytometry crossmatches (CDCXM and FCXM respectively). The prozone phenomenon was involved in all cases. Because it relies on complement activa-tion, the CDCXM was not sensitive to this phenomenon, but the FCMXM was not either, although it resembles in its principle to the SAFB assay. Four additional anti-human conjugates targeting the IgG Fc fragment or the light chains did not circumvent the SAFB drawback. Therefore, a quick decrease in antibody strength must alert against a potential risk for recipients at the time of the transplant, using virtual crossmatch strategies. A prospective pre-transplant crossmatch still remains an ultimate safeguard. [ABSTRACT FROM AUTHOR]

The long-lived plasma cells, which develop after alloantigen sensitization, produce donor specific alloantibodies (DSAs) that generate a positive serum cross-match and preclude transplantation. Bortezomib, a proteasome inhibitor, is being investigated in clinical desensitization protocols, however preclinical studies in a transplant model are nonexistent. We hypothesized that sustained treatment with only a proteasome inhibitor would eliminate plasma cells and reduce DSA over time. Cardiac allografts were transplanted into murine recipients. Eight weeks after allograft rejection the proteasome inhibitor, bortezomib, was injected intravenously twice weekly for 60 days. Serum alloantibody responses were assayed using flow cross-match. Total and alloreactive plasma cell numbers were enumerated using flow cytom-etry and EL1SP0T. All recipients of cardiac allografts rejected their graft promptly within 16 days and demonstrated alloantibody by flow cross-match. DSA was sustained in the control mice while mice treated with bortezomib had sustained elimination of DSA and a marked reduction in plasma cell population. Also, bortezomib was associated with an increased level of BLyS. Within a murine model, proteasome inhibition can eliminate alloantibody secreting plasma cells, and reduce alloantibody. Cessation of bortezomib is not associated with return of DSA. [ABSTRACT FROM AUTHOR]

Although short-term graft survival has been improved by recent desensitization protocols including B cell depletion therapy, little is known about risk factors of chronic antibody-mediated rejection (CAMR) in HLA-incompatible (HLA-I) renal transplantation (RTx). Twenty-six HLA-I RTx with positive donor-specific antibodies (DSA) and negative T cell cytotoxic crossmatches were compared with 88 ABO-incompatible (ABO-I) and 207 ABO-identical/compatible (ABO-Id/C) RTx. The desensitization therapy consisted of mycophenolate mofetil, rituximab and double-filtration plasmapheresis. Protocol biopsies within 1year revealed subclinical CAMR in 36% of HLA-I, 5% of ABO-I and 3% of ABO-Id/C, although clinical acute AMR was observed in 8%, 3% and 1%, respectively. The incidence of CAMR was not different between class I and class II DSA. Most of class I DSA (94%) changed to negative 1year after RTx, whereas 77% of class II DSA remained positive. In addition, the remaining DRB±DQB DSA caused CAMR in 80% of patients, while DQB DSA alone did not. The progress of subclinical CAMR within 1year could not be circumvented by rituximab. Sustained class II (DRB±DQB) DSA detection after RTx may pose a potential risk for developing CAMR, but negative change in class I DSA could also elicit CAMR. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate by way of a systematic review the effectiveness of argininecontaining desensitising toothpastes in comparison to control agents in reducing dentine hypersensitivity. Data sources: Electronic databases were searched including: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS (30/03/2012). Reference lists of eligible studies and systematic reviews were cross-checked in an attempt to identify additional studies. Strategies to identify grey literature were employed. Study selection inclusion criteria: Controlled Clinical Trials (CCTs) and Randomised Controlled Trials (RCTs) comparing arginine-containing desensitising toothpastes to non-argininecontaining control toothpastes. Two review authors independently screened the titles and abstracts of studies identified. Data collection forms were completed for included studies. Outcomes: Changes in sensitivity to tactile and air-blast stimuli. A subjective assessment of sensitivity was also sought. Conclusion: Data identified indicates a potential role for arginine-containing toothpastes in managing dentine hypersensitivity. However, this conclusion is based on small sample sizes and the studies identified did not follow patients up in the medium to long term. The authors recommend that there is a need for well-designed RCTs to be conducted prior to any definitive recommendations being made. Clinical significance: Dentine hypersensitivity is a common condition. Its multi-factorial aetiology has led to several treatment modalities being advocated. The continued introduction of new desensitising agents suggests that no product has yet proven ultimately successful. Arginine-containing toothpastes have recently been introduced, this article systematically reviews the evidence relating to their effectiveness. [ABSTRACT FROM AUTHOR]

Highlights: [•] Distinct mechanism of receptor internalization of VPAC2, a member of class II family of GPCRs. [•] Identification of a regulatory role caveolin-1 in VPAC2 receptor functions in smooth muscle. [•] Caveolin-1 is important for VPAC2 receptor internalization and desensitization. [•] Activation of Src kinase by VIP regulates VPAC2 receptor internalization. [Copyright &y& Elsevier]

Abstract: The presence of donor human leukocyte antigen (HLA)-specific antibodies (DSA) increases engraftment failure risk in partially HLA-mismatched, or HLA-haploidentical, allogeneic marrow (alloBMT) transplantation. As pre-existing sensitization to HLA antigens is not well characterized among candidates for HLA-haploidentical alloBMT, we retrospectively evaluated both the incidence and relative strength of DSA in this patient population. Based on correlations of solid-phase antibody assays on the Luminex (Luminex, Austin, TX) platform with actual crossmatch tests, DSA were characterized as weak for results that were consistent with negative flow cytometric crossmatch results or as moderate-to-strong for results consistent with positive flow cytometric or cytotoxicity crossmatches. We evaluated 296 alloBMT candidates; 111 (37.5%) were female. DSA were detected in 43 (14.5%) candidates, mostly among female candidates (42.9% female versus 12.5% male). Moderate-to-strong DSA strength was more frequently encountered when directed against haploidentical donors as compared with mismatched unrelated donors. DSA were most commonly detected in female patients directed against their children. Because the presence of DSA has been considered prohibitive for HLA-mismatched alloBMT, we additionally report a desensitization methodology used to reduce DSA to negative or weak levels, ie, levels well below those detectable in a flow cytometric crossmatch. Nine patients without other available donors underwent desensitization. Eight who reduced their DSA to negative or weak levels proceeded to alloBMT and achieved full donor engraftment. These data support routine DSA evaluation in all patients considered for mismatched alloBMT; however, for patients with no other viable options, desensitization to weak or negative DSA levels may afford the opportunity for successful transplantation. [Copyright &y& Elsevier]