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[Display omitted] Chagas disease is a potentially fatal infection in 21 endemic Latin America countries for which the effectiveness of reference antiparasitic chemotherapy is limited. Thus, we developed three biopharmaceuticals and evaluated the effectiveness of different immunization strategies (recombinant protein NTPDase-1 [rNTPDase-1], DNA plasmid encoding Trypanosoma cruzi NTPDase-1 [TcNTPDase-1] and DNA-NTPDase-1 prime/rNTPDase-1 boost [Prime-boost]) based on the surface ecto-nucleoside triphosphate diphosphohydrolase (ecto-NTPDase) enzyme of T. cruzi in animals challenged with a virulent strain (Y) of this parasite. BALB/c mice were immunized three times at 30 days intervals, challenged with T. cruzi 15 days after the last immunization, and euthanized 30 days after T. cruzi challenge. Our results showed limited polarization of specific anti-ecto-NTPDase immunoglobulins in mice receiving both immunization protocols. Conversely, the Prime-boost strategy stimulated the Th1 protective phenotype, upregulating TNF-α and downregulating IL-10 production while increasing the activation/distribution of CD3+/CD8+, CD4+/CD44hi and CD8+/CD44hi/CD62L cells in immunized and infected mice. Furthermore, IL-6 and IL10 levels were reduced, while the distribution of CD4+/CD44hi and CD3+/CD8+ cells was increased from rNTPDase-1 and DNA-NTPDase1-based immunization strategies. Animals receiving DNA-NTPDase1 and Prime-boost protocols before T. cruzi challenged exhibited an enhanced immunological response associated with IL-17 upregulation and remarkable downregulation of heart parasitism (T. cruzi DNA) and mortality. These findings indicated that NTPDase-1 with Prime-boost strategy induced a protective and sustained Th17 response, enhancing host resistance against T. cruzi. Thus, ecto-NTPDase is a potentially relevant and applicable in the development of biopharmaceuticals with greater immunoprophylactic potential for Chagas disease. [ABSTRACT FROM AUTHOR]

p38 MAPK has been implicated in the pathogenesis of asthma as well as pro-allergic Th2 cytokines, orosomucoid-like protein isoform 3 (ORMDL3), regulation of sphingolipid biosynthesis, and regulatory T cell-derived IL-35. To elucidate the role of p38 MAPK in the pathogenesis of asthma, we examined the effect of NJK14047, an inhibitor of p38 MAPK, against ovalbumin (OVA)-induced allergic asthma; we administrated NJK14047 before OVA sensitization or challenge in BALB/c mice. As ORMDL3 regulation of sphingolipid biosynthesis has been implicated in childhood asthma, ORMDL3 expression and sphingolipids contents were also analyzed. NJK14047 inhibited antigen-induced degranulation of RBL-2H3 mast cells. NJK14047 administration both before OVA sensitization and challenge strongly inhibited the increase in eosinophil and lymphocyte counts in the bronchoalveolar lavage fluid. In addition, NJK14047 administration inhibited the increase in the levels of Th2 cytokines. Moreover, NJK14047 reduced the inflammatory score and the number of periodic acid-Schiff-stained cells in the lungs. Further, OVA-induced increase in the levels of C16:0 and C24:1 ceramides was not altered by NJK14047. These results suggest that p38 MAPK plays crucial roles in activation of dendritic and mast cells during sensitization and challenge periods, but not in ORMDL3 and sphingolipid biosynthesis.

Liquiritin is a natural flavone with a variety of pharmacological effects derived from the medicinal food homology plant Glycyrrhiza uralensis Fisc h. As a kind of lethal allergic reactions, pseudo-allergic reactions (PARs) arise from the Mas-related G protein coupled receptor X2 (MRGPRX2)-triggered fast degranulation of mast cells (MCs). In the current work, the anti-pseudo-allergy action and potential mechanisms of liquiritin were explored in vivo and in vitro . Liquiritin suppressed the calcium influx and degranulation elicited by Compound 48/80 (C48/80) in mouse peritoneal mast cells (MPMCs). In mice, liquiritin also inhibited the C48/80-elicited hind paw extravasation, as well as the elevations in TNF-α and histamine levels. Molecular docking combined with detection of HEK293T cells expressing human MRGPRX2 showed that liquiritin was a potential MRGPRX2 antagonist and inhibited PARs through the PI3K/AKT and PLCγ signaling pathways downstream of MRGPRX2. The present work opens a new avenue for the PARs management., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Inflammatory demyelination of the central nervous system (CNS) is the hallmark of multiple sclerosis (MS), a chronic debilitating disease that affects more than 2.5 million individuals worldwide. It has been widely accepted, although not proven, that the major pathogenic mechanism of MS involves myelin-reactive T cell activation in the periphery and migration into the CNS, which subsequently triggers an inflammatory cascade that leads to demyelination and axonal damage. Virtually all MS medications now in use target the immune system and prevent tissue damage by modulating neuroinflammatory processes. Although current therapies such as commonly prescribed disease-modifying medications decrease the relapse rate in relapsing-remitting MS (RRMS), the prevention of long-term accumulation of deficits remains a challenge. Medications used for progressive forms of MS also have limited efficacy. The need for therapies that are effective against disease progression continues to drive the search for novel pharmacological targets. In recent years, due to a better understanding of MS immunopathogenesis, new approaches have been introduced that more specifically target autoreactive immune cells and their products, thus increasing specificity and efficacy, while reducing potential side effects such as global immunosuppression. In this review we describe several immunopharmacological targets that are currently being explored for MS therapy. [ABSTRACT FROM AUTHOR]

This special issue of International Immunopharmacology is the proceedings of the Fourth International Symposium on Non-neuronal Acetylcholine that was held on August 28–30, 2014 at the Justus Liebig University of Giessen in Germany. It contains original contributions of meeting participants covering the significant progress in understanding of the biological and medical significance of the non-neuronal cholinergic system extending from exciting insights into molecular mechanisms regulating this system via miRNAs over the discovery of novel cholinergic cellular signaling circuitries to clinical implications in cancer, wound healing, immunity and inflammation, cardiovascular, respiratory and other diseases. [ABSTRACT FROM AUTHOR]

Antibody-drug conjugates (ADCs) are emerging modalities in the pharmaceutical industry. Characterization of ADC's drug-to-antibody ratio (DAR) becomes a key assessment because of its importance in ADC efficacy and safety. DAR characterization by conventional intact protein MS analysis, however, is challenging because of high heterogeneity of ADC samples. The analysis often requires protein deglycosylation, disulfide-bond reduction, or partial fragmentation. In this study, we illustrate the practical utility of ion mobility mass spectrometry (IM-MS) in a routine LC/MS workflow for DAR measurements. This strategy allows analyte 'cleanup' in the gas phase, providing significant improvement of signal-to-noise ratios of ADC intact mass spectra for accurate DAR measurements. In addition, protein drift time analysis offers a new dimension in monitoring the changes of DAR in lot-to-lot analysis. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Drugs targeting the immune system such as corticosteroids, antihistamines and immunosuppressants have been widely exploited in the treatment of inflammatory, allergic and autoimmune disorders during the second half of the 20th century. The recent advances in immunopharmacological research have made available new classes of clinically relevant drugs. These comprise protein kinase inhibitors and biologics, such as monoclonal antibodies, that selectively modulate the immune response not only in cancer and autoimmunity but also in a number of other human pathologies. Likewise, more effective vaccines utilizing novel antigens and adjuvants are valuable tools for the prevention of transmissible infectious diseases and for allergen-specific immunotherapy. Consequently, immunopharmacology is presently considered as one of the expanding fields of pharmacology. Immunopharmacology addresses the selective regulation of immune responses and aims to uncover and exploit beneficial therapeutic options for typical and non-typical immune system-driven unmet clinical needs. While in the near future a number of new agents will be introduced, improving the effectiveness and safety of those currently in use is imperative for all researchers and clinicians working in the fields of immunology, pharmacology and drug discovery. The newly formed ImmuPhar () is the Immunopharmacology Section of the International Union of Basic and Clinical Pharmacology ( IUPHAR, ). ImmuPhar provides a unique international expert-lead platform that aims to dissect and promote the growing understanding of immune (patho)physiology. Moreover, it challenges the identification and validation of drug targets and lead candidates for the treatment of many forms of debilitating disorders, including, among others, cancer, allergies, autoimmune and metabolic diseases. [ABSTRACT FROM AUTHOR]

The rejection process remains the key unsolved issue after transplantation of disparate tissue. The CC chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2) has been reported to be involved in the process of alloimmune interaction. Spiegelmers are L-oligonucleotides that can be designed to bind to pharmacologically relevant target molecules. Here, we tested a high-affinity Spiegelmer-based MCP-1 inhibitor (mNOX-E36) in an allogeneic heart transplant model. Fully vascularized allogeneic heterotopic heart transplantations from BALB/c to C57BL/6 mice were performed. Mice were either treated with the anti-MCP-1-Spiegelmer (mNOX-E36) in monotherapy or in combination with subtherapeutic doses of cyclosporine A (CsA) (10 mg/kgBW/day) for 10 days. Controls received equivalent doses of a non-functional Spiegelmer (revmNOX-E36). Graft survival of allogeneic heart transplants was slightly but significantly prolonged under mNOX-E36 monotherapy (median graft survival 10 day ± 0.7) compared to revmNOX-E36 (median graft survival 7 day ± 0.3; P = 0.001). A synergistic beneficial effect could be seen when mNOX-E36 was administered in combination with subtherapeutic doses of CsA (18 day ± 2.8 versus 7 day ± 0.3; P < 0.0001). Levels of inflammatory cytokines and 'alarmins' were significantly reduced, and the number of F4/80+ cells was lower under combination therapy (1.8% ± 1.3%; versus 14.6% ± 4.4%; P = 0.0002). This novel inhibitor of the MCP-1/CCR2 axis (mNOX-E36), which has already proven efficacy and tolerability in early clinical trials, alleviates acute rejection processes in allogeneic transplantation especially when combined with subtherapeutic doses of CsA. Thus, mNOX-E36 may have potential as an adjunct immunomodulatory agent. [ABSTRACT FROM AUTHOR]

Second-generation chimeric antigen receptors (CARs) retarget and reprogramme T cells to augment their antitumour efficacy. The combined activating and co-stimulatory domains incorporated in these CARs critically determine the function, differentiation, metabolism and persistence of engineered T cells. CD19-targeted CARs that incorporate CD28 or 4-1BB signalling domains are the best known to date. Both have shown remarkable complete remission rates in patients with refractory B cell malignancies. Recent data indicate that CD28-based CARs direct a brisk proliferative response and boost effector functions, whereas 4-1BB-based CARs induce a more progressive T cell accumulation that may compensate for less immediate potency. These distinct kinetic features can be exploited to further develop CAR-based T cell therapies for a variety of cancers. A new field of immunopharmacology is emerging. [ABSTRACT FROM AUTHOR]

Background Long-term data of ciclosporin A (CsA) treatment in daily practice in patients with severe atopic dermatitis ( AD) are lacking. Objectives To perform a detailed analysis of drug survival, which is the length of time a patient continues to take a drug, for CsA in a long-term daily practice cohort of patients with AD. The secondary objective was to identify determinants of drug survival. Methods Data were extracted from a retrospective cohort of patients treated with CsA for AD. Drug survival was analysed using Kaplan-Meier survival curves. Determinants of drug survival were analysed using uni- and multivariate Cox regression analyses with backward selection. Results In total, 356 adult patients were analysed (386 patient-years). The overall drug survival rates were 34%, 18%, 12% and 4% after 1, 2, 3 and 6 years, respectively. Reasons for discontinuation were controlled AD (26·4%), side-effects (22·2%), ineffectiveness (16·3%), side-effects plus ineffectiveness (6·2%) or other reasons (11·0%). Older age was associated with a decreased drug survival related to controlled AD [hazard ratio ( HR) 0·91]. Older age was also associated with a decreased drug survival related to side-effects ( HR 1·14). An intermediate-to-high starting dose (> 3·5-5·0 mg kg−1 daily) was associated with an increased drug survival related to ineffectiveness ( HR 0·63). Conclusions This is the first study on drug survival for CsA treatment in AD. Older age was associated with decreased drug survival related to controlled AD and side-effects. An intermediate-to-high starting dose was associated with an increased drug survival related to ineffectiveness. [ABSTRACT FROM AUTHOR]

Background: We tested the strategy of mTOR inhibitors with calcineurin inhibitor minimization in renal transplant recipients with known chronic allograft dysfunction. Methods: In this open-label, single-arm study, renal transplant patients were recruited after biopsy-confirmed chronic allograft dysfunction in the absence of acute rejection episode within 2 months, with proteinuria <0.8 g/day, and serum creatinine <220 μmol/L or estimated glomerular filtration rate >40 mL/min/1.73 m2. They were converted to everolimus (aiming for trough everolimus level 3-8 ng/mL) with cyclosporine minimization, to assess the effect on renal function, rate of glomerular filtration rate decline, and longitudinal transplant biopsy at 12 months. Results: Seventeen Chinese patients (median transplant duration, 4.2 years) were recruited; no patients discontinued study medication. The mean slope of the glomerular filtration rate over time was -4.31±6.65 mL/min/1.73 m2 per year in the year before everolimus, as compared with 1.29±5.84 mL/min/1.73 m2 per year in the 12 months of everolimus therapy, a difference of 5.61 mL/min/1.73 m2 per year (95% confidence interval [CI], 0.40-10.8) favoring everolimus therapy (P=0.036). Serial renal biopsy histology showed significant decrease of tubular atrophy (15.7%±11.3% versus 7.1%±7.3%, P=0.005) and interstitial fibrosis (14.8%±11.5% versus 7.2%±8.2%, P=0.013). Intrarenal expression of TGF-β1 mRNA showed a nonsignificant decrease after everolimus treatment. Conclusion: In renal transplant recipients with biopsy-confirmed chronic allograft dysfunction, we found a significant beneficial effect of everolimus rescue therapy and calcineurin inhibitor minimization strategy on the improvement of glomerular filtration rate decline rate. In secondary analysis, everolimus was shown to slow down the disease progression by reducing the tubular atrophy and interstitial fibrosis scoring. [ABSTRACT FROM AUTHOR]

Background Immunosuppression is effective in the secondary prevention of neuromyelitis optica spectrum disorder ( NMOSD) relapse. However, some of the newer immunosuppressive agents are costly or unavailable in resource-poor countries; older immunosuppressive agents might be just as effective. We aimed to evaluate the efficacy and tolerability of methotrexate in treating NMOSD in an Asian cohort. Methods We retrospectively reviewed all patients with NMOSD treated with methotrexate at the National Neuroscience Institute, Singapore, between 1992 and September 2012. We compared the annualized relapse rates and disability as measured by the Expanded Disability Status Scale before and after methotrexate treatment. Results Eight of 180 patients with central nervous system demyelinating diseases fulfilled the inclusion criteria. At median follow up of 53 months (range 42-70 months), the median post-treatment annualized relapse rate was significantly lower than the pretreatment rate (0.00 [range 0.00-3.09] vs 0.97 [range 0.08-10.14] relapses). The median Expanded Disability Status Scale remained stable (pretreatment 6.5 [range 3.0-8.0] vs post-treatment 6.0 [range 2.0-8.0], P = 0.238); 75% of our cohort remained relapse-free on treatment. None of our patients were intolerant of methotrexate. Conclusions Methotrexate is well-tolerated in our NMOSD patients, and appears to be effective in decreasing relapse rates and preventing disability progression. It is widely available and less costly than newer immunomodulatory agents. As such, it can be recommended as a therapeutic option for NMOSD in patients who fail first-line therapy. [ABSTRACT FROM AUTHOR]

This study was conducted to compare the characteristics of patients, with and without diabetes mellitus, presenting with myocardial infarction (MI) and treated with coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), or thrombolytic therapy. Factors related to mortality due to MI in Iran were also determined. This study was a prospective analysis. To analyze the data, Stata software (chi square, t test, Cox and logistic regression) was used. Participants were patients hospitalized for MI for the first time in 540 hospitals from April, 2012 to March, 2013. Out of 20,750 patients with MI, 461 2 (22.3%) had type 2 diabetes. MI case fatality rate was 13.22% (95%CI: 12.24–14.19) and 11.78% (95%CI: 11.28–12.27) in patients with and without diabetes, respectively. The rates of CABG, PCI, and thrombolytic therapy use were 4.2%, 8%, and 58% in patients with diabetes, and 2.1%, 6.5%, and 55% in patients without diabetes. The odds ratio of mortality for ST segment elevation myocardial infarction (STEMI) and chest pain resistant to treatment was, respectively, 6.3 and 2.8 in those with diabetes, and 3.9 and 3.7 in patients without diabetes. The hazard ratio of mortality for gender, education, smoking, left bundle branch block, PCI, and type of MI was different between the two groups ( P < 0.05). Characteristics of patients dying post MI were different in those with or without diabetes mellitus. Although use of CABG, PCI, and thrombolytic therapy was more frequent in patients with diabetes than without, mortality was higher in diabetes patients. [ABSTRACT FROM AUTHOR]

ABSTRACT 3-deoxy- d-manno-octulosonic acid-lipid A (Kdo2-lipid A) is the essential component of lipopolysaccharide in most Gram-negative bacteria and the minimal structural component to sustain bacterial viability. It serves as the active component of lipopolysaccharide to stimulate potent host immune responses through the complex of Toll-like-receptor 4 ( TLR4) and myeloid differentiation protein 2. The entire biosynthetic pathway of Escherichia coli Kdo2-lipid A has been elucidated and the nine enzymes of the pathway are shared by most Gram-negative bacteria, indicating conserved Kdo2-lipid A structure across different species. Yet many bacteria can modify the structure of their Kdo2-lipid A which serves as a strategy to modulate bacterial virulence and adapt to different growth environments as well as to avoid recognition by the mammalian innate immune systems. Key enzymes and receptors involved in Kdo2-lipid A biosynthesis, structural modification and its interaction with the TLR4 pathway represent a clear opportunity for immunopharmacological exploitation. These include the development of novel antibiotics targeting key biosynthetic enzymes and utilization of structurally modified Kdo2-lipid A or correspondingly engineered live bacteria as vaccines and adjuvants. Kdo2-lipid A/ TLR4 antagonists can also be applied in anti-inflammatory interventions. This review summarizes recent knowledge on both the fundamental processes of Kdo2-lipid A biosynthesis, structural modification and immune stimulation, and applied research on pharmacological exploitations of these processes for therapeutic development. [ABSTRACT FROM AUTHOR]

Even though a lot of reports have suggested the anti-inflammatory activity of kaempferol (KF) in macrophages, little is known about its exact anti-inflammatory mode of action and its immunopharmacological target molecules. In this study, we explored anti-inflammatory activity of KF in LPS-treated macrophages. In particular, molecular targets for KF action were identified by using biochemical and molecular biological analyses. KF suppressed the release of nitric oxide (NO) and prostaglandin E2 (PGE2), downregulated the cellular adhesion of U937 cells to fibronectin (FN), neutralized the generation of radicals, and diminished mRNA expression levels of inflammatory genes encoding inducible NO synthase (iNOS), TNF-α, and cyclooxygenase- (COX-) 2 in lipopolysaccharide- (LPS-) and sodium nitroprusside- (SNP-) treated RAW264.7 cells and peritoneal macrophages. KF reduced NF-κB (p65 and p50) and AP-1 (c-Jun and c-Fos) levels in the nucleus and their transcriptional activity. Interestingly, it was found that Src, Syk, IRAK1, and IRAK4 responsible for NF-κB and AP-1 activation were identified as the direct molecular targets of KF by kinase enzyme assays and by measuring their phosphorylation patterns. KF was revealed to have in vitro and in vivo anti-inflammatory activity by the direct suppression of Src, Syk, IRAK1, and IRAK4, involved in the activation of NF-κB and AP-1. [ABSTRACT FROM AUTHOR]

Membranous nephropathy is one of the leading causes of nephrotic syndrome in adults, which is characterized by edema, hypoalbuminemia, hyperlipidemia, lipiduria, and proteinuria. Determination of idiopathic membranous nephropathy ( IMN) disease progression risk is important for guiding initial therapy, with immunosuppressive therapy being reserved for high-risk patients. Because IMN may spontaneously remit in approximately 30% of patients, it is important to carefully select which patients should begin immunosuppressive therapy so as to maximize clinical benefit while limiting toxicity. An observation period of at least 6 months with conservative management that includes the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers is recommended. Initial treatment in high-risk IMN is a 6-month course of alternating steroids and alkylating agents. Calcineurin inhibitors ( CNIs) represent an alternative first-line therapeutic option for high-risk patients who refuse treatment with steroid or alkylating agent therapy or for whom these treatments are contraindicated. Additional options are essential for patients with IMN who fail to adequately respond to initial therapies or who cannot use recommended therapies due to contraindications or intolerance, risks associated with repetitive dosing with alkylating agents, or potential exacerbation of impaired renal function with CNIs. While evidence for the use of alternative therapies in IMN is modest at best, our review summarizes the available literature for rituximab, mycophenolate mofetil, adrenocorticotropic hormone, intravenous immunoglobulin, and azathioprine. Rituximab has generally demonstrated beneficial outcomes with limited toxicity. Evidence supports a role for mycophenolate mofetil, although the evidence is of low quality and limited duration. Results from ongoing studies are required before adrenocorticotropic hormone can be recommended as therapy for treatment-resistant patients. Intravenous immunoglobulin and azathioprine are unlikely to have a role in IMN. With the advent of new tools and biomarkers measuring disease activity combined with new data regarding possible treatment options, the management and prognosis of IMN are likely to improve. [ABSTRACT FROM AUTHOR]

Determining the efficacy contribution of an investigational drug as part of a novel combination regimen that also includes a previously untested dose of a standard treatment is challenging, particularly when 'placebo control' data (combination regimen minus the investigational drug) is not available for comparison. This situation was encountered in a phase III trial that tested the combination of the investigational drug everolimus with a dose of tacrolimus lower than used in standard liver transplantation therapy. The challenge was addressed by predicting the efficacy of the placebo control from the study data using a pharmacometric-based exposure-response analysis, selected to account for features specific to the transplant setting: systematic change in drug exposure over time and sparse pharmacokinetic sampling. The efficacy contribution of everolimus was then demonstrated by comparing this prediction to the efficacy of the combination regimen. This pharmacometrics-based approach may contribute to characterization of therapeutic agents in real-world settings. [ABSTRACT FROM AUTHOR]

Background Graves' disease (GD) is an organ-specific autoimmune disease. A significant decrease of the distribution of NK cells in the peripheral blood in children and adolescents with untreated GD has been observed. However, the role of NK and its subsets in adults with GD remains unclear. Methods A total of 28 adult patients with new onset of GD and 23 healthy controls (HC) were recruited. The number of activated inhibitory NK cells in peripheral blood of individual subjects was determined by flow cytometry. Results The number of CD3 − CD56 + and CD3 − CD16 + NK cells in peripheral blood was significantly decreased in the GD patients than the HC. Compared to the HCs, decreased number of NKG2D + , NKG2C + , NKp30 + and NKG2A + NK cells and increased number of KIR3DL1 + NK cells were detected in the GD patients. Moreover, the number of inducible CD107a + and IFN-γ-secreting NK cells in GD patients significantly decreased than those in HC. Interestingly, the number of NKG2A + NK cells was negatively correlated with the level of serum TRAb in GD patients. Conclusion Our data indicate that decreased number and impaired function of NK cells may contribute to the pathogenesis of GD. [ABSTRACT FROM AUTHOR]

This paper presents a case with refractory relapsing polychondritis (RPC), complicated with severe aortic involvement, which is successfully treated with tocilizumab. Previous treatments consisted of methotrexate, corticosteroids, cyclosporine, cyclophosphamide, infliximab, and etanercept. With these treatments, the patient had recurrent episodes of fever, polyarthritis, tenosynovitis, subcutaneous nodules, and progressive cardiac disease. One year after the start of treatment with tocilizumab, there is resolution of all symptoms, normalization of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), and the dose of prednisolone is tapered down to 2 mg/day. We have reviewed the English literature for reports of patients with refractory RPC, successfully treated with tocilizumab. We found five additional case reports. In one case report, a patient with refractory RPC complicated with aortitis was successfully treated with tocilizumab. In three case reports, patients with refractory RPC complicated with laryngotracheal involvement were successfully treated with tocilizumab. All cases had, like our patient, failed conventional treatment. We also reviewed the literature for reports of the effect of biologicals on cardiac involvement in RPC. Current literature is presented and discussed. [ABSTRACT FROM AUTHOR]

A pony presented with a severe, chronic dermatitis around the ears, neck and trunk of the body, hind quarters and ventral abdomen. The pony was intensely pruritic as was an in-contact pony and both owners. A superficial skin scraping demonstrated multiple living mites, identified as Sarcoptes scabiei. Equine pituitary pars intermedia dysfunction ( PPID) was diagnosed as an underlying, potentially immunosuppressive disorder. The pony was treated for Sacroptes scabiei as well as PPID and is doing well 2 months after initial presentation. [ABSTRACT FROM AUTHOR]

Background: New-onset diabetes after transplantation (NODAT) is a serious complication in transplant recipients. Transcription factor-7-like 2 (TCF7L2) is a Wnt signaling-associated transcription factor that plays an important role in β-cell proliferation and insulin secretion. The association between TCF7L2 SNP rs7903146 and NODAT was documented in renal transplant patients. Objective: To determine the association between TCF7L2 rs7903146 variants and the risk of NODAT after liver transplantation. Methods: This study was conducted on 140 liver transplant recipients who had received tacrolimusbased immunosuppressive drugs. The patients were divided into NODAT (n=70) and non-NODAT (n=70) groups and were genotyped using PCR-RFLP. In addition, 100 normal subjects were considered as the comparison group. Results: There was a significant difference (p<0.05) between the two study groups regarding donor and recipient age, recipient body mass index, and recipient fasting plasma glucose before the transplantation. No significant relationship was observed between TCF7L2 rs7903146 genotypes and development of NODAT. No significant difference was also found between the two groups in terms of the tacrolimus and mycophenolate mofetil daily dosage as well as tacrolimus blood level. However, the prednisolone daily dosage was significantly (p=0.01) higher in the NODAT group compared to those without NODAT. The majority of the patients in the NODAT group also had an episode of acute rejection. Furthermore, a significant difference was found between the transplant recipients and the comparison subjects regarding T allele (p<0.001, OR=1.96) and TT genotype (p<0.001, OR=3.47) frequencies. Conclusion: No correlation was found between TCF7L2 genotypes and development of NODAT. Acute rejection and prednisolone pulse therapy predisposed the susceptible patients to NODAT. [ABSTRACT FROM AUTHOR]

The human immune system is capable of learning. To investigate how it communicates with the brain during learning processes, researchers employ the paradigm of classical conditioning. Their aim is to achieve a better understanding of immune responses and to establish learning protocols as supportive therapy for the treatment of diseases. [ABSTRACT FROM AUTHOR]

Brentuximab vedotin is an anti-CD30 antibody-drug conjugate with proven efficacy in patients with CD30+ malignancies, including classical Hodgkin lymphoma and anaplastic large cell lymphoma. Promising activity has also been seen in other lymphomas that express CD30. Because of its acceptable toxicity profile and significant clinical efficacy, single-agent brentuximab vedotin is an approved treatment for relapsed patients with these diseases. Brentuximab vedotin has safely been combined with chemotherapy and is now being compared with standard treatments in randomized trials. [ABSTRACT FROM AUTHOR]

Background: End-stage renal disease is the irreversible final stage of chronic kidney disease and is fatal when not managed by either transplantation or dialysis. Transplantation is generally preferred over dialysis. However, to prevent graft rejection or loss, lifelong immunosuppression is required. Tacrolimus is currently the cornerstone of post-transplantation immunosuppression. The study aim was to carry out an economic evaluation of immunosuppression, including more recent agents such as a once-daily prolonged-release formulation of tacrolimus (Advagraf™) and belatacept, relative to a twice-daily immediate-release formulation of tacrolimus (Prograf™). Methods: A model was constructed comprising six states: onset of biopsy-confirmed acute rejection, functioning graft with or without a biopsy-confirmed acute rejection, non-functioning graft (dialysis), re-transplantation, and death. Data on clinical effectiveness were derived from a systematic literature review and the model captured the effects of patient adherence to immunosuppressant therapy on graft survival using relative risk of graft survival and published data on adherence in patients using Advagraf and Prograf. In the base case, the time horizon was 25 years and one-way and probabilistic sensitivity analyses were conducted. Results: The analysis demonstrated that Prograf was cost-effective when compared with cyclosporin and belatacept and was more effective than sirolimus, but would not be considered cost-effective against sirolimus. The modeled improvement in the adherence profile of patients using Advagraf relative to Prograf resulted in both improved clinical outcomes and reduced costs. Conclusion: Prograf was more clinically effective than cyclosporin, belatacept, and sirolimus, supporting its current positioning as the mainstay of immunosuppressive therapy in renal transplant recipients. Based on improved patient adherence with Advagraf, the model projected that Advagraf would be both more effective and less costly than Prograf. Replacing Prograf with Advagraf as the standard of care for post-transplant immunosuppression could likely result in both cost savings and improved clinical outcomes. [ABSTRACT FROM AUTHOR]

Dendrobium tosaense is a medicinal Dendrobium species widely used in traditional medicine. This study demonstrated some structural characterizations and immunomodulatory activity of the water-soluble polysaccharides derived from the stem of D. tosaense (DTP). DTP was fractioned using DEAE-650M anion-exchange gel filtration chromatography, producing one neutral polysaccharide fraction (DTP-N), which was investigated for its structural characteristics, using HPAEC-PAD, HP-SEC, GC-MS, and NMR spectroscopy. DTP and DTP-N consisted of galactose, glucose, and mannose in ratios of 1:9.1:150.7 and 1:12.2:262.5, respectively. DTP-N comprised (1→4)Man as its main backbone, and its average molecular weight was 220 kDa. We also investigated the immunomodulatory effects of DTP administered orally to BALB/c mice for 3 weeks. DTP substantially boosted the population of splenic natural killer (NK) cells, NK cytotoxicity, macrophage phagocytosis, and cytokine induction in splenocytes. This is the first study to demonstrate the structural characteristics of an active polysaccharide derived from D. tosaense and its immunopharmacological effects in vivo. [ABSTRACT FROM AUTHOR]

Background Teriflunomide is a once-daily oral immunomodulator approved for the treatment of relapsing-remitting multiple sclerosis. We aimed to assess the efficacy and safety of teriflunomide in patients with a first clinical episode suggestive of multiple sclerosis. Methods In this randomised, double-blind, placebo-controlled, parallel-group study, we enrolled patients aged 18–55 years with clinically isolated syndrome (defined as a neurological event consistent with demyelination, starting within 90 days of randomisation, and two or more T2-weighted MRI lesions ≥3 mm in diameter) from 112 centres (mostly hospitals) in 20 countries. Participants were randomly assigned (1:1:1) in a double-blind manner (by an interactive voice response system) to once-daily oral teriflunomide 14 mg, teriflunomide 7 mg, or placebo, for up to 108 weeks. Patients, staff administering the interventions, and outcome assessors were masked to treatment assignment. The primary endpoint was time to relapse (a new neurological abnormality separated by ≥30 days from a preceding clinical event, present for ≥24 h in the absence of fever or known infection), which defined conversion to clinically definite multiple sclerosis. The key secondary endpoint was time to relapse or new gadolinium-enhancing or T2 lesions on MRI, whichever occurred first. The primary outcome was analysed for the modified intention-to-treat population; safety analyses included all randomised patients who were exposed to the study drug, as treated. This trial is registered with ClinicalTrials.gov , number NCT00622700 . Findings Between Feb 13, 2008, and Aug 22, 2012, 618 patients were enrolled and randomly assigned to teriflunomide 14 mg (n=216), teriflunomide 7 mg (n=205), or placebo (n=197). Two patients in each of the teriflunomide groups did not receive the study drug, so the modified intention-to-treat population comprised 214 patients in the teriflunomide 14 mg group, 203 in the teriflunomide 7 mg group, and 197 in the placebo group. Compared with placebo, teriflunomide significantly reduced the risk of relapse defining clinically definite multiple sclerosis at the 14 mg dose (hazard ratio [HR] 0·574 [95% CI 0·379–0·869]; p=0·0087) and at the 7 mg dose (0·628 [0·416–0·949]; p=0·0271). Teriflunomide reduced the risk of relapse or a new MRI lesion compared with placebo at the 14 mg dose (HR 0·651 [95% CI 0·515–0·822]; p=0·0003) and at the 7 mg dose (0·686 [0·540–0·871]; p=0·0020). During the study, six patients who were randomly assigned to placebo accidently also received teriflunomide at some point: four received 7 mg and two received 14 mg. Therefore, the safety population comprised 216 patients on teriflunomide 14 mg, 207 on teriflunomide 7 mg, and 191 on placebo. Adverse events that occurred in at least 10% of patients in either teriflunomide group and with an incidence that was at least 2% higher than that with placebo were increased alanine aminotransferase (40 [19%] of 216 patients in the 14 mg group, 36 [17%] of 207 in the 7 mg group vs 27 [14%] of 191 in the placebo group), hair thinning (25 [12%] and 12 [6%] vs 15 [8%]), diarrhoea (23 [11%] and 28 [14%] vs 12 [6%]), paraesthesia (22 [10%] and 11 [5%] vs 10 [5%]), and upper respiratory tract infection (20 [9%] and 23 [11%] vs 14 [7%]). The most common serious adverse event was an increase in alanine aminotransferase (four [2%] and five [2%] vs three [2%]). Interpretation TOPIC is to our knowledge the first study to report benefits of an available oral disease-modifying therapy in patients with early multiple sclerosis. These results extend the stages of multiple sclerosis in which teriflunomide shows a beneficial effect. Funding Genzyme, a Sanofi company. [ABSTRACT FROM AUTHOR]

Modulation of immune responses for therapeutic purposes is a particularly relevant area, given the central role of anomalous immunity in a wide variety of diseases, from the most typically immune-related syndromes (autoimmune diseases, allergy and asthma, immunodeficiencies) to those in which altered immunity and inflammation define the pathological outcomes (chronic infections, tumors, chronic inflammatory and degenerative diseases, metabolic disorders, etc .). This brief review will summarize some of the most promising perspectives of immunopharmacology, in particular in the area of immunosuppression, by considering the following aspects: – molecular pathways : investigating the fine mechanisms of immune modulation, to define novel targets and new clinical applications, with particular emphasis to approaches for re-education of anomalous immunity, including induction of tolerance. – personalized medicine : how pharmacogenomics can help in selecting the optimal treatment for each patient, focusing on human immunology for obtaining relevant information that animal models cannot provide. – microbiome : considering immune responses as the result of the interaction between human cells and commensal bacteria, for a new perspective in the use of immunosuppressive treatments. – natural products : providing a scientific basis to the huge body of pharmacological knowledge and products of traditional medicine for identifying new active molecules and new treatment concepts. – nanomedicine : exploiting the intelligent design of engineered nanoparticles offered by nanotechnologies in tailoring shape-, size-, surface-controlled carriers for targeted delivery of drugs. [ABSTRACT FROM AUTHOR]

Mast cells produce a wide spectrum of mediators and they have been implicated in several physiopathological conditions (e.g. allergic reactions and certain tumors). Pharmacologic agents that modulate the release of mediators from mast cells has helped to elucidate the biochemical mechanisms by which immunological and non-immunological stimuli activate these cells. Furthermore, the study of surface receptors and signaling pathways associated with mast cell activation revealed novel pharmacologic targets. Thus, the development of pharmacologic agents based on this new wave of knowledge holds promise for the treatment of several mast cell-mediated disorders. [ABSTRACT FROM AUTHOR]

Purpose: To describe the findings of optical coherence tomography and clinical characteristics in patients of zonal outer retinopathy associated with punctuate inner choroidopathy. Method: Review of consecutive cases on fundus photographs, spectral domain ocular coherence tomography, fluorescein angiography, indocyanine green angiography, visual field, and electrophysiological studies of patients with punctate inner choroidopathy and associated zonal outer retinopathy. Results: This study involves 4 patients suffering visual field defect far beyond the area corresponding to punctate inner choroidopathy lesions. Findings in optical coherence tomography include attenuated signals of photoreceptor inner/outer segment areas corresponding to visual field defect, and increased choroidal thickness. After treatment with immunosuppressive agents, improvements are noted in all 4 patients. Conclusion: Optical coherence tomography is helpful in the diagnosis of patients suffering zonal ocular outer retinopathy associated with punctate inner choroidopathy. All those patients responded well to immunosuppressive agents. [ABSTRACT FROM AUTHOR]

Akin to other physiological responses, immune functions can be modified through behavioral conditioning as part of a learned placebo response. However, like every learning process, learned immune responses are subject to extinction. We analyzed the extinction of learned immunosuppression in healthy male volunteers, using an established conditioning paradigm with the immunosuppressive drug cyclosporin A (CsA) as unconditioned stimulus (US) and a gustatory stimulus as conditioned stimulus (CS). We observed a learned suppression of T-cell function after two and four reexposures to the CS, which was extinguished after 14 unreinforced CS reexposures. However, administration of 'subtherapeutic' CsA dosages together with the CS counteracted the extinction of the learned immunosuppression. These findings provide the basis for a potentially successful implementation of conditioning paradigms as supportive therapy to immunopharmacological regimens in clinical settings. The aim is to reduce the required amount of medication while maximizing the therapeutic outcome for the patient's benefit. [ABSTRACT FROM AUTHOR]

Antibody-drug conjugates hold considerable promise as anticancer agents, however, producing them remains a challenge and there is a need for mild, broadly applicable, site-specific conjugation methods that yield homogenous products. It was envisaged that enzymatic remodeling of the oligosaccharides of an antibody would enable the introduction of reactive groups that can be exploited for the site-specific attachment of cytotoxic drugs. This is based on the observation that glycosyltransferases often tolerate chemical modifications in their sugar nucleotide substrates, thus allowing the installation of reactive functionalities. An azide was incorporated because this functional group is virtually absent in biological systems and can be reacted by strain-promoted alkyne-azide cycloaddition. This method, which does not require genetic engineering, was used to produce an anti-CD22 antibody modified with doxorubicin to selectively target and kill lymphoma cells. [ABSTRACT FROM AUTHOR]

The T-cell-dependent antibody response (TDAR) is a functional assay used in immunopharmacology and immunotoxicology to assess ability to mount an antibody response to immunization. Keyhole limpet hemocyanin (KLH) is extensively used as the immunogen of choice in non-clinical and clinical settings. Native KLH is comprised of high molecular weight (HMW; 4-8 MDa) assemblies of KLH subunit dimers (> 600-800 kDa). It is not known how the different forms (HMW vs subunit) and manufacturing processes (commercial sources) may impact the nature of anti-KLH immune responses (e.g. magnitude and inter-animal variability). Anti-KLH IgM and IgG responses were studied in Sprague-Dawley rats immunized with different forms and commercial sources of KLH: 100 µg of HMW KLH from two different sources or subunit KLH from three different sources. Biophysical and biochemical analyses were conducted to characterize the KLH formulations. Anti-KLH IgM and IgG responses were measured using a proprietary indirect quantitative electrochemiluminescence immunoassay. The HMW KLH preparations showed a greater number of sub-visible particles (2-150 µm size range) than the subunit KLH preparations. All HMW KLH and all subunit KLH were equivalent on SEC (hydrodynamic volume), PAGE (size and charge), and SDS-PAGE (molecular radius). Robust primary and secondary anti-KLH responses were detected for both sources of HMW KLH. The subunit KLH immunizations resulted in lower IgG and IgM responses compared to the HMW KLH, with the exception of Stellar Biotechnologies subunit KLH that produced both robust primary and secondary responses, which approached the HMW KLH responses. Inter-animal variability for IgM and IgG responses was lower with HMW KLH than with subunit KLH. In conclusion, different forms and commercial sources of KLH were associated with different magnitudes and inter-animal variability in IgM and IgG responses, a critical finding to take into consideration when designing TDAR studies for robust immunotoxicology or immunopharmacology testing. [ABSTRACT FROM AUTHOR]

CD33 is a valid target for acute myeloid leukemia (AML) but has proven challenging for antibody-drug conjugates. Herein, we investigated the cellular determinants for the activity of the novel CD33/CD3-directed bispecific T-cell engager antibody, AMG 330. In the presence of T cells, AMG 330 was highly active against human AML cell lines and primary AML cells in a dose- and effector to target cell ratio-dependent manner. Using cell lines engineered to express wild-type CD33 at increased levels, we found a quantitative relationship between AMG 330 cytotoxicity and CD33 expression; in contrast, AMG 330 cytotoxicity was neither affected by common CD33 single nucleotide polymorphisms nor expression of the adenosine triphosphate-binding cassette (ABC) transporter proteins, P-glycoprotein or breast cancer resistance protein. Unlike bivalent CD33 antibodies, AMG 330 did not reduce surface CD33 expression. The epigenetic modifier drugs, panobinostat and azacitidine, increased CD33 expression in some cell lines and augmented AMG 330-induced cytotoxicity. These findings demonstrate that AMG 330 has potent CD33-dependent cytolytic activity in vitro, which can be further enhanced with other clinically available therapeutics. As it neither modulates CD33 expression nor is affected by ABC transporter activity, AMG 330 is highly promising for clinical exploration as it may overcome some limitations of previous CD33-targeted agents. [ABSTRACT FROM AUTHOR]

A major development in drug addiction research in recent years has been the discovery that immune signaling within the central nervous system contributes significantly to mesolimbic dopamine reward signaling induced by drugs of abuse, and hence is involved in the presentation of reward behaviors. Additionally, in the case of opioids, these hypotheses have advanced through to the discovery of the novel site of opioid action at the innate immune pattern recognition receptor Toll-like receptor 4 as the necessary triggering event that engages this reward facilitating central immune signaling. Thus, the hypothesis of major proinflammatory contributions to drug abuse was born. This review will examine these key discoveries, but also address several key lingering questions of how central immune signaling is able to contribute in this fashion to the pharmacodynamics of drugs of abuse. It is hoped that by combining the collective wisdom of neuroscience, immunology and pharmacology, into Neuroimmunopharmacology, we may more fully understanding the neuronal and immune complexities of how drugs of abuse, such as opioids, create their rewarding and addiction states. Such discoveries will point us in the direction such that one day soon we might successfully intervene to successfully treat drug addiction. This article is part of a Special Issue entitled ‘NIDA 40th Anniversary Issue’. [ABSTRACT FROM AUTHOR]

Abstract: The pharmacological support and stimulation of endogenous and transplanted neural stem cells (NSCs) is a major challenge in brain repair. Trauma to the central nervous system (CNS) results in a distinct inflammatory response caused by local and infiltrating immune cells. This makes NSC-supported regeneration difficult due to the presence of inhibitory immune factors which are upregulated around the lesion site. The continual and dual role of the neuroinflammatory response leaves it difficult to decipher upon a single modulatory strategy. Therefore, understanding the influence of cytokines upon regulation of NSC self-renewal, proliferation and differentiation is crucial when designing therapies for CNS repair. There is a plethora of partially conflicting data in vitro and in vivo on the role of cytokines in modulating the stem cell niche and the milieu around NSC transplants. This is mainly due to the pleiotropic role of many factors. In order for cell-based therapy to thrive, treatment must be phase-specific to the injury and also be personalized for each patient, i.e. taking age, sex, neuroimmune and endocrine status as well as other key parameters into consideration. In this review, we will summarize the most relevant information concerning interleukin (IL)-1, IL-4, IL-10, IL-15, IFN-γ, the neuropoietic cytokine family and TNF-α in order to extract promising therapeutic approaches for further research. We will focus on the consequences of neuroinflammation on endogenous brain stem cells and the transplantation environment, the effects of the above cytokines on NSCs, as well as immunopharmacological manipulation of the microenvironment for potential therapeutic use. [Copyright &y& Elsevier]