Ig G1 Research Articles

P520 Association between ustekinumab trough levels and biomarkers in patients with Crohn’s disease

Abstract Background Ustekinumab (UTK) is a human immunoglobulin (Ig) G1 kappa monoclonal antibody approved in 2017 for the treatment of Crohn’s Disease (CD). Up until now, there has not been enough evidence of the relationship between ustekinumab trough levels (UTL) and the clinical evolution and biological markers of the disease. Our study aimed to investigate the relationship between UTL and different biomarkers in a real-world setting. Methods We performed a retrospective observational study including patients up to 18 years with CD receiving subcutaneous maintenance regimen of 90 mg UTK every 8 weeks and available UTL. Biochemical response and remission were evaluated with faecal calprotectin (FC) and C-Reactive Protein (CRP) levels. The biochemical response was defined as a decrease of 50% or more of FC and/or CRP baseline levels, and biochemical remission as FC level <150µg/ml and/or PCR<0.4 mg/dl. UTL was determined from serum samples collected prior to the injection using a commercially available validated enzyme-linked immunosorbent assay (ELISA). Continuous variables were tested using the Mann–Whitney U-test. Receiver operating characteristic (ROC) curves were used to estimate the cut-off of the UTK trough level; for scoring purposes, we chose a cut-off that would maximise the sum of sensitivity and specificity. A value of p < 0.05 was considered statistically significant. Statistical analysis was performed using SPSS for Windows. Results Forty-two patients were included (27 men and 15 female), with an average age of 47.7 years. The average FC levels were 1358,5μg/ml at the beginning of the treatment. In the maintenance period, we observed a biochemical response in 69% of patients, whose UTL were significantly higher than in non-responders (2.25 µg/ml [IQR: 3.08] vs. 0..65 µg/ml [IQR: 1.95]. respectively; p = 0.037). Likewise. 38% of patients achieved biochemical remission (responders 2.125 µg/ml [IQR: 2.25] vs. non-responders 1.5 µg/ml [IQR: 3.26]; p = 0.476). The AUC for predicting biochemical response by means of UTL was 0.703 [CI 95%: 0.529–0.877] (p = 0.037), with sensitivity of 51%, specificity of 76% and a cut-off of 2.20 μg/ml. Conclusion There is limited data on the association between UTL and patient outcome. Our study demonstrates the association between improvement of different biomarkers and higher levels of UTL, with a significant statistic result for biochemical response and non-significant statistic result for biochemical remission, maybe due to a small sample, but with a positive trend. Further studies are necessary in order to conclude that UTL is significant in the management and evolution of the disease and to determinate the optimal cut-off.

Efficacy of Phellinus linteus (sanghuang) extract for improving immune functions: Study protocol for a randomized, double-blinded, placebo-controlled pilot trial.

Background:With the increase in the prevalence of chronic diseases, enhancing immunity has become an important challenge. Health functional foods, such as Phellitus linteus (PL), are known to improve immune function. In previous laboratory studies, it has been reported that PL has anticancer activities. In this study, we will evaluate if PL improves immune functions in adults with reduced immunity and identify its effects on immunity factors.Methods:This study will be a single-center, randomized, double-blinded, and placebo-controlled trial. Study participants will be randomly allocated to 3 experimental groups: those taking PL 1000 mg, PL 2000 mg, or placebo. Total duration of the clinical trial will be 8 to 10 weeks. Study participants will have follow-up visits every 4 weeks and the effect and safety will be assessed at the second and third visits. All participants will be asked to maintain a dosage schedule for this protocol. The primary outcome will be natural killer (NK) cell activity and the secondary outcomes will include peripheral white blood cell (WBC) count; levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL)-1β, IL-2, IL-6, and IL-12 to assess autoimmune reactivity; and levels of immunoglobulin (Ig)G1, IgG2, and Immunoglobulin M (IgM) to assess allergic activity. Repeated measure analysis will be used to measure primary efficacy based on full analysis set.Discussion:This study has limited inclusion and exclusion criteria and a well-controlled intervention. It will be the first randomized controlled trial to assess the efficacy and safety of PL in adults with reduced immunity. This study will provide insights into the mechanisms underlying the immune-stimulating effects of PL and lay the groundwork for further studies.

From This Month's Histopathology

From This Month's Histopathology

First-in-human clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody.

Iscalimab is a fully human, CD40 pathway blocking, nondepleting monoclonal antibody being developed as an immunosuppressive agent. We describe a first-in-human, randomized, double-blind, placebo-controlled study investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of iscalimab in healthy subjects and rheumatoid arthritis patients. Healthy subjects (n=56) received single doses of intravenous iscalimab (0.03, 0.1, 0.3, 1, or 3mg/kg), or subcutaneous iscalimab (3mg/kg), or placebo. Rheumatoid arthritis patients (n=20) received single doses of intravenous iscalimab (10 or 30mg/kg) or placebo. Iscalimab exhibited target-mediated drug disposition resulting in dose-dependent and nonlinear pharmacokinetics. Complete (≥90%) CD40 receptor occupancy on whole blood B cells was observed at plasma concentrations >0.3-0.4µg/mL. In subjects receiving 3mg/kg iscalimab, antibody responses to keyhole limpet hemocyanin were transiently suppressed. CD40 occupancy by iscalimab prevented ex vivo human rCD154-induced expression of CD69 on B cells in whole blood. All doses were generally safe and well tolerated, with no clinically relevant changes in any safety parameters, including no evidence of thromboembolic events. Iscalimab appears to be a promising blocker of the CD40-CD154 costimulatory pathway with potential use in transplantation and other autoimmune diseases.

Effects of a Cloth Panel Containing a Specific Ore Powder on Patients with Japanese Cedar Pollen Allergy During the Pollen Dispersal Season.

Pollen allergy remains a big problem in contemporary societies. We have shown in previous studies that a cloth containing a special natural ore powder (CCSNOP) is effective in relieving symptoms in patients with pollen allergies. However, in that study, subjects were exposed to CCSNOP for only one hour. In the present study, CCSNOP or control (non-woven cloth; NWC) panels were placed in the bedrooms of pollen allergy patients for two weeks during the pollen dispersal season in 2018, and the effects were investigated. Twenty-one subjects were exposed to CCSNOP panels and 10 subjects were exposed to NWC panels. Our investigations showed that use of CCSNOP resulted in relief of symptoms and reduced use of therapeutics. Moreover, the ratio of eosinophil count decrease during exposure was higher in the CCSNOP group. Furthermore, a formula for measuring various cytokines and other parameters was established and clearly showed a distinction between the CCSNOP and NWC groups. In this formula, Granulocyte Macrophage colony-stimulating Factor (GM-SCF), Interleukin (IL)-12p40, Immunoglobulin (Ig) G4 and eosinophil count were extracted. These results indicated that CCNSNOP has a beneficial effect on pollen allergy patients. Future studies shall engage in long-term monitoring of pollen allergy patients who will utilize this mineral powder for at least one year.

Clinical Pharmacokinetics and Pharmacodynamics of Risankizumab in Psoriasis Patients.

Risankizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody developed and approved for the treatment of moderate-to-severe plaque psoriasis at a dose of 150 mg administered subcutaneously at weeks 0 and 4, and every 12 weeks thereafter. Ongoing trials are investigating the use of risankizumab in other inflammatory autoimmune diseases. Risankizumab exhibits linear pharmacokinetics when administered intravenously (0.01 mg/kg–1200 mg) or subcutaneously (0.25 mg/kg–300 mg), with a long terminal half-life of approximately 28 days. Following subcutaneous administration, peak plasma concentration was reached approximately 3–14 days after dosing, with an estimated bioavailability of 89%. Population pharmacokinetic analyses identified bodyweight, high titers of antidrug antibodies occurring in < 2% of evaluated subjects, baseline serum albumin, baseline high-sensitivity C-reactive protein, and baseline serum creatinine to be statistically correlated with risankizumab clearance, but none of them had a clinically meaningful impact on risankizumab efficacy in psoriasis patients following the clinical dosing regimen. Exposure–response analyses in psoriasis patients demonstrated that the maximum efficacy was achieved with the clinically approved regimen and there was no apparent correlation between risankizumab exposure and safety. A dedicated drug interaction cocktail study in patients with psoriasis demonstrated a lack of therapeutic protein–drug interaction potentials for risankizumab and various cytochrome P450 substrates. In this article, we review the clinical pharmacology data available to date for risankizumab, which supported the clinical development program and ultimately regulatory approvals for risankizumab in the treatment of patients with moderate-to-severe plaque psoriasis.

ANTI-PD-1 Treatment in a Family with Constitutional Mismatch Repair Deficiency Syndrome with Multiple Cancers from Turkey. Is Cancer Immunoprevention with Checkpoint Inhibitors HAS a Role in CASES with Homozygous Mutationis

Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare childhood cancer predisposition syndrome resulting from biallelic germline mutations of MMR genes and it is poorly recognised by clinicians so far. Here we present affected children of 1st degree consanguinous parents diagnosed with CMMRD syndrome due to germline bi-allelic MSH 6 mutations with multiple cancers and mimicking NF 1 in a family from Turkey A 8-yr-old female,referred with brain tumor with follow up Neurofibromatosis 1 and Familial Mediterranean Fever. One of the female siblings had died of aggressive brain tumor at 4yrs of age, one male sibling due to medulloblastoma, followed by diagnosis of a metachronous metastatic colon adenocarcinoma at 15yrs of age. No additional cancers have been reported in the extended family, with the exception of colorectal cancer in the maternal and paternal great uncle diagnosed at age 45 years, paternal grandfather with brain tumor at 70 age of years and maternal aunt with papillary thyroid cancer at age 50 years. Her physical examination was unremarkable other than 8 to 10 cafe-au- lait spots and hipodense macules with irregular borders on her body. Laboratory tests were normal with low IG G2 levels. Cranial MRI revealed a mass in the left cerebellar region, subcortical hyperdens lesions in fronto-parietal area. She underwent near-total resection,histopathology revealed classic desmoplastic medulloblastoma.Postoperative craniospinal MRI showed no residue or metastasis.Craniospinal RT and CT of CCNU, cisplatin,VCR were given. At initial, due to colon adenocarcinoma history in her family, the colonoscopy was performed which did not reveal any polypoid lesions. In addition, because of the family history, the genetic analysis was carried out and disclosed a novel homozygous single base insertion mutation in exon 5 of the MSH 6 gene ( c.3261dupC/ p.Phe1088Leu ).Five cycles of previously mentioned chemotherapy combination and Nivolumab, obtained by pediatric extended use, was commenced at 3 mg/kg/dose in every 2 weeks as new polyps were detected in the following colonoscopy. After 10th dose,9 polyps were removed of tubular adenoma histopathology .She is still on antiPD1 treatment (18.th dose and in remission. Last colonoscopy revealed only one polyp mm in size. The genetic test results of the family: Blood samples were obtained from parents and siblings. One of the siblings was also found to be homozygous. She is 24- months- old age and has multiple cafe-au-lait spots on her body. She is still under follow up with screening tests for development of possible neoplasms. The parents and the other two siblings ( 11 and 6 years old boys) were heterozygous for the mutation. The male sibling who died from medulloblastoma and metastatic colorectal carcinoma genetic test had revealed same homozygous mutation. Conclusions: As the use of immune modulation for cancer prevention rather than therapy has gained considerable attention, we wonder if 24-months-old female sibling with homozygous mutation will be a candidate for cancer immunoprevention with AntiPD1drugs. We think that an international collaboration is required to evaluate guidelines for screening and treatment of malignancies and to explore prevention strategies patients with CMMRD syndrome. Disclosures Beksac: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau.

717 The Vedolizumab Pregnancy Exposure Registry: An OTIS Pregnancy Study Update

INTRODUCTION: Vedolizumab is a gut-selective immunoglobulin (Ig) G1 monoclonal antibody that binds to α4β7 integrin; it is approved for the treatment of moderately to severely active Crohn's disease (CD) and ulcerative colitis (UC) in the U.S. and elsewhere. Published studies on the effect of vedolizumab during human pregnancy are limited. Data from the ongoing Vedolizumab Pregnancy Exposure Registry (NCT02678052) in the U.S. and Canada have been collected by the MotherToBaby Pregnancy Studies conducted by the Organization of Teratology Information Specialists (OTIS). This prospective observational cohort study intends to enroll and analyze the outcomes of 100 vedolizumab-exposed participants compared to 100 disease-matched (DM) comparison and 100 healthy comparison (HC) participants. This abstract describes progress of the study through March 1, 2019. METHODS: Pregnant women treated with vedolizumab for UC or CD for at least some part of the first trimester were enrolled in the vedolizumab-exposed group. Pregnant women with no exposure to vedolizumab were enrolled in a DM comparison group. Pregnant women with no exposure to any biologic during pregnancy and not diagnosed with an autoimmune disease or any other disease as defined by the OTIS Research Center were enrolled in a HC group. Pregnancy exposure and outcome data were collected from telephone interviews and medical records. The Short Quality of Life in Inflammatory Bowel Disease Questionnaire (SIBDQ) was administered to women with CD or UC at enrollment and 32 weeks' gestation. Follow-up of live born children included a dysmorphological exam, pediatric records review and developmental screening at one year of age. RESULTS: Between December 2015 and March 2019, outcomes were collected for 223 women, 53 in the vedolizumab group, 88 in the DM group, and 82 in the HC group. Preliminary descriptive data are shown in Table 1. No major structural birth defects were reported in the vedolizumab group, compared to 5 (5.7%) in the DM group, and 4 (5.3%) in the HC group. There was no evidence of a pattern of minor structural defects in the vedolizumab group. CONCLUSION: Updated data indicate pregnant women treated with vedolizumab in at least the 1st trimester have similar birth outcomes to disease-matched and healthy comparison women. The Vedolizumab Pregnancy Exposure Registry is ongoing with formal statistical analysis to be performed when the study is completed.

P43 Immunoglobulin G4-related disease in a 10 year-old girl with multisystem involvement

Abstract Background IgG4-related disease (IgG4RD) is an immune-mediated fibroinflammatory condition characterized by the infiltration of IgG4-carrying plasma cells and storiform fibrosis in most of the tissues. The condition is reported to cause multisystem involvement, however salivary gland is the most commonly affected organ with IgG4-related sialadenitis. Raised IgG4 concentrations in the serum and prominent infiltration by plasmacytes expressing IgG4 in the lacrimal and salivary glands have been confirmed. Methods We conducted a retrospective case review of a 10 year-old girl who was diagnosed with IgG4-RD at Great Ormond Street Hospital for Children in 2017. Patient’s clinical, laboratory and imaging data was extracted from our database and literature search was done to find out different manifestations of the IgG4-RD in Children. Results 10 year-old-girl with lacrimal and salivary gland swelling, sicca symptoms and fatigue. Ultrasound scan neck revealed multiple small lymph nodes and enlargement of both submandibular glands (Picture1) Salivary glands also appeared bulky and heterogenous with multiple small hypoechoic focci. Appearances likely to represent sialoadenitis and there was no evidence of malignancy or lymphoma. USS abdomen normal. Full blood count, routine biochemistry and urine microscopy normal. Autoantibodies came back negative (ANA: Negative, ANCA: Negative, Anti-Ro and Anti-La: Negative, RF:Negative, Thyroid autoantibodies:Negative) IgG level elevated (in repeated samples). IgA, IgM and IgE levels normal. IgG subgroups revealed significantly elevated IgG4 levels (21.49 Normal range: 0-1.1) IgG1, IgG2 and Ig G3 levels elevated as well. Lymphocyte subsets were normal. The biopsy of salivary gland: Chronic inflammation with IgG4 staining, suggestive of IgG4 related disorder. Lung function test showed decreased DLCO at 76 %, FEV1 at 82% and FVC at 89% suggestive of interstitial lung involvement. CT Thorax: Multiple abnormalities including moderate lymphadenopathy, renal parenchymal lesions and interstitial lung abnormality. MRI Abdomen: T2 hypointense renal foci, suggestive of infiltration as part of the IgG4 related disease. Diagnosed with IgG4 related disease. Treatment started with intravenous methylprednisolone followed by Anti-CD20 (Rituximab) therapy and a weaning plan for steroids. Mycophenolate mofetil commenced for the maintenance therapy. Patient has shown good response with clinical and lung function improvement. Conclusion IgG4-RD is a rare condition which can cause multisystem involvement with the infiltration of IgG4-bearing plasma cells in the tissues. We wanted to emphasize that this condition could also be seen in the paediatric population. We also wanted to highlight that after further investigations multisystem involvement can be discovered. Steroids are mainstay of the treatment with Anti-CD20 medication (Rituximab) and steroid sparing agents such as mycophenolate mofetil could be the choice for maintenance therapy. However, further studies need to be done in paediatric age group. Conflicts of Interest The authors declare no conflicts of interest.

Inflammatory abdominal aortic aneurysms: place of Ig G4related diseases

Aim. Inflammatory abdominal aortic aneurysm may be one of the manifestations of Ig G4-related disease. This study analyzes the clinical manifestations of Ig G4related inflammatory abdominal aortic aneurysm. Material and methods. We examined twenty patients with abdominal aortic aneurysm (AAA). The clinical performance of the disease, the results of laboratory and pathomorphological studies were studied. In 8 cases, Ig G4-related inflammatory AAA criteria were identified. Results. Compared to atherosclerotic AAA, Ig G4-related cases were characterized by a less frequent presence of abdomen or back pain. The concentration of IgG4 in serum in Ig G4-related cases was significantly increased. Patients with Ig G4-related inflammatory AAA often had a history of allergic reactions to drugs, autoimmune diseases, a high concentration of Ig E and a high titer of antinuclear antibodies in blood serum. According to a histological study of intraoperative biopsy samples, Ig G4-related cases were characterized by thickening of adventitia and numerous infiltrates with Ig G4-positive plasma cells. Conclusion. The presence of Ig G4-related disease is diagnosed in the presence of irregular fibrous tissue proliferation with Ig G4 plasma cell infiltrates and with an increase in the concentration of Ig G4 in blood serum. Ig G4-related inflammatory AAA has clinical specifics in comparison with atherosclerotic aneurysm.

Distinguishing Features of Cetuximab and Panitumumab in Colorectal Cancer and Other Solid Tumors.

Cetuximab and panitumumab are two distinct monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR), and both are widely used in combination with chemotherapy or as monotherapy to treat patients with RAS wild-type metastatic colorectal cancer. Although often considered interchangeable, the two antibodies have different molecular structures and can behave differently in clinically relevant ways. More specifically, as an immunoglobulin (Ig) G1 isotype mAb, cetuximab can elicit immune functions such as antibody-dependent cell-mediated cytotoxicity involving natural killer cells, T-cell recruitment to the tumor, and T-cell priming via dendritic cell maturation. Panitumumab, an IgG2 isotype mAb, does not possess these immune functions. Furthermore, the two antibodies have different binding sites on the EGFR, as evidenced by mutations on the extracellular domain that can confer resistance to one of the two therapeutics or to both. We consider a comparison of the properties of these two antibodies to represent a gap in the literature. We therefore compiled a detailed, evidence-based educational review of the known molecular, clinical, and functional differences between the two antibodies and concluded that they are distinct therapeutic agents that should be considered individually during treatment planning. Available data for one agent can only partly be extrapolated to the other. Looking to the future, the known immune activity of cetuximab may provide a rationale for this antibody as a combination partner with investigational chemotherapy plus immunotherapy regimens for colorectal cancer.

Development of a Novel Humanized Monoclonal Antibody to Secreted Frizzled-Related Protein-2 That Inhibits Triple-Negative Breast Cancer and Angiosarcoma Growth In Vivo.

We previously reported that secreted frizzled-related protein-2 (SFRP2) is expressed in a variety of tumors, including sarcoma and breast carcinoma, and stimulates angiogenesis and inhibits tumor apoptosis. Therefore, we hypothesized that a humanized SFRP2 monoclonal antibody (hSFRP2 mAb) would inhibit tumor growth. The lead hSFRP2 antibody was tested against a cohort of 22 healthy donors using a time course T-cell assay to determine the relative risk of immunogenicity. To determine hSFRP2 mAb efficacy, nude mice were subcutaneously injected with SVR angiosarcoma cells and treated with hSFRP2 mAb 4mg/kg intravenously every 3days for 3weeks. We then injected Hs578T triple-negative breast cells into the mammary fat pad of nude mice and treated for 40days. Control mice received an immunoglobulin (Ig) G1 control. The SVR and Hs578T tumors were then stained using a TUNEL assay to detect apoptosis. Immunogenicity testing of hSFRP2 mAb did not induce proliferative responses using a simulation index (SI) ≥ 2.0 (p < 0.05) threshold in any of the healthy donors. SVR angiosarcoma tumor growth was inhibited in vivo, evidenced by significant tumor volume reduction in the hSFRP2 mAb-treated group, compared with controls (n = 10, p < 0.001). Likewise, Hs578T triple-negative breast tumors were smaller in the hSFRP2 mAb-treated group compared with controls (n = 10, p < 0.001). The hSFRP2 mAb treatment correlated with an increase in tumor cell apoptosis (n = 11, p < 0.05). Importantly, hSFRP2 mAb treatment was not associated with any weight loss or lethargy. We present a novel hSFRP2 mAb with therapeutic potential in breast cancer and sarcoma that has no effect on immunogenicity.

Impact of immunoglobulin G2 subclass level on late-onset bacterial infection after allogeneic hematopoietic stem cell transplantation.

Immunoglobulin (Ig) G2 subclass deficiency is known to be associated with recurrent bacterial respiratory infections caused by capsulated bacteria and is found mostly in pediatric patients. However, its impact after allogeneic hematopoietic stem cell transplantation (HSCT) has not been fully assessed. We retrospectively evaluated the relationship between IgG2 subclass levels and bacterial pneumonia in 74 adult patients who survived longer than 2years after allogeneic HSCT. During the evaluation period, nine patients developed bacterial pneumonia. The median IgG2 level was significantly lower in patients with an infectious episode than in those without (143mg/dL vs 287mg/dL; P<0.01). In multivariate analysis, a history of rituximab therapy and cord blood as a stem cell source were significantly associated with decreased levels of both IgG2 and IgG2/IgG ratios (P<0.05). Suboptimal serum IgG2 levels could increase susceptibility to late-onset bacterial pneumonia after allogeneic HSCT. IgG2 levels should be considered carefully, especially in patients receiving cord blood transplantation and/or rituximab treatment.

Relation of HLA-DRB1 to IgG4 autoantibody and cytokine production in muscle-specific tyrosine kinase myasthenia gravis (MuSK-MG).

A small subset of myasthenia gravis (MG) patients develop autoantibodies against muscle-specific kinase (MuSK), which are predominantly of the immunoglobulin (Ig)G4 isotype. MuSK-MG is strongly associated with HLA-DRB1*14, HLA-DRB1*16 and HLA-DQB1*05. In this study, the possible effects of these HLA associations on MuSK IgG autoantibody or cytokine production were investigated. Samples from 80 MG patients with MuSK antibodies were studied. The disease-associated HLA types were screened in the DNA samples. The IgG1, IgG2, IgG3 and IgG4 titres of the MuSK antibodies and the levels of interleukin (IL)-4, IL-6, IL-17A and IL-10 were measured in the sera. Comparisons were made among the groups with or without HLA-DRB1*14, HLA-DRB1*16 or HLA-DQB1*05. The IgG4 titres of the MuSK antibodies were higher than those of the IgG1, IgG2 and IgG3 isotypes among the whole group of patients. DRB1*14 (+) DRB1*16 (-) patients had higher levels of IgG4 antibodies than those of DRB1*14 (-) DRB1*16 (+) patients. DRB1*14 (+) DRB1*16 (+) patients also had higher levels of IgG4 antibodies than those of DRB1*14 (-) DRB1*16 (+) and DRB1*14 (-) DRB1*16 (-) patients. Higher IL-10 and lower IL-17A levels were measured in DRB1*14 (+) DRB1*16 (-) patients than in DRB1*14 (-) DRB1*16 (-) patients. The higher IgG4 titres of MuSK autoantibodies in patients carrying HLA-DRB1*14 than those in the other patients suggest a role for HLA in the production of the antibodies. The differences in IL-10 and IL-17A support the role of DRB1 in the etiopathogenesis of this autoimmune response.

BAY 1213790, a fully human IgG1 antibody targeting coagulation factor XIa: First evaluation of safety, pharmacodynamics, and pharmacokinetics

BackgroundCoagulation factor XI (FXI) contributes to the development of thrombosis but appears to play only a minor role in hemostasis and is therefore an attractive anticoagulant drug target. ObjectivesTo evaluate the safety, pharmacodynamic, and pharmacokinetic properties of BAY 1213790, a fully human immunoglobulin (Ig) G1 antibody targeting activated coagulation FXI (FXIa), in healthy men. MethodsIn this phase 1, single‐blind, parallel‐group, placebo‐controlled, dose‐escalation study, 83 healthy Caucasian men were randomized 4:1 to receive a single 60‐minute intravenous infusion of BAY 1213790 (0.015‐10 mg/kg) or placebo. Adverse events, pharmacodynamic parameters (including activated partial thromboplastin time [aPTT]) and pharmacokinetic parameters were determined. Volunteers were followed up for 150 days. ResultsBAY 1213790 demonstrated favorable safety and tolerability; there were no observed cases of bleeding or clinically relevant antidrug antibody formation. One volunteer (1.2%) experienced an infusion reaction. Following intravenous administration of BAY 1213790, dose‐dependent increases in aPTT (maximal mean increase relative to baseline: 1.85 [conventional method] and 2.17 [kaolin‐triggered method]) and rotational thromboelastometry whole blood clotting time were observed, as well as dose‐dependent reductions in FXI activity. Bleeding times did not increase following administration of BAY 1213790 and were similar for all dose cohorts, including placebo. Measurable and dose‐dependent increases in systemic exposure were detected for all doses of BAY 1213790 of 0.06 mg/kg or higher. ConclusionsBased on these safety, pharmacodynamic, and pharmacokinetic results, further evaluation of BAY 1213790 in patients with, or at risk of, thrombosis is warranted.

Lower levels of leptin are associated with severity parameters in visceral leishmaniasis patients.

Visceral leishmaniasis (VL) is the most severe clinical form of leishmaniasis, and if untreated may be fatal. It affects important organs of the immune system and is characterized by a specific immunosuppression, along with intense cellular activation and cytokine storm. Moreover, VL is now recognized as a systemic inflammatory response syndrome (SIRS), in which multiple cytokines and other pro-inflammatory molecules are released. The action of these inflammatory mediators may be considered risk factors for poor prognosis and death. Leptin, a hormone derived from adipose tissue, has been described with several immunoregulatory functions in vitro and in vivo Leishmania infection models, particularly for enhancing the macrophage microbicidal mechanisms. Considering that evaluation of immunologic parameters that may be associated with this clinical scenario may help to decrease VL lethality, we evaluated whether leptin is associated with VL pathogenesis. Thirty-one patients were recruited in the active phase of VL, of which 22 were followed up until one month after therapy (1mpt). Except for creatinine levels, all clinical parameters were altered in active VL patients, especially leucocyte counts and albumin and hemoglobin levels. Also, elevated levels of lipopolysaccharide (LPS), immunoglobulins (Ig)G1 and G3 anti-Leishmania and interleukins (IL)-6 and -10 were higher than in healthy individuals. In contrast, active VL patients presented diminished serum leptin levels and positive correlation with leukocytes counts and hemoglobin and albumin levels. After 1mpt, VL patients showed a significant increase in leptin levels, reaching values similar to healthy volunteers. As expected, only LPS levels remained elevated after 1mpt. These findings suggest that leptin levels are affected in Leishmania infection and the correlation with important parameters associated with the prognosis of VL points to the involvement of this molecule in VL immunopathogenesis. Additional studies are needed to evaluate the possibility of leptin as a prognostic marker of VL.

Schistosoma mansoni PCR+ -infected individuals in the Sudan present elevated systemic levels of chemokines when compared to uninfected and egg+ cohorts.

Infections with Schistosoma mansoni remain a major health problem in the Sudan where endemic communities, such as those in Kassala and Khartoum states, continue to face severe social-economic difficulties. Our previous immunoepidemiological findings revealed different immune [cytokine and S. mansoni egg (SEA) antibody] profiles in individuals with active infections (eggs in stool n=110), individuals positive for S. mansoni via polymerase chain reaction (PCR) using sera (SmPCR+ n=63) and those uninfected (Sm uninf). As antibody responses to eggs and worms are known to change during infection, we have expanded the profiling further by determining levels of adult worm (SWA) antibodies and nine chemokines in the serum of each individual in the three different cohorts. With the exception of C-C motif chemokine ligand (CCL)2, all measured chemokines were significantly higher in SmPCR+ individuals when compared to the egg+ group and in addition they also presented elevated levels of SWA-specific immunoglobulin (Ig)G2. Multivariable regression analysis further revealed that infection per se was strongly linked to SWA-specific IgG3 levels and CCL5 was strongly associated with a SmPCR+ diagnostic state. In the absence of PCR diagnostics that recognize juvenile worms or schistosomulae motives, identifying schistosome-specific traits should provide better insights into current prevalence rates in endemic communities and, in doing so, take into consideration PCR+ non-egg+ individuals in current treatment programmes.

Detection of Immunoglobulin G1 Against rK39 Improves Monitoring of Treatment Outcomes in Visceral Leishmaniasis.

BackgroundVisceral leishmaniasis (VL), caused by the Leishmania donovani complex, is a fatal, neglected tropical disease that is targeted for elimination in India, Nepal, and Bangladesh. Improved diagnostic tests are required for early case detection and for monitoring the outcomes of treatments. Previous investigations using Leishmania lysate antigen demonstrated that the immunoglobulin (Ig) G1 response is a potential indicator of a patient’s clinical status after chemotherapy.MethodsIgG1 or IgG enzyme-linked immunosorbent assays (ELISAs) with rK39 or lysate antigens and novel IgG1 rK39 rapid diagnostic tests (RDTs) were assessed with Indian VL serum samples from the following clinical groups: paired pre- and postchemotherapy (deemed cured); relapsed; other infectious diseases; and endemic, healthy controls.ResultsWith paired pre- and post-treatment samples (n = 37 pairs), ELISAs with rK39- and IgG1-specific conjugates gave a far more discriminative decrease in post-treatment antibody responses when compared to IgG (P < .0001). Novel IgG1 rK39 RDTs provided strong evidence for decreased IgG1 responses in patients who had successful treatment (P < .0001). Furthermore, both IgG1 rK39 RDTs (n = 38) and ELISAs showed a highly significant difference in test outcomes between cured patients and those who relapsed (n = 23; P < .0001). RDTs were more sensitive than corresponding ELISAs.ConclusionsWe present strong evidence for the use of IgG1 in monitoring treatment outcomes in VL, and the first use of an IgG1-based RDT using the rK39 antigen for the discrimination of post-treatment cure versus relapse in VL. Such an RDT may have a significant role in monitoring patients and in targeted control and elimination of this devastating disease.

Antibody immunoglobulin G1 and immunoglobulin G2a responses against some cystic fluid proteins of Cysticercus bovis in Balb/c mice.

Background and Aim:Immunoglobulin (Ig) G1 and IgG2a are the surrogate markers respectively for humoral and cellular immune responses of hosts against antigens including cystic fluid proteins of Cysticercus bovis. A study was conducted to investigate the IgG1 and IgG2a responses of Balb/c mice against some individual cystic fluid proteins of C. bovis in an effort to determine the roles of each protein in inducing the humoral and cellular immune responses in host.Materials and Methods:Individual p71, p31, and p14 proteins of C. bovis were purified by separation of the proteins using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and elution of individual proteins from the gel. Six female Balb/c mice were immunized 4 times at 10-day intervals with the crude cystic fluid proteins, and sera were collected for the measurement of IgG1 and IgG2a levels against the individual proteins. Sera samples collected before the first immunization were used as negative antibody control, sera samples collected after the fourth immunization were used as positive antibody control, and crude cystic fluid protein was used as positive antigen control.Results:All immunized mice were immune to p71, p31, p14, and crude cystic fluid proteins of C. bovis. The crude cystic fluid proteins of C. bovis induced a higher IgG2a than IgG1 level following the first and the second immunizations but switched into a higher IgG1 than IgG2a level following the fourth immunization. Protein 71 kDa (p71) induced a higher IgG2a than IgG1 level following the fourth immunization. In contrast, p14 induced a higher IgG1 than IgG2a level following the fourth immunization. Low and balance IgG1 and IgG2a levels against p31 were observed following the first to the fourth immunizations.Conclusion:Using IgG1 and IgG2a levels as the surrogate markers, it appears that cystic fluid antigens of C. bovis induce both humoral and cellular immune responses in Balb/c mice. The p71 appears to be a better inducer of cellular immune response, whereas p14 is a better inducer of humoral immune response of mice.

PERSISTENT LIP AND FACIAL SWELLING IN A 9 YEAR OLD BOY

Introduction Orofacial Granulomatosis (OFG) is a chronic granulomatous condition characterized by persistent or recurring swelling of soft tissues in the face. It is thought to be caused by a delayed hypersensitivity reaction involving a Th1-mediated immune response. There have been reports of cases associated with Sarcoidosis and Crohn's disease. Case Description A 9-year old male presented to clinic with 15 months of lip and facial swelling. Episodes last 2-3 weeks with resolution periods of 1-2 weeks. Antihistamines failed to improve the swelling. He has normal growth and development. He denies any fevers, headaches, eye redness/pain, oral/nasal ulcerations, difficulty swallowing, decrease in physical conditioning, nausea/vomiting/diarrhea, or bone/joint/muscle complaints. He was started on high dose steroids which improved his lip swelling but as the prednisone was tapered, the swelling returned. He had a mild elevation in Ig G4 and CRP, positive histone antibodies, and elevated C3/C4 and Ig G levels. His Hereditary Angioedema, Sarcoidosis, and Crohn's disease evaluation were negative. Eventually a biopsy of the vestibule of the anterior mandible was done which showed non-necrotizing granulomas. Discussion OFG symptoms can be indistinguishable to those caused by angioedema, contact dermatitis, melkersson-rosenthal syndrome, and lymphangioedema. OFG is made from a diagnosis of exclusion as biopsy cannot distinguish between OFG and Crohn's or Sarcoidosis. Treatment of this condition can be challenging and include steroids, NSAIDs, antibiotics, and TNF-alfa inhibitors. The goal of this case is to provide insight on this uncommon condition whose symptoms present as known sequela of frequent diseases that allergists encounter in their practice.