Effects of burnt tire-ash on Na+/K+, Ca2+-ATPase, serum immunoglobulin and brain acetylcholinesterase activities in clarias gariepinus (Burchell, 1822).

Aquatic pollution may continue to deepen following the emergence of new class of toxicants. The present study investigated the effect of water-soluble fraction of burnt tire-ash on Clarias gariepinus. The fish were exposed to sublethal doses; 0.00 g/L, 2.24 g/L, 1.12 g/L and 0.56 g/L of tire-ash solution, representing 1/5, 1/10 and 1/20 of 11.2 g/L median lethal concentration (96 LC50), for 28 days, followed by 14 days recovery trial. Biological sampling was done on exposure day 1, 14 and 28, and on day14 recovery period for biochemical analysis such as the liver and gill Na+/K+ and Ca2+-ATPase, serum immunoglobulin (IgM) and brain acetylcholinesterase (AChE) of the experimental fish. Also, body biomass and behavior were evaluated. The behavioral responses exhibited by the fish to BTA exposure include reduced feeding, hypoactivity, air gulping and skin discoloration, which was observed to be concentration dependent. The body weight of 2.24 g/L and 1.12 g/L BTA-exposed fish decreased significantly than 0.56 g/L exposed fish and the control. Furthermore, findings revealed evident induction of Na+/K+ and Ca2 +-ATPase activities in both tissues, elevation of serum immunoglobulin content and inhibition of AChE activity in the brain of the exposed fish relative to the control. However, it was also observed that the biochemical parameters normalized after the recovery period. In conclusion, water-soluble fraction of burnt tire-ash produced toxicological effects in the experimental model, hence the present study provides the ecotoxicological insight of tire ash.

Aptamer-Assisted Blockade of the Immune Suppressor Sialic Acid-Binding Immunoglobulin-Like Lectin-15 for Cancer Immunotherapy.

The percentage of low response and adaptive resistance to current antibody-based immune checkpoint blockade (ICB) therapy requires the development of novel immunotherapy strategies. Here, we developed an aptamer-assisted immune checkpoint blockade (Ap-ICB) against sialic acid-binding immunoglobulin-like lectin-15 (Siglec-15), a novel immune suppressor broadly upregulated on cancer cells and tumor infiltrating myeloid cells, which is mutually exclusive of programmed cell death ligand 1 (PD-L1). Using protein aptamer selection, we identified WXY3 aptamer with high affinity against Siglec-15 protein/Siglec-15 positive cells. We demonstrated that WXY3 aptamer rescued antigen-specific T cell responses in vitro and in vivo. Importantly, the WXY3 Ap-ICB against Siglec-15 amplified anti-tumor immunity in the tumor microenvironment and inhibited tumor growth/metastasis in syngeneic mouse model, which may result from enhanced macrophage and T cell functionality. In addition, by using aptamer-based spherical nucleic acids, we developed a synergetic ICB strategy of multivalent binding and steric hindrance, which further improves the in vivo anti-tumor effect. Taken together, our results support Ap-ICB targeted Siglec-15 as a potential strategy for normalization cancer immunotherapy.

Egg yolk immunoglobulin (IgY) targeting SARS-CoV-2 S1 as potential virus entry blocker.

AIMS: COVID-19 pandemic caused by SARS-CoV-2 has become a public health crisis worldwide. In this study, we aimed at demonstrating the neutralizing potential of the IgY produced after immunizing chicken with a recombinant SARS-CoV-2 spike protein S1 subunit. METHODS AND RESULTS: E. coli BL21 carrying plasmid pET28a-S1 was induced with IPTG for the expression of SARS-CoV-2 S1 protein. The recombinant His-tagged S1 was purified and verified by SDS-PAGE, Western blot and biolayer interferometry (BLI) assay. Then S1 protein emulsified with Freund's adjuvant was used to immunize layer chickens. Specific IgY against S1 (S1-IgY) produced from egg yolks of these chickens exhibited a high titer (1:25,600) and a strong binding affinity to S1 (KD  = 318 nmol L-1 ). The neutralizing ability of S1-IgY was quantified by a SARS-CoV-2 pseudotyped virus-based neutralization assay with an IC50  value of 0.99 mg ml-1 . In addition, S1-IgY exhibited a strong ability in blocking the binding of SARS-CoV-2 S1 to hACE2, and it could partially compete with hACE2 for the binding sites on S1 by BLI assays. CONCLUSIONS: We demonstrated here that after immunization of chickens with our recombinant S1 protein, IgY neutralizing antibodies were generated against the SARS-CoV-2 spike protein S1 subunit; therefore, showing the potential use of IgY to block the entry of this virus. SIGNIFICANCE AND IMPACT OF THE STUDY: IgY targeting S1 subunit of SARS-CoV-2 could be a promising candidate for pre- and post-exposure prophylaxis or treatment of COVID-19. Administration of IgY-based oral preparation, oral or nasal spray may have profound implications for blocking SARS-CoV-2.

B7 Family Members in Pancreatic Ductal Adenocarcinoma: Attractive Targets for Cancer Immunotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with a five-year survival rate of approximately 5-10%. The immune checkpoint blockade represented by PD-1/PD-L1 inhibitors has been effective in a variety of solid tumors but has had little clinical response in pancreatic cancer patients. The unique suppressive immune microenvironment is the primary reason for this outcome, and it is essential to identify key targets to remodel the immune microenvironment. Some B7 family immune checkpoints, particularly PD-L1, PD-L2, B7-H3, B7-H4, VISTA and HHLA2, have been identified as playing a significant role in the control of tumor immune responses. This paper provides a comprehensive overview of the recent research progress of some members of the B7 family in pancreatic cancer, which revealed that they can be involved in tumor progression through immune-dependent and non-immune-dependent pathways, highlighting the mechanisms of their involvement in tumor immune escape and assessing the prospects of their clinical application. Targeting B7 family immune checkpoints is expected to result in novel immunotherapeutic treatments for patients with pancreatic cancer.

hIgDFc-Ig inhibits B cell function by regulating the BCR-Syk-Btk-NF-κB signalling pathway in mice with collagen-induced arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease targeting the synovium. Previous studies have found that IgD may be a potential target for the treatment of RA. We designed a new type of fusion protein, hIgDFc-Ig (DG), to block the binding of IgD to IgD receptor (IgDR). In this study, we found that DG has a significant therapeutic effect in mice with collagen-induced arthritis (CIA). DG improved the claw of irritation symptoms in these mice, inhibited the pathological changes in spleen and joint tissues, and had a moderating effect on B cell subsets at different inflammatory stages. Moreover, DG could also decrease the levels of IgA, IgD, IgM and IgG subtypes of immunoglobulin in the serum of mice with CIA. In vitro, B cell antigen receptor (BCR) knockout Ramos cells were established using the CRISPR/Cas9 technology to further study the activation of BCR signalling by IgD and the effect of DG. We found that the therapeutic effect of DG in mice with CIA may be achieved by inhibiting the activation of BCR signalling by IgD, which may be related to the activation of Igß. In summary, DG may be a potential biological agent for the treatment of RA and it has broad application prospects in the future.

Efficacy of Nucleotide/Nucleoside Analogues and Hepatitis B Immunoglobulin Therapy in Blocking Mother-to-Child Transmission of Hepatitis B in an Eastern Chinese Group.

The objective of this study was to investigate the efficacy and potential side-effects of nucleotide/nucleoside analogues and hepatitis B immunoglobulin injection of newborns in blocking mother-to-child transmission of hepatitis B virus in the middle and late pregnancy period. 238 cases of enrolled pregnant women were divided into the Telbivudine group, the Tenofovir group, the Lamivudine group, and the hepatitis B immunoglobulin (HBIG) group. Enrolled patients received corresponding therapies. Clinical and laboratory data were collected. Results showed that the levels of HBV DNA of the enrolled pregnant women in the Telbivudine, Tenofovir, and Lamivudine groups decreased rapidly after 12 weeks of drug intervention compared with those in the control. HBsAg positive rate in newborns and in children 24 weeks after birth was 0/60, 0/60, 0/60, 3/30, and 11/28 in the Telbivudine, Tenofovir, Lamivudine, HBIG, and control groups, respectively. No significant side-effects were identified after following up to 12 months after birth. Our results show that routine HBV vaccine plus HBIG injections is insufficient in blocking mother-to-child HBV transmission. Administration of nucleotide/nucleoside analogues or HBIG at pregnancy is suggested to maximize the blocking of vertical HBV transmission.

Exposure-response analyses demonstrate no evidence of interleukin 17A contribution to efficacy of ABT-122 in rheumatoid or psoriatic arthritis.

Objectives: ABT-122 is a dual-variable-domain immunoglobulin that neutralizes both TNF-α and IL-17A. The objective of this work was to characterize exposure-response relationships for ABT-122 relative to adalimumab (TNF-α inhibitor) using ABT-122 phase 2 trials in patients with RA or PsA. Methods: Patients received subcutaneous doses of ABT-122 ranging from 60 mg every other week (EOW) to 240 mg every week, adalimumab 40 mg EOW, or placebo (PsA patients only) for 12 weeks. Relationships between ABT-122 or adalimumab serum concentrations and time course of ACR20, ACR50 and ACR70 and PASI50, PASI75 and PASI90 responses were characterized using a non-linear mixed-effects Markov modelling approach. Results: A total of 221 RA patients and 240 PsA patients were included in the analyses. At comparable molar exposures, there was no differentiation of efficacy between ABT-122 and adalimumab and there were no consistent differences between ABT-122 and adalimumab in the potency estimates for different efficacy endpoints based on the Markov models. Plateau of ABT-122 efficacy was achieved at exposures associated with the 120 mg EOW dose in patients with RA, which were comparable to molar exposures of adalimumab 40 mg EOW, and at the lowest dose of 120 mg every week in patients with PsA. Conclusion: The exposure-response relationships for ABT-122 were not distinguishably different from those of adalimumab in patients with RA or PsA. Overall, there was no clear evidence that inhibition of the IL-17 pathway provided incremental benefit in the presence of TNF-α inhibition. Trial registration: ClinicalTrials.gov, NCT02433340, NCT02349451.

Production of anti-Trichophyton rubrum egg yolk immunoglobulin and its therapeutic potential for treating dermatophytosis.

The aim of this study was to estimate the therapeutic potential of specific egg yolk immunoglobulin (IgY) on dermatophytosis caused by Trichophyton rubrum. The IgY was produced by immunizing hens with cell wall proteins of T. rubrum, extracted from eggs by PEG precipitation and then purified by ammonium sulfate precipitation. The cross-reactivity (CR) with other fungi, growth inhibition on T. rubrum in vitro and therapeutic effect on T. rubrum infection in BALB/C mice of the specific IgY were then evaluated. Anti- T. rubrum cell wall proteins IgY (anti-trCWP IgY) presented a certain degree of cross-reactivity with different fungi. In the in vitro and in vivo activity researches, Anti-trCWP IgY showed a significant dose-dependent growth inhibitory effect on T. rubrum in vitro and a significant dose-dependent therapeutic effect on T. rubrum infection in BALB/C mice.

Inclusion of IgY in a dog's diet has moderate impact on the intestinal microbial fermentation.

AIMS: This study aimed to evaluate the impact of immunoglobulin Y (IgY) in a diet on the systemic health and the gastrointestinal tract (GIT) of dogs. METHODS AND RESULTS: Sixteen healthy 11-month-old Beagle dogs were distributed at random (eight animals per treatment) in two treatments groups: control (0 g kg-1 IgY) and test (2 g IgY per day). The animals were evaluated on days 0 and 40 for a complete blood count (CBC) and biochemical profiles (ALT, ALP, creatinine and urea). Faecal samples were collected from days 35 to 40 to measure nutrient digestibility, faecal characteristics, sialic acid, intestinal microbiota composition and microbial metabolites. The CBC, biochemical profiles, apparent nutrient digestibility and faecal characteristics did not differ between the two treatment groups (P > 0·05). Dog faeces that received IgY were characterized by lower sialic acid and n-valeric concentration, as well as an increase in n-butyric concentration, in contrast to dogs fed a diet without IgY (P < 0·05). The other microbial faecal metabolites did not differ between the two treatment groups (P > 0·05). There tended to be an increase in the copy number of Clostridium cluster XIVa (Clostridium coccoides group) in the IgY group in contrast to the control group (P = 0·07). The other bacteria analysed did not differ between the treatment groups (P > 0·05). The colonic pH in the IgY group was lower than in control group (P < 0·05). CONCLUSIONS: The addition of IgY in the diet of healthy dogs maintains the microbial balance and has an interesting effect on microbial metabolites. SIGNIFICANCE AND IMPACT OF THE STUDY: The use of IgY, antibodies produced by laying hens, in animal feed is an alternative for the prevention and treatment of intestinal diseases in companion animals.

Protective effect of chicken egg yolk immunoglobulins (IgY) against enterotoxigenic Escherichia coli K88 adhesion in weaned piglets.

BACKGROUND: Enterotoxigenic Escherichia coli K88 (E. coli K88) are considered as a major cause of diarrhea and death in newly weaned piglets. Oral passive immunization with chicken egg yolk immunoglobulins (IgY) have attracted considerable attention for treatment of gastrointestinal infection due to its high specificity. In this study it was estimated the protective effect of anti-K88 fimbriae IgY against E. coli K88 adhesion to piglet intestinal mucus in vitro and to investigate the potential use of IgY for controlling E. coli-induced diarrhea in weaned piglets in vivo. RESULTS: E. coli K88 was incubated with IgY for 24 h, and the bacterial growth profiles showed that specific IgY with a concentration higher than 5 mg/mL was observed to significantly inhibit the growth of E. coli K88 compared to nonspecific yolk powder in a liquid medium. Moreover, pretreatment with 50 mg/mL of IgY was found to significantly decrease the adhesion ability of E. coli K88 to porcine jejunal and ileal mucus, further supported by the observations from our immunofluorescence microscopic analysis. In vivo, administration of IgY successfully protected piglets from diarrhea caused by E. coli K88 challenge. Additionally, IgY treatment efficiently alleviated E. coli-induced intestinal inflammation in piglets as the gene expression levels of inflammatory cytokines TNF-α, IL-22, IL-6 and IL-1ß in IgY-treated piglets remained unchanged after E. coli K88 infection. Furthermore, IgY significantly prevented E. coli K88 adhering to the jejunal and ileal mucosa of piglets with E. coli infection and significantly decreased E. coli and enterotoxin expression in colonic contents. CONCLUSION: Outcome of the study demonstrated that IgY against the fimbrial antigen K88 was able to significantly inhibit the growth of E. coli K88, block the binding of E. coli to small intestinal mucus, and protect piglets from E. coli-induced diarrhea. These results indicate that passive immunization with IgY may be useful to prevent bacterial colonization and to control enteric diseases due to E. coli infection. The study has great clinical implication to provide alternative therapy to antibiotics in E coli induced diarrhea.

Extraction of specific egg yolk antibodies and application in chitosan coating: effect on microbial and sensory properties of rainbow trout fillet during chilled storage.

BACKGROUND: This study investigated the effect of chitosan coating enriched with extracted egg yolk antibodies on microbial and sensory quality of rainbow trout fillet during refrigeration (4 ± 1 °C). Firstly, bacterial antigen suspensions (total psychrophilic bacteria, Pseudomonas fluorescens and Shewanella putrefaciens) were injected into the breast muscles of chickens. Eggs of immunized chickens were then collected to isolate immunoglobulin from egg yolks (IgY). Fresh fish fillets were coated by chitosan solution containing different types of IgY separately, at two concentrations (60 and 90 mg mL-1 ), refrigerated for 16 days and analysed for total viable count, psychrotrophic, Pseudomonas spp., P. fluorescens and S. putrefaciens count as well as sensorial properties. RESULTS: The tested microbial values increased in all samples during the storage period; however, CH + IgY treated samples could significantly retard microbial growth compared to control. The shelf life of CH + IgY-P samples was extended for about 4 days, while it was extended for about 8 days in CH + IgY-S and CH + IgY-T samples, when they were compared to control (p < 0.05). Higher scores for sensory attributes were also observed in CH + IgY treated samples, especially in CH + IgY-S samples until the end of storage period. CONCLUSIONS: Accordingly, use of chitosan coating containing IgY increases the microbial and sensory quality of fish flesh at 4 °C. Therefore, given the consumer interest in natural additives, chitosan coating containing IgY can be a promising candidate. © 2018 Society of Chemical Industry.

The preparation and antibacterial effect of egg yolk immunoglobulin (IgY) against the outer membrane proteins of Vibrio parahaemolyticus.

BACKGROUND: Vibrio parahaemolyticus causes not only various diseases in aquaculture animals but also seafood-borne illness in humans. Outer membrane proteins (OMPs) are species-specific proteins found in bilayer membranes of gram-negative bacteria. Egg yolk immunoglobulin (IgY) has been reported to serve as oral administration of antibodies against bacteria and virus. RESULTS: The present research extracted and identified OMPs from V. parahaemolyticus, and then the extracted OMPs were used to immunize hens to obtain specific IgY. The efficacy of IgY against V. parahaemolyticus were investigated in vitro and in vivo. The specific IgY effectively inhibited the growth of V. parahaemolyticus in liquid medium rather than Escherichia coli and Staphylococcus aureus. Specific IgY antibodies were incorporated into extruded food pellets and fed to bacteria-challenged white pacific shrimp to observe the anti-bacterial effect in vivo. The bacterial loads in muscles of V. parahaemolyticus infected shrimp fed with specific IgY-included diets were significantly fewer than those fed with non-specific IgY-included diets. The superoxide dismutase activities in muscles of infected shrimp fed with specific IgY-included diets were significantly higher than the control group. CONCLUSION: The results suggested that the specific IgY effectively inhibited the growth of V. parahaemolyticus and introduced passive immunity to shrimp. © 2018 Society of Chemical Industry.

Ecto-enzymes activities in splenic lymphocytes of mice experimentally infected by Trypanosoma cruzi and treated with specific avian immunoglobulins: an attempt to improve the immune response.

The aim of this study was to evaluate the therapeutic efficacy of specific avian polyclonal antibodies (IgY) against Trypanosoma cruzi and their interaction with ecto-enzymes of the purinergic system (NTPDase and adenosine deaminase (ADA) activities) in splenic lymphocytes. For this, mice were divided into six groups: three non-infected (A, B, and C) and three infected (D, E, and F). The groups A and D were composed by negative and positive controls, respectively; while the groups B and E were treated prophylactically with IgY (50 mg/kg), and the groups C and F were treated therapeutically with IgY (50 mg/kg). Treatment with IgY reduced parasitemia on day 6 post-infection (PI) compared to the infected control group, but it was similar on day 8 PI. Moreover, infected and treated animals (the groups E and F) did not show neither amastigotes in the cardiac tissue nor cardiac lesions when compared to the positive control group (the group D). The E-NTPDase (ATP and ADP as substrate) and ADA activities in splenic lymphocytes increased significantly in the positive control group (the group D) compared to the negative control group (the group A). The therapeutic treatment of IgY (the group F) was able to prevent the increase of E-NTPDase and E-ADA activities compared to the positive control group (the group D), but this finding was not observed in animals that received the prophylactic treatment (the group E). The therapeutic treatment of IgY may be considered an interesting approach to improve the immune response of mice experimentally infected by T. cruzi.

The growing role of structural mass spectrometry in the discovery and development of therapeutic antibodies.

The comprehensive structural characterization of therapeutic antibodies is of critical importance for the successful discovery and development of such biopharmaceuticals, yet poses many challenges to modern measurement science. Mass spectrometry has evolved into a rapid and sensitive tool for assessing the structures, stabilities, and dynamics of such proteins. Here, we review the current state-of-the-art mass spectrometry technologies focusing on the characterization of antibody-based therapeutics. We conclude by discussing the future of structural mass spectrometry, and its role in enabling the biopharmaceutical pipeline.

Headache and Ophthalmoparesis: Case Report of an "Atypical" Incomplete Miller-Fisher Syndrome.

OBJECTIVE: To expand the differential diagnosis of headache and ophthalmoparesis by describing a case report in which anti-GQ1b was demonstrated to be the cause. BACKGROUND: Anti-GQ1b antibody syndrome refers to a clinical spectrum of conditions that share common mechanisms and overlapping manifestations, including the Miller-Fisher syndrome, pharyngeal-cervical-brachial weakness, and Bickerstaff brainstem encephalitis. Rare atypical cases presenting as acute ophthalmoparesis (AO) without ataxia or areflexia have been described. Headache is a rare condition in these disorders. METHODS: A 49-year-old woman with no history of headaches began experiencing an acute severe bilateral throbbing headache associated with nausea and photophobia. Five days later, she developed constant binocular horizontal diplopia. RESULTS: Bilateral paresis of both sixth nerves was noted. Her ocular fundi, tendon reflexes, and other findings of the physical exam were normal. In addition, both a brain MRI performed with gadolinium and a lumbar puncture yielded normal results. Serum anti-GQ1b IgG was found to be positive. Her symptoms resolved completely following treatment with immunoglobulins (0.4 g/kg/day for 5 days). CONCLUSIONS: This is the first reported case of AO related to anti-GQ1b antibodies presenting with headache as its initial symptom. The presence of anti-GQ1b antibodies should be determined in patients with headache and AO of unknown origin. Immunoglobulins could hasten the resolution of symptoms in these patients.

Refractory septic shock: our pragmatic approach.

Despite timely intervention, there exists a small subgroup of patients with septic shock who develop progressive multi-organ failure. Seemingly refractory to conventional therapy, they exhibit a very high mortality. Such patients are often poorly represented in large clinical trials. Consequently, good evidence for effective treatment strategies is lacking. In this article, we describe a pragmatic, multi-faceted approach to managing patients with refractory septic shock based on our experience of toxin-mediated sepsis in a specialist referral centre. Many components of this strategy are inexpensive and widely accessible, and so may offer an opportunity to improve outcomes in these critically ill patients.

Developments in human rabies prophylaxis.

Rabies is entirely preventable. All deaths are the result of failed prophylaxis. Rabies encephalomyelitis has never been reported in anyone who received both pre-exposure vaccination and a post-exposure booster. Awareness of the risk of contact with rabid animals is crucial. A lack of basic knowledge and the inaccessibility of expensive rabies vaccines can discourage patients bitten by suspected rabid animals from seeking prompt post-exposure prophylaxis. Similarly, people working with mammals, residents of areas where dog rabies is endemic, travellers, and others at risk often fail to take advantage of pre-exposure prophylaxis. However, since human infection by a dog rabies virus has always proved fatal in unvaccinated patients, there is understandable reluctance to accept any change in vaccine protocols. The intramuscular route of delivery is wasteful and the current, low-dose intradermal (ID) regimen is not always economical or universally trusted. A new, one-week ID regimen, using less vaccine, injected at multiple sites, and involving two clinic visits, could increase the accessibility of highly immunogenic prophylaxis and reduce the prohibitive cost. The recent 2018 World Health Organization recommendations for rabies prophylaxis are included.

La rage est une maladie parfaitement évitable. Tous les décès par rage sont le résultat d'une prophylaxie déficiente. L'encéphalomyélite rabique n'a jamais été notifiée chez des sujets ayant reçu à la fois une vaccination pré-exposition et un rappel post-exposition. Il est essentiel de prendre conscience des risques liés au contact avec des animaux enragés. L'absence de connaissances élémentaires et le coût prohibitif des vaccins contre la rage empêchent parfois les patients mordus par des animaux suspectés de rage de recourir à une prophylaxie postexposition d'urgence. De même, les personnes exposées à des mammifères de par leur profession, celles vivant dans des régions où la rage canine est endémique, les voyageurs et d'autres catégories à risque n'ont pas toujours bénéficié d'une prophylaxie pré-exposition. Étant donné que l'infection humaine par le virus de la rage canine a toujours entraîné la mort chez les patients non vaccinés, la modification des protocoles de vaccination se heurte à des réticences bien compréhensibles. L'administration du vaccin par voie intramusculaire est peu rentable, tandis que la posologie actuelle d'une faible dose administrée par voie intradermique n'est pas nécessairement moins onéreuse et ne suscite pas une confiance universelle. Un nouveau protocole de vaccination intradermique consistant à administrer moins de vaccin mais sur une semaine, en changeant les sites d'injection et en encadrant le protocole par deux examens cliniques pourrait améliorer l'accessibilité d'une prophylaxie fortement immunogène tout en réduisant son coût pour le rendre moins prohibitif. L'auteure présente les récentes (2018) recommandations de l'Organisation mondiale de la santé (OMS) en matière de prophylaxie de la rage.

La rabia es una enfermedad totalmente prevenible. Todos los casos de muerte se deben a una profilaxis defectuosa. Nunca se ha descrito encefalomielitis rábica en una persona que hubiera recibido vacunación previa a la exposición y un refuerzo tras la exposición. Un aspecto crucial es la sensibilización respecto de los riesgos ligados al contacto con animales rabiosos. La falta de conocimientos básicos y la imposibilidad de acceder a las onerosas vacunas antirrábicas pueden disuadir a pacientes mordidos por animales posiblemente rabiosos de solicitar con prontitud medidas de profilaxis tras exposición. Análogamente, tampoco las personas que trabajan con mamíferos, los residentes de zonas donde la rabia canina es endémica, los viajeros y otras personas expuestas al riesgo suelen aprovechar las posibilidades que ofrece la profilaxis previa a la exposición. No obstante, dado que hasta ahora la infección humana por un virus de la rabia canina ha resultado invariablemente letal en pacientes no vacunados, existe una comprensible reticencia a aceptar el menor cambio en los protocolos de vacunación. La administración por vía intramuscular conduce al despilfarro, y el vigente régimen de vacunación con pequeñas dosis intradérmicas no siempre resulta económico ni inspira confianza generalizada. La aplicación de un nuevo régimen de vacunación intradérmica consistente en la inyección en múltiples sitios de una menor cantidad de vacuna en apenas dos visitas al practicante en el curso de una semana puede hacer más accesible una profilaxis muy inmunógena y a la vez reducir los costos prohibitivos de la prevención. La autora expone también las recientes (2018) recomendaciones de la Organización Mundial de la Salud (OMS) en materia de profilaxis antirrábica.

Marked in Vivo Donor Regulatory T Cell Expansion via Interleukin-2 and TL1A-Ig Stimulation Ameliorates Graft-versus-Host Disease but Preserves Graft-versus-Leukemia in Recipients after Hematopoietic Stem Cell Transplantation.

Regulatory T cells (Tregs) are critical for self-tolerance. Although adoptive transfer of expanded Tregs limits graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT), ex vivo generation of large numbers of functional Tregs remains difficult. Here, we demonstrate that in vivo targeting of the TNF superfamily receptor TNFRSF25 using the TL1A-Ig fusion protein, along with IL-2, resulted in transient but massive Treg expansion in donor mice, which peaked within days and was nontoxic. Tregs increased in multiple compartments, including blood, lymph nodes, spleen, and colon (GVHD target tissue). Tregs did not expand in bone marrow, a critical site for graft-versus-malignancy responses. Adoptive transfer of in vivo-expanded Tregs in the setting of MHC-mismatched or MHC-matched allogeneic HSCT significantly ameliorated GVHD. Critically, transplantation of Treg-expanded donor cells facilitated transplant tolerance without GVHD, with complete sparing of graft-versus-malignancy. This approach may prove valuable as a therapeutic strategy promoting transplantation tolerance.

Acute Intravenous Infusion of Immunoglobulins Protects Against Myocardial Ischemia-Reperfusion Injury Through Inhibition of Caspase-3.

BACKGROUND/AIMS: To investigate the cardioprotective effects of intravenous immunoglobulins (IVIG) in rats subjected to regional myocardial ischemia reperfusion (I/R). METHODS: Langendorff-perfused rat hearts were used in this study. Hearts subjected to regional ischemia served as a negative untreated control. The effects of IVIG pre- and post-ischemic treatment on left ventricular function, coronary vascular dynamics and contractility were assessed. IVIG were administered in either a low or high dose. The infarct size was determined using triphenyltetrazolium chloride and through biochemical assays using the measured creatine kinase and lactate dehydrogenase levels. Apoptosis was evaluated by the TUNEL assay, and the caspase-3 expression level was assessed by immunoblotting. The cytokine levels were measured by ELISA. RESULTS: Low and high doses of immunoglobulins administered 2 hours before sacrifice, before the ischemic insult or at reperfusion resulted in a significant improvement in cardiac hemodynamics, coronary vascular dynamics and heart contractility. A significant decrease in the infarct size and cardiac enzymes was also evident compared to those in the control. IVIG administered as an infusion at reperfusion or pre-treatment resulted in a marked decrease in myocyte apoptosis, which was associated with decreased levels of caspase-3 expression in the supernatants of homogenized left ventricles. Infusion of IVIG both pre-ischemia and at reperfusion did not show the same protective effects. CONCLUSIONS: This study demonstrates a novel protection to the heart by low and high doses of IVIG given either pre- or post-ischemia.

Broad neutralization of hepatitis C virus-resistant variants by Civacir hepatitis C immunoglobulin.

Hepatitis C virus (HCV)-induced end-stage liver disease is the major indication for liver transplantation (LT). However, reinfection of the liver graft is still common, especially in patients with detectable viral load at the time of LT. Limited data are available on direct-acting antivirals in the transplant setting for prevention of graft infection. The human hepatitis C immunoglobulin (HCIG) Civacir is an investigational drug that is currently being developed in an ongoing phase 3 clinical trial assessing its safety and efficacy at preventing HCV recurrence after liver transplantation (LT) in the United States. Using well-characterized patient-derived HCV variants selected during LT, we studied the molecular mechanism of action of Civacir. Inhibition of HCV infection was studied using infectious HCV models including HCV pseudoparticles (HCVpp) and cell culture-derived HCV (HCVcc) containing patient-derived viral envelope glycoproteins from 22 HCV variants isolated from patients before and after LT. The human hepatitis C immune globulin Civacir is an investigational drug that is currently being developed in an ongoing phase 3 clinical trial assessing safety and efficacy to prevent HCV recurrence after LT in the United States. Using well-characterized patient-derived HCV variants selected during LT, we studied the molecular mechanism of action of Civacir. Inhibition of HCV infection was studied using infectious HCV models including HCV pseudoparticles and cell culture-derived HCV containing patient-derived viral envelope glycoproteins from 22 HCV variants isolated from patients before and after liver transplantation. Additionally, we studied neutralization of different HCV genotypes and of direct-acting antiviral-resistant viruses. Our results indicate that Civacir potently, broadly, and dose-dependently neutralizes all tested patient variants in HCV pseudoparticles and cell culture-derived HCV assays including variants displaying resistance to host neutralizing antibodies and antiviral monoclonal antibodies. The half-maximal inhibitory concentrations were independent of the phenotype of the viral variant, indicating that virus neutralization by Civacir is not affected by viral selection. Furthermore, Civacir is equally active against tested direct-acting antiviral-resistant HCV isolates in cell culture. CONCLUSION: Collectively, these results demonstrate broad neutralizing activity of Civacir against resistant viruses, likely due to synergy between anti-HCV antibodies derived from different plasma donors, and support its further clinical development for prevention of liver graft infection. (Hepatology 2016;64:1495-1506).