Ageing enhances cellular immunity to myeloperoxidase and experimental anti-myeloperoxidase glomerulonephritis

Objectives Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disease characterised by small blood vessel inflammation, commonly affecting the kidneys and respiratory tract. It is unclear why the incidence of this condition increases with age. Previous studies in a passive antibody transfer system in aged mice have implicated innate effectors. To test the hypothesis that autoimmunity to myeloperoxidase, an autoantigen responsible for ANCA-associated vasculitis, increases with age, anti-myeloperoxidase autoimmunity was studied in murine models of active autoimmunity and disease induced by cellular immunity. Methods Young (8 weeks) and aged (either 15 or 22 month) mice were immunised with whole proteins or peptides from ovalbumin, as a model foreign antigen, or myeloperoxidase protein or peptides. Mice were subjected to a model of active anti-myeloperoxidase glomerulonephritis. Cellular and humoral immune responses and tissue inflammation were assessed. Results While cellular immunity to ovalbumin was diminished in aged mice, cellular autoimmunity to myeloperoxidase and its immunodominant CD4+ and CD8+ T cell epitopes was increased after immunization with either MPO peptides or whole MPO protein, assessed by peptide and antigen specific production of the pro-inflammatory cytokines interferon-γ and interleukin-17A. MPO-ANCA titres were not increased in aged mice compared with young mice. In experimental anti-MPO glomerulonephritis, cell mediated injury was increased, likely due to CD4+ and CD8+ T cells, innate immunity and the increased vulnerability of aged kidneys. Conclusion Heightened cellular immunity to MPO develops with ageing in mice and may contribute to the increased incidence and severity of ANCA-associated vasculitis in older people.

Therapeutic Management of Coronavirus Disease 2019 (COVID-19): A Systematic Review and Treatment Algorithm

Coronavirus disease 2019 (COVID-19) is emerging contagious pneumonia due to the new Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). It initially appeared in Wuhan China in December 2019 then rapidly spread worldwide and became a pandemic. For the time being, there is no specific therapeutic treatment for this disease. Herein, the "state-of-the-art" of treatment modalities was systematically reviewed and ultimately a practical therapeutic algorithm for the COVID-19 management was proposed. The systematic review was performed by using published articles retrieved from Science Direct, MEDLINE, and Scopus databases concerning this topic. Among 1060 articles collected from the different databases, 19 publications were studied in-depth and incorporated in this review. The most three frequently used medications for the treatment of COVID-19 was: the available anti-viral drugs (n= 9), the antimalarial hydroxychloroquine or chloroquine (n = 8), and the passive antibody transfer therapy (n = 2). Among all treatment modalities, antimalarial hydroxychloroquine ranked the highest cure rate. Therefore, this drug is considered as the first‐line of COVID-19 treatment. The second‐line treatment includes the lopinavir/ritonavir drugs combined with interferon β-1b and ribavirin. Finally, the third‐line treatments include the remdesivir drug and passive antibody transfer therapy. However, our review emphasis the urgent need for adequately designed randomized controlled trials, enabling a more significant comparison between the most used treatment modalities.

Sustained Delivery of a Broadly Neutralizing Antibody in Nonhuman Primates Confers Long-Term Protection against Simian/Human Immunodeficiency Virus Infection

ABSTRACTPathogen-specific neutralizing antibodies protect against many viral infections and can potentially prevent human immunodeficiency virus (HIV) transmission in humans. However, neutralizing antibodies have so far only been shown to protect nonhuman primates (NHP) against lentiviral infection when given shortly before challenge. Thus, the clinical utility and feasibility of passive antibody transfer to confer long-term protection against HIV-1 are still debated. Here, we investigate the potential of a broadly neutralizing HIV-1 antibody to provide long-term protection in a NHP model of HIV-1 infection. A human antibody was simianized to avoid immune rejection and used to sustain therapeutic levels for ∼5 months. Two months after the final antibody administration, animals were completely protected against viral challenge. These findings demonstrate the feasibility and potential of long-term passive antibody for protection against HIV-1 in humans and provide a model to test antibody therapies for other diseases in NHP.IMPORTANCEAntibodies against HIV are potential drugs that may be able to prevent HIV infection in humans. However, the long-term protective capacity of antibodies against HIV has not been assessed. Here, we repetitively administered a macaque version of a human anti-HIV antibody to monkeys, after which the antibody persisted in the blood for >5 months. Moreover, the antibody could be sustained at protective levels for 108 days, conferring protection 52 days after the last dose in a monkey model of HIV infection. Thus, passive antibody transfer can provide durable protection against infection by viruses that cause AIDS in primates.

Steroids Are Less Effective In Treating Thrombocytopenia Caused by Immune Responses Against Platelet GPIbα: A Comparative Study Using Passive and Active ITP Models.

Abstract 1433 Introduction: Immune thrombocytopenia (ITP) is a common autoimmune disorder in which autoantibodies are generated against a patient's platelets, leading to decreased platelet counts and bleeding diatheses. Autoantibodies in ITP mainly target platelet receptors GPIIbIIIa (αIIbβ3 integrin) and GPIbα. Current first-line therapy for ITP patients is steroids, while intravenous immunoglobulin (IVIG) is a common second-line therapy. However, not all patients are responsive and we lack useful exclusion criteria for steroid therapy. Appropriate identification of non-responsive patients would facilitate proper treatment and limit side effects. We previously showed anti-GPIbα (versus anti-GPIIbIIIa) mediated ITP is less responsive to IVIG (Blood. 2006;108(3):943-6). Our preliminary data from human patients also suggests that patients with anti-GPIbα antibodies are less responsive to steroids. However, these data need to be confirmed and mechanisms remain to be elucidated. Methods: To examine whether antibody specificity (GPIIbIIIa or GPIbα) correlates with responsiveness to steroids and determine the target immune cells for steroid action, we used two murine ITP models (passive antibody transfer model and active splenocyte transfer model (Blood. 2010;115:1247-53)). In both models, mice are treated with the corticosteroid Dexamethasone (DEX) and platelet counts are monitored. In the passive antibody transfer model: BALB/c or C57 mice were pretreated for 3 days with 0.1mg/kg, 1mg/kg, or 10 mg/kg of DEX prior to injection with our newly developed mouse-anti-mouse monoclonal antibodies (mAbs) targeting GPIIbIIIa or GPIbα. A second group of mice were treated with DEX 1 day following mAb injection (i.e. after becoming thrombocytopenic) and daily thereafter. In both groups, platelet counts were monitored for 4 consecutive days post mAb injection. In the active splenocyte transfer model: β3-/- and GPIbα-/- mice were immunized with wild-type (WT) platelets resulting in an antibody titer of >1:12,800. Purified splenocytes from immunized mice were transferred into syngeneic WT or SCID recipients, such that they developed ITP. Recipient mice were treated with 1mg/kg or 10 mg/kg of DEX starting 1 day after splenocyte transfer, and daily thereafter. Platelet counts were monitored. Results and Discussion: In the passive ITP model, irrespective of DEX dose, route of administration (i.p. or s.c.) or mouse strain, pretreatment with DEX was unable to ameliorate ITP induced by either anti-GPIIbIIIa or anti-GPIbα mAbs. In addition to pretreating with DEX, administration of DEX following ITP induction also appeared to be unable to ameliorate ITP induced by either anti-GPIIbIIIa or anti-GPIbα mAbs. Similar results were obtained in the passive model when using the corticosteroid Prednisolone in a different experimental setting. In the active splenocyte transfer model, we found that varying doses of DEX ameliorated ITP in mice engrafted with anti-GPIIbIIIa reactive splenocytes while untreated mice remained thrombocytopenic. Importantly, DEX failed to show a significant effect on ITP amelioration in mice engrafted with anti-GPIbα reactive splenocytes. Since the passive model involves exogenous administration of mAb, the effect of steroid treatment is largely limited to effects on the reticuloendothelial system (RES) and destruction of opsonized platelets. Conversely, the splenocyte transfer model allows for steroid effects on active immune responses (i.e. it may affect dendritic cells, T cells, B cells, etc.) in addition to the RES. As DEX was efficacious in only the splenocyte transfer model, this suggests steroids primarily affect upstream of the immune responses in ITP. Ongoing experiments involving depletion of CD4+, CD8+, or CD19+ splenocytes will help elucidate specific immune cells as targets of DEX. Conclusions: Our data clearly demonstrated that DEX ameliorated anti-GPIIbIIIa mediated ITP but was not significantly effective for amelioration of anti-GPIbα mediated ITP in the active splenocyte transfer model. We also demonstrated that steroid therapy failed in our passive ITP model. This finding is consistent with our preliminary data in human patients (patients with anti-GPIbα antibodies may be refractory to both IVIG and steroids). This may explain the clinical variability seen in response to steroids and lead to new diagnostic/therapeutic approaches. Disclosures: No relevant conflicts of interest to declare.

Sepsis, Failure of Passive Transfer, and Fluid Therapy in Calves.

VM-173, a 5-page fact sheet by Amanda M. House, Max Irsik, and Jan K. Shearer, describes septicemia and neonatal infection in calves, how to ensure adequate passive antibody transfer as a preventative health measure, and how to manage fluid therapy for dehydrated calves. Includes references. Published by the UF School of Veterinary Medicine, August 2008.

Porphyromonas gingivalis-Specific Immunoglobulin G Prevents P. gingivalis-Elicited Oral Bone Loss in a Murine Model

ABSTRACT Active immunization with Porphyromonas gingivalis whole-cell preparations has been shown to prevent P. gingivalis infection and oral bone loss. Employing passive antibody transfer and opsonization, we demonstrate with this study that immunization-elicited P. gingivalis-specific immunoglobulin G facilitates clearance of P. gingivalis in a subcutaneous chamber model and prevents P. gingivalis-elicited oral bone loss.