Background 
Chronic obstructive pulmonary disease is a progressive lung disease that is punctuated by periods of exacerbations (worsening of symptoms) that are attributable to viral infections. While rhinoviruses are most commonly isolated viruses during episodes of exacerbation, influenza viruses have the potential to become even more problematic with the increased likelihood of an epidemic.


Methodology and Principal Findings 
This study examined the impact of current and potential pharmacological targets namely the systemic corticosteroid dexamethasone and the peroxisome proliferator-activated receptor- gamma agonist pioglitazone on the outcome of infection in smoke-exposed mice. C57BL/6 mice were exposed to room air or cigarette smoke for 4 days and subsequently inoculated with an H1N1 influenza A virus. Interventions were delivered daily during the course of infection. We show that smoke-exposed mice have an exacerbated inflammatory response following infection. While smoke exposure did not compromise viral clearance, precision cut lung slices from smoke-exposed mice showed greater expression of CC (MCP-1, -3), and CXC (KC, MIP-2, GCP-2) chemokines compared to controls when stimulated with a viral mimic or influenza A virus. While dexamethasone treatment partially attenuated the inflammatory response in the broncho-alveolar lavage of smoke-exposed, virally-infected animals, viral-induced neutrophilia was steroid insensitive. In contrast to controls, dexamethasone-treated smoke-exposed influenza-infected mice had a worsened health status. Pioglitazone treatment of virally-infected smoke-exposed mice proved more efficacious than the steroid intervention. Further mechanistic evaluation revealed that a deficiency in CCR2 did not improve the inflammatory outcome in smoke-exposed, virally-infected animals.


Conclusions and Significance 
This animal model of cigarette smoke and H1N1 influenza infection demonstrates that smoke-exposed animals are differentially primed to respond to viral insult. While providing a platform to test pharmacological interventions, this model demonstrates that treating viral exacerbations with alternative anti-inflammatory drugs, such as PPAR-gamma agonists should be further explored since they showed greater efficacy than systemic corticosteroids.

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Treating viral exacerbations of chronic obstructive pulmonary disease: insights from a mouse model of cigarette smoke and H1N1 influenza infection.

https://air.unimi.it/bitstream/2434/60487/1/carbonatto200.pdf

Nonclinical safety, pharmacokinetics, and pharmacodynamics of atacicept.

Background: Recent data suggest a key role for B cells in the pathogenesis of many autoimmune diseases including rheumatoid arthritis (RA), and biological therapies targeting B cells are promising treatments for patients with RA. Atacicept inhibits B cell maturation, differentiation and survival, and immunoglobulin production by depriving B cells of growth and development signals. Therefore, atacicept may represent an effective strategy in RA treatment. Objective: To evaluate the potential value of atacicept in RA treatment based on preclinical and clinical studies. Methods: Preclinical and clinical data on atacicept were identified using PubMed and systematically reviewed. Results/conclusion: Preclinical and clinical studies show that atacicept is well tolerated, with no increased incidence of infections. Atacicept displays non-linear pharmacokinetics, with a more than dose-proportional increase in free drug and less than dose-proportional, saturated increase in atacicept–ligand complex. Overall, the pha...

/pdf/atacicept-a-novel-b-cell-targeting-biological-therapy-for-1tq8czrpwf.pdf

Atacicept, a novel B cell-targeting biological therapy for the treatment of rheumatoid arthritis.

The purpose of immunotoxicity testing is to obtain data that is meaningful for safety assessment. Host resistance assays are the best measure of a toxicant's effect on the overall ability to mount an effective immune response and protect the host from infectious disease. An outline is presented for immunotoxicological evaluation using host resistance assays. The influenza virus host resistance model is useful to evaluate the overall health of the immune system and is one of the most thoroughly characterized host resistance models. Viral clearance requires all aspects of the immune system to work together and is the ultimate measure of the health of the immune system in this model. Mechanistic immune functions may be included while measuring viral clearance and include: cytokines, macrophage activity, natural killer (NK) cell activity, cytotoxic T-lymphocyte (CTL) activity, and influenza-specific IgM and IgG. Measurement of these immunological functions provides an evaluation of innate immunity (macrophage or NK activity), an evaluation of cell-mediated immunity (CMI) (CTL activity), and an evaluation of humoral-mediated immunity (HMI) (influenza-specific IgM or IgG). Measurement of influenza-specific IgM or IgG also provides a measurement of T-dependent antibody response (TDAR) since influenza is a T-dependent antigen. There are several targeted host resistance models that may be used to answer specific questions. Should a defect in neutrophil and/or macrophage function be suspected, Streptococcus pneumoniae, Pseudomonas aeruginosa, or Listeria monocytogenes host resistance models are useful. Anti-inflammatory pharmaceuticals or therapeutics for rheumatoid arthritis or Crohn's disease that target TNFalpha may also be evaluated for immunotoxicity using the S. pneumoniae intranasal host resistance assay. Marginal zone B (MZB) cells are required for production of antibody to T-independent antigens such as the polysaccharide capsule of the encapsulated bacteria that are so prominent in causing blood-borne infections and pneumonia. Intravenous infection with Streptococcus pneumoniae, an encapsulated bacterium, results in a blood-borne infection that requires MZB cells for clearance. The systemic S. pneumoniae host resistance assay evaluates whether a therapeutic test article exerts immunotoxicity on MZB cells and measures the T-independent antibody response (TIAR). Suppression of CMI or in some cases HMI may result in reactivation of latent virus that may result in a fatal disease such as progressive multifocal leukoencephalopathy (PML). The murine cytomegalovirus (MCMV) reactivation model may be used to evaluate a pharmaceutical agent to determine if suppression of CMI or HMI results in reactivation of latent virus. Candida albicans is another host resistance model to test potential immunotoxicity. Host resistance assays have been the ultimate measure of immunotoxicity testing for environmental chemicals and pharmaceutical small molecules. Human biologicals are now an important component of the drug development armamentarium for biotech and pharmaceutical companies. Many human biologicals are fusions of IgG, and/or target immune mediators, immunological receptors, adhesion molecules, and/or are indicated for diseases that have immune components. It is therefore necessary to thoroughly evaluate human biological therapeutics for immunotoxicity. Numerous biologicals that are pharmacologically active in rodents can be evaluated using well-characterized rodent host resistance assays. However, biologicals not active in rodents may use surrogate biologicals for testing in rodent host resistance assays, or may use host resistance assays in genetically engineered mice that mimic the effect of the human biological pharmacological agent.

https://www.tandfonline.com/doi/pdf/10.1080/15476910801897557

Testing human biologicals in animal host resistance models.

Therapeutic effects of TACI-Ig on collagen-induced arthritis by regulating T and B lymphocytes function in DBA/1 mice

TACI-Ig is a soluble glycoprotein comprised of a human IgG1-Fc fused with the extracellular domain of the human TACI receptor. Chronic exposure to TACI-Ig is associated with reduced circulating B cells in mouse and non-human primates, and a concomitant decrease in circulating immunoglobulin. Because of these activities, TACI-Ig is in clinical evaluation for treatment of various autoimmune diseases and B cell malignancies. In this study, the effect of TACI-Ig treatment on the ability of C57Bl/6 mice to clear influenza virus was evaluated. C57Bl/6 mice were exposed to vehicle (negative control), dexamethasone (positive control), or TACI-Ig (0.05, 0.50, or 5.0 mg/kg, SC, thrice weekly) from within one week prior to viral exposure through 21 days thereafter. Dexamethasone treatment of influenza-infected mice prolonged the infection, and decreased survival, body weight, lymphoid organ weight, influenza-specific IgM and IgG, and viral clearance relative to control animals, consistent with its expected immunosuppressive activity. Animals treated with TACI-Ig (0.05, 0.50, and 5.0 mg/kg) demonstrated a dose-dependent decrease in spleen weight and influenza-specific IgG and IgM in both lung and serum relative to control animals. In addition, flow cytometric analyses showed a decrease in B cells, but not T cells, in peripheral blood in animals treated with TACI-Ig. However, neither viral clearance nor survival was affected by TACI-Ig treatment. These data demonstrate the expected B cell-specific pharmacological effects of TACI-Ig in influenza-challenged C57Bl/6 mice without apparent effect on influenza virus clearance. It is concluded that non-B cell related antiviral competence remains intact during TACI-Ig treatment.

F Burleson

Papers

Influenza Virus Host Response of C57Bl/6 Mice Treated with TACI-Ig