Over the past decades, there has been significant progress in understanding the mechanisms of autoimmune diseases at a molecular level. Diseases such as juvenile diabetes, multiple sclerosis, celiac disease, rheumatoid arthritis, and others appear to be mediated by pathogenic T cells that recognize self-epitopes and escape natural tolerance. Seminal observations correlating autoimmunity with HLA and disease-associated epitopes, in conjunction with recent characterization of T regulatory (Treg) cells, promoted a renewed interest in antigen or epitope-based methods of interfering with pathogenic autoimmune reactions. Recombinant immunoglobulin-peptides encompassing disease-associated self-epitopes (IgPP) integrate effective targeting of antigen-presenting cells (APCs) with a potential to generate Treg cells and thus are being developed for treatment of selected autoimmune disorders. In the current review, we outline the main features of this new class of active immunotherapeutics and directions of future development.

Parenteral administration of immunoglobulins (Ig) for prevention or treatment of respiratory diseases achieves only modest concentrations of antibody in the pulmonary interstitial tissue and airways. Aerosols, including spray-dried particles, must overcome two limiting factors in order to be effective vehicles for pulmonary delivery of Ig: (i) Fc receptor (FcR)-mediated scavenging by macrophages and (ii) clearance by the mucociliary system. Ig-incorporated spray-dried lipid microparticles (SDLM), coformulated with or without a biocompatible surfactant (1% w:w) to modulate protein release, were designed and tested for their capability to deliver Ig to the respiratory tract. To determine efficacy, rodents were immunized with SDLM containing antiinfluenza antibody followed by virus challenge and clinical parameters measured. Control of the release kinetics resulted in enhanced delivery of immunoglobulins to the respiratory tract and interstitial tissue with slow translocation into the systemic circulation. As much as 60% of the IgG delivered from nonretentive SDLM could be recovered from the lung interstitial tissue within 1 h after aerosol administration at a dose of 1 mg of Ig/kg of body weight. In addition, nonretentive rather than slow-release particles loaded with antiinfluenza antibody were effective in curbing virus replication with a resulting positive clinical outcome. Thus, controlled release of Ig by manipulating aerosol characteristics and composition allows for a significant increase in the efficiency of pulmonary delivery of antibodies.

Influenza viruses are among the most significant human pathogens, responsible for increased seasonal morbidity and mortality particularly in immunodepressed and chronically ill. Conventional vaccination with non-replicative vaccine is currently performed by injection. In the present study, we explore simple spray-dried lipid formulations containing whole inactivated virus or split-subunit vaccine that allow aerosolization and thus, mucosal vaccination of the pulmonary tract. We show that by using biocompatible excipients already approved for human use, one could engineer microparticles that induce substantial local and systemic immunity subsequent to pulmonary administration. Exposure of the bronchial-associated lymphoid tissue (BALT) to vaccine was more effective than parenteral or nasal administration in triggering specific immunity. Co-formulation of a biocompatible surfactant detergent greatly ameliorated the immune profile of microparticles containing a whole inactivated virus vaccine. In addition, mere formulation of a licensed split-subunit vaccine significantly enhanced its immunogenicity. Together, our data underline a simple strategy to convert conventional parenteral vaccination of currently available non-replicative vaccines against influenza virus, into one that is more effective and practical upon respiratory administration.

The adaptive immune response is triggered by recognition of T and B cell epitopes and is influenced by "danger" motifs that act via innate immune receptors. This study shows that motifs associated with noncoding RNA are essential features in the immune response reminiscent of viral infection, mediating rapid induction of proinflammatory chemokine expression, recruitment and activation of antigen-presenting cells, modulation of regulatory cytokines, subsequent differentiation of Th1 cells, isotype switching, and stimulation of cross-priming. The heterogeneity of RNA-associated motifs results in differential binding to cellular receptors, and specifically impacts the immune profile. Naturally occurring double-stranded RNA (dsRNA) triggered activation of dendritic cells and enhancement of specific immunity, similar to selected synthetic dsRNA motifs. Based on the ability of specific RNA motifs to block tolerance induction and effectively organize the immune defense during viral infection, we conclude that such RNA species are potent danger motifs. We also demonstrate the feasibility of using selected RNA motifs as adjuvants in the context of novel aerosol carriers for optimizing the immune response to subunit vaccines. In conclusion, RNA-associated motifs produced during viral infection bridge the early response with the late adaptive phase, regulating the activation and differentiation of antigen-specific B and T cells, in addition to a short-term impact on innate immunity.

Purpose. To assess the pharmacokinetics and biodistribution of gentamicin, delivered as PulmoSpheres® formulations in rabbit serum and lung tissue following intratracheal instillation in a perflubron vehicle.

Purpose. Spray-dried lipid-based microparticles (SDLM) serve as a platform for delivery of a wide variety of compounds including peptides, proteins, and vaccines to the respiratory mucosa. In the present study, we assessed the impact of IgG-mediated targeting to phagocytic cells of inactivated influenza virus formulated in SDLM, on subsequent immune responses.

Purpose. To assess the physical stability and aerosol characteristicsof suspensions of hollow porous microspheres (PulmoSpheres™) inHFA-134a.

Purpose. Delivery of specific antibodies or immunoglobulin constructsto the respiratory tract may be useful for prophylaxis or active treatmentof local or systemic disorders. Therefore, we evaluated the utilityof lipid-based hollow-porous microparticles (PulmoSpheres™) as apotential delivery vehicle for immunoglobulins.

alkane propellants have now been approved: HFA-134a Luis A. Dellamary,1 Thomas E. Tarara,1 (1,1,1,2-tetrafluoroethane), and HFA-227 (1,1,1,2,3,3,3 hepDan J. Smith,1 Christopher H. Woelk,1 tafluoropropane). Unfortunately, the transition to the new more Anastasios Adractas,1 Michael L. Costello,2 environmentally acceptable HFA propellants has been difficult, Howard Gill,1 and Jeffry G. Weers1,3 due in large part to the poor solvency of the HFA, which limits