Investigational new drug enabling angiotensin oral-delivery studies to attenuate pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a deadly and uncurable disease characterized by remodeling of the pulmonary vasculature and increased pulmonary artery pressure. Angiotensin Converting Enzyme 2 (ACE2) and its product, angiotensin-(1-7) [ANG-(1-7)] were expressed in lettuce chloroplasts to facilitate affordable oral drug delivery. Lyophilized lettuce cells were stable up to 28 months at ambient temperature with proper folding, assembly of CTB-ACE2/ANG-(1-7) and functionality.

Phosphodiesterase 4 Inhibitors Attenuate the Asthma Phenotype Produced by β2-Adrenoceptor Agonists in Phenylethanolamine N-Methyltransferase-Knockout Mice.

Mice lacking the endogenous β2-adrenoceptor (β2AR) agonist epinephrine (phenylethanolamine N-methyltransferase [PNMT]-knockout mice) are resistant to developing an "asthma-like" phenotype in an ovalbumin sensitization and challenge (Ova S/C) model, and chronic administration of β2AR agonists to PNMT-KO mice restores the phenotype. Based on these and other studies showing differential effects of various β2AR ligands on the asthma phenotype, we have speculated that the permissive effect of endogenous epinephrine and exogenous β2AR agonists on allergic lung inflammation can be explained by qualitative β2AR signaling. The β2AR can signal through at least two pathways: the canonical Gαs-cAMP pathway and a β-arrestin-dependent pathway.

Oral tolerization with cardiac myosin peptide (614-629) ameliorates experimental autoimmune myocarditis: role of STAT 6 genes in BALB/CJ mice.

Introduction: Experimental autoimmune myocarditis (EAM) is mediated by myocardial infiltration by myosin-specific T cells secreting inflammatory cytokines.

Materials And Methods: To clarify the role of cytokines in EAM, we compared STAT 6-deficient ((-/-)) with STAT 4(-/-) and wild-type (BALB/CJ) mice following immunization with cardiac myosin peptide (614-629).

Results: Wild-type mice developed severe disease with a small increase in severity in STAT 6(-/-) mice, while STAT 4(-/-) mice were resistant to EAM.

Inhibition of experimental autoimmune myocarditis: peripheral deletion of TcR Vbeta 8.1, 8.2+ CD4+ T cells in TLR-4 deficient mice.

Toll-like receptors (TLR) are pattern recognition receptors that are an essential feature of host defense against pathogens. Expression of TLR-4 on dendritic cells was reported to be required for initiation of experimental autoimmune myocarditis (EAM) but the mechanism by which TLR-4 signaling affects autoimmunity is incompletely understood. To determine the role of TLR-4 in EAM, wild type and TLR-4-/- mice were immunized with myosin peptide (614-629) in CFA.

Induction of oral tolerization in CD86 deficient mice: a role for CD86 and B cells in the up-regulation of TGF-beta.

Feeding myelin oligodendrocyte glycoprotein (MOG) followed by immunization results in induction of oral tolerance evidenced by the amelioration of experimental autoimmune encephalomyelitis (EAE). Oral tolerization is characterized by the suppression of Th1 responses and up-regulation of Th2 responses and TGF-beta. To identify the costimulatory molecules and cell types involved in cytokine-mediated suppression we examined wild type mice and mice deficient for either CD86 (CD86-/-) or B cells (muMT).

Induction of low dose oral tolerance in IL-10 deficient mice with experimental autoimmune encephalomyelitis.

IL-10 has been shown to be an important anti-inflammatory mediator that has both down-regulatory and immunomodulatory effects. Utilizing IL-10(-/-) mice we demonstrate the induction of low dose oral tolerance characterized by the up-regulation of TGF-beta and IL-4 and the suppression of Ag specific proliferation with little suppression of INF-gamma. More severe EAE was found in IL-10(-/-) mice than in wild type controls, however, feeding resulted in amelioration of disease severity in both groups.

Induction of low dose oral tolerance in monocyte chemoattractant protein-1- and CCR2-deficient mice.

The chemokine monocyte chemoattractant protein-1 (MCP-1) and its receptor CCR2 have been shown to play an important role in the migration and trafficking of macrophages and Th1 effector cells in experimental autoimmune encephalomyelitis. Also, MCP-1 has been reported to regulate oral tolerance induction by inhibition of Th1 cell-related cytokines and by the ability of Abs to MCP-1 to inhibit oral tolerance. This study demonstrates that neither MCP-1 nor its receptor CCR2 is required for the induction of oral tolerance.