GDNF fusion protein dosing induced response lesions in the liver and the skin, associated with anaphylactic responses.

<p>(A to C) Microphotographs of the liver (A) and the skin (B and C) of a monkey (rh2134) treated with 5 mg/kg HIRmAb-GDNF (H&E staining). Scale bar: 100 µm (A and B); 50 µm (C). (A) Liver shows mild multifocal lymphocytic hepatitis with necrosis of individual hepatocytes. (B) Dermis shows subdermal hemorrhage (a) saponification of tissue adipocytes, and mild lymphocytic dermatitis. (b). (C) Dermis shows mild lymphocytic perivascular and periadnexal dermatitis.</p

GDNF fusion protein dosing was associated with myocarditis.

<p>(A to D) Microphotographs of the heart of monkeys treated with vehicle (A and C) or 5 mg/kg HIRmAb-GDNF (B and D) (H&E staining). The HIRmAb-GDNF-treated animal [rh2134 (B)] shows a moderate multifocal degeneration with interstitial fibrosis (*) and individual myocardiocyte hypertrophy (arrow). Higher-magnification images in (C) and (D) correspond to boxed areas in (A) and (B). Note the presence of lymphocytes, plasma cells, and rare eosinophils in (D). Scale bar: 100 µm (A and B); 25 µm (C and D).</p

GDNF was not intracerebrally detected by immunohistochemistry or ELISA methods.

<p>(A to C) Coronal images of GDNF immunostained striatal sections of vehicle (A), 1 mg/kg (B), and 5 mg/kg (C) HIRmAb-GDNF treatments. *Inset in (A) corresponds to a positive control tissue stained in parallel from a monkey that received intracerebral injections of human neuroprogenitor cells expressing GDNF. Scale bar: 1 mm. (D and E) ELISA determination of GDNF levels in the brain (D) and in the pancreas (E).</p

Tyrosine Hydroxylase (TH) expression is not affected by HIRmAb-GDNF.

<p>(A to F) Coronal images of the TH immunostained striatum at the level of the anterior commissure (A, C, and E) and of the substantia nigra at the level of the red nucleus (B, D, and F) of monkeys treated with vehicle (A and B), 1 mg/kg (C and D), or 5 mg/kg (E and F) HIRmAb-GDNF. Scale bar: 2.5 mm (A, C, and E); 1 mm (B, D, and F); 110 µm (insets b, d, and f). (G) Average TH optical density (OD) in the caudate and putamen nucleus. (H) Stereological cell counts of TH-positive neuron cells in the substantia nigra (SN).</p

Number of animals used per treatment group in the efficacy and safety experiments.

<p>Number of animals used per treatment group in the efficacy and safety experiments.</p

GDNF fusion protein dosing was associated with pancreatic lesions in low dose treatment groups.

<p>(A and B) Microphotographs of H&E-stained pancreas from monkeys treated with vehicle [r02048 (A) normal pancreas] or 1 mg/kg HIRmAb-GDNF [r99022 (B) pancreas with ADM]. Scale bar: 125 µm. (C normal pancreas and D pancreas with ADM) Higher-magnification views correspond to the boxed areas in (A) and (B). Scale bar: 25 µm. In the HIRmAb-GDNF-treated animal (B), note the extensive acinar to ductular metaplasia (green outline) surrounding large pancreatic ducts (*) and extending irregularly into the exocrine parenchyma; the corresponding higher-magnification image (D) shows the junction between normal pancreas (right) and acinar to ductular metaplasia (left), with a lobule of acinar cells replaced by cells with ductal differentiation (a) surrounded by fibrous stroma (b) and an exocrine acinus with both acinar and ductal cell morphology (arrow).</p

HIRmAb-GDNF treatment did not affect food consumption, feces output, or body weight.

<p>(A) Ratio of food consumption overtime (average per week after treatment/average at baseline) (B) Frequency of abnormal feces. (C) Body weight over time.</p

VMAT2 expression is not affected by HIRmAb-GDNF treatment.

<p>(A to F) Coronal images of the striatum at the level of the anterior commissure (A, C, and E) and of the substantia nigra at the level of the red nucleus (B, D, and F) stained with the dopaminergic marker VMAT2 of monkeys treated with vehicle (A and B), 1 mg/kg (C and D), or 5 mg/kg (E and F) HIRmAb-GDNF. Scale bar: 2.5 mm (A, C, and E); 1 mm (B, D, and F); 110 µm (insets b, d, and f). (G) VMAT2 optical density (OD) in the caudate and putamen nucleus. (H) Stereological cell counts of VMAT2-positive neuron cells in the substantia nigra.</p

HIRmAb-GDNF does not induce improve parkinsonian signs and is associated with type I hypersensitivity reaction.

<p>(A) Clinical rating score. (B) Fine motor skills task. (C) Hypersensitivity response over time, by treatment group. (D) Optical density (OD) of HIRmAb-GDNF antibody levels in serum.</p

Pegivirus avoids immune recognition but does not attenuate acute-phase disease in a macaque model of HIV infection

<div><p>Human pegivirus (HPgV) protects HIV+ people from HIV-associated disease, but the mechanism of this protective effect remains poorly understood. We sequentially infected cynomolgus macaques with simian pegivirus (SPgV) and simian immunodeficiency virus (SIV) to model HIV+HPgV co-infection. SPgV had no effect on acute-phase SIV pathogenesis–as measured by SIV viral load, CD4+ T cell destruction, immune activation, or adaptive immune responses–suggesting that HPgV’s protective effect is exerted primarily during the chronic phase of HIV infection. We also examined the immune response to SPgV in unprecedented detail, and found that this virus elicits virtually no activation of the immune system despite persistently high titers in the blood over long periods of time. Overall, this study expands our understanding of the pegiviruses–an understudied group of viruses with a high prevalence in the global human population–and suggests that the protective effect observed in HIV+HPgV co-infected people occurs primarily during the chronic phase of HIV infection.</p></div