Histopathological Findings in Cynomolgus Macaques (Macaca fascicularis) Consistent with Secondary Immunological Reaction to Biotherapeutics with an Emphasis on the CNS and Eye

Biotherapeutics are pharmaceutical products derived from or synthesized by biological systems. Such molecules carry the potential for immunogenicity which may lead to adverse immune responses. The cynomolgus macaque ( Macaca fascicularis) is the species of choice in nonclinical safety assessment of biotherapeutics. The main aim of this study was to confirm whether mononuclear cell infiltrates at specific locations represent a generic effect of biotherapeutics, and therefore the result of their immunogenicity. Following a review of microscopic findings in studies conducted over a 10-year period at one test facility, 15% of biotherapeutics were reported to have such findings. The most commonly affected site was the choroid plexus and less frequently the meninges and ciliary body. The reporting of such findings as test article–related becomes more subjective as the severity and incidence decreases. To assess the accuracy of such associations, a mathematical approach was employed to determine the probability of obtaining the observed results by chance. There was good agreement between this approach and the original findings. In addition to an increased number and size of mononuclear cell infiltrates in the brain, biotherapeutic administration was strongly associated with the presence of plasma cells and eosinophils.

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Comparative Histological Subtyping of Immune Cell Infiltrates in MPO-ANCA and PR3-ANCA Glomerulonephritis

Frontiers in Immunology ◽

10.3389/fimmu.2021.737708 ◽

2021 ◽

Vol 12 ◽

Author(s):

Samy Hakroush ◽

Désirée Tampe ◽

Philipp Ströbel ◽

Peter Korsten ◽

Björn Tampe

Keyword(s):

Mononuclear Cell ◽

Plasma Cells ◽

Immune Cell ◽

Interstitial Fibrosis ◽

Kidney Injury ◽

Tubular Atrophy ◽

Interstitial Inflammation ◽

Tubulointerstitial Lesions ◽

Mononuclear Cell Infiltrates ◽

Immune Cell Infiltrates

BackgroundAcute kidney injury (AKI) is a common and severe complication of anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), potentially leading to chronic kidney disease (CKD), end-stage renal disease (ESRD), or death. Pathogenic ANCAs, in particular proteinase 3 (PR3) and myeloperoxidase (MPO), trigger a deleterious immune response with intrarenal immune cell infiltration resulting in a pauci-immune necrotizing and crescentic glomerulonephritis (GN). However, a systematic analysis of intrarenal immune cell subtypes concerning neutrophils, eosinophils, plasma cells, and mononuclear cell infiltrates (macrophages, lymphocytes) in ANCA GN remains elusive. Therefore, we aimed to compare distinct immune cell infiltrates in association with clinicopathological findings in ANCA GN.MethodsA total of 53 kidney biopsies with ANCA GN at the University Medical Center Göttingen were retrospectively analyzed. Histological infiltrates of neutrophils, eosinophils, plasma cells, and mononucleated cells (macrophages, lymphocytes) were quantified as a fraction of the total area of inflammation.ResultsNeutrophilic infiltrates were associated with glomerular necrosis and severe kidney injury in ANCA GN. Among tubulointerstitial lesions, intrarenal neutrophils correlated with interstitial inflammation, tubulitis, and inflammation in areas of interstitial fibrosis/tubular atrophy (IFTA), representing active inflammatory lesions. Concerning eosinophils, infiltrates were associated with severe kidney injury, interstitial inflammation, and cellular casts independent of glomerular lesions, implicating a distinct role in inflammation and damage in ANCA GN. Plasma cell infiltrates correlated with tubulitis and interstitial fibrosis and were associated with renal replacement therapy during the short-term disease course. Finally, mononuclear cell infiltrates correlated with severe kidney injury and active histopathological lesions (glomerular crescents, interstitial inflammation, tubulitis, inflammation, and tubulitis in areas of IFTA) besides chronic lesions (interstitial fibrosis and tubular atrophy) in ANCA GN. Interestingly, intrarenal subtypes of immune cell infiltrates differed in MPO-ANCA versus PR3-ANCA GN and were associated with distinct glomerular and tubulointerstitial lesions, implicating different pathogenic mechanisms of kidney injury in ANCA subtypes.ConclusionOur observations imply distinct pathomechanisms contributing to inflammation and renal injury in MPO vs. PR3-associated ANCA GN and potentially contribute to new therapeutic targets in specific ANCA subtypes.

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Spontaneous Frenkelia Infection in a Laboratory-Reared Rat

Veterinary Pathology ◽

10.1177/030098587601300503 ◽

1976 ◽

Vol 13 (5) ◽

pp. 337-342 ◽

Cited By ~ 10

Author(s):

D. W. Hayden ◽

N. W. King ◽

A. S. K. Murthy

Keyword(s):

Spinal Cord ◽

Mononuclear Cell ◽

Cervical Spinal Cord ◽

Wild Rodents ◽

Electron Microscopic ◽

Microscopic Features ◽

Thin Walled ◽

Mononuclear Cell Infiltrates ◽

The Brain

Numerous, lobulated, thin-walled protozoan cysts were found in the brain and cervical spinal cord of a male Fischer rat with granulomatous encephalitis. The cysts were compartmented, 470–1000 μm in diameter, and packed with crescent-shaped organisms. Light- and electron-microscopic features of the organism were characteristic of the protozoan Frenkelia, a parasite usually found in the brain of wild rodents. Many cysts were replaced by granulomas, whereas others elicited no inflammation. Perivascular and meningeal mononuclear cell infiltrates and gliosis were common.

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Presence of antibody in virus-infected brain cells of SSPE ferrets

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100077591 ◽

1983 ◽

Vol 41 ◽

pp. 804-805

Author(s):

Hannah R. Brown ◽

Tammy L. Donato ◽

Halldor Thormar

Keyword(s):

Measles Virus ◽

Plasma Cells ◽

Subacute Sclerosing Panencephalitis ◽

Protein A ◽

Neutralizing Antibody ◽

Brain Cells ◽

Antibody Titers ◽

A Cell ◽

The Central Nervous System ◽

The Brain

Measles virus specific immunoglobulin G (IgG) has been found in the brains of patients with subacute sclerosing panencephalitis (SSPE), a slowly progressing disease of the central nervous system (CNS) in children. IgG/albumin ratios indicate that the antibodies are synthesized within the CNS. Using the ferret as an animal model to study the disease, we have been attempting to localize the Ig's in the brains of animals inoculated with a cell associated strain of SSPE. In an earlier report, preliminary results using Protein A conjugated to horseradish peroxidase (PrAPx) (Dynatech Diagnostics Inc., South Windham, ME.) to detect antibodies revealed the presence of immunoglobulin mainly in antibody-producing plasma cells in inflammatory lesions and not in infected brain cells.In the present experiment we studied the brain of an SSPE ferret with neutralizing antibody titers of 1:1024 in serum and 1:512 in CSF at time of sacrifice 7 months after i.c. inoculation with SSPE measles virus-infected cells. The animal was perfused with saline and portions of the brain and spinal cord were immersed in periodate-lysine-paraformaldehyde (P-L-P) fixative. The ferret was not perfused with fixative because parts of the brain were used for virus isolation.

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