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

Abstract

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.

Mucosa-Associated Lymphoid Tissue and Tertiary Lymphoid Structures of the Eye and Ear in Laboratory Animals

“…Lymphoid aggregates are also an infrequent, but possible finding in the nonmucosal sites of the healthy eye including ciliary body, limbus, and choroid. 49,56,96,97,99,119 It is recommended that these aggregates be called infiltrates. 95 However, these noninflammatory lymphoid aggregates appear to be at preferred sites of formation in healthy eyes, and these foci should be investigated for a possible relationship to the normal immunosurveillance system of the eye.…”

“…Immune privilege does not exclude surveillance by immune cells transiently crossing the retina or passing through the intraocular compartments to the uveal drainage system. Discrete mononuclear cell aggregates recorded as mononuclear cell infiltrates or inflammation 95 in healthy animals have been reported in the choroid of rabbits 49 and monkeys, 49,56,96 in the ciliary body in cynomolgus monkeys, 60,97 in the limbus of normal cynomolgus monkeys 56,98 and New Zealand White rabbits ( Figure 2E), and in ciliary body, iris, choroid, and limbus of human eyes. 99,100 These lymphocytic aggregates are generally not expected in a normal eye, but a possible relationship of these cell aggregates to the development of CALT or general intraocular and periocular immunosurveillance needs to be investigated.…”

“…99,100 These lymphocytic aggregates are generally not expected in a normal eye, but a possible relationship of these cell aggregates to the development of CALT or general intraocular and periocular immunosurveillance needs to be investigated. Inflammatory cell aggregates have been reported in the ciliary body of monkeys treated with biologics, 97 at injection sites for intravitreal therapeutics, 101,102 and in experimental and spontaneous autoimmune uveitis. [103][104][105] In the limbus of rats after corneal allograft transplantation, CALT and infiltrates of mixed leukocytes extending to the limbus were suggested as a point of entry for leukocytes trafficking into the conjunctiva.…”

A Review of Specific Biomarkers of Chronic Renal Injury and Their Potential Application in Nonclinical Safety Assessment Studies

“…While by far the most common glomerular toxicity encountered by nonclinical toxicologic pathologists is related to immune complex disease associated with the administration of humanized antibodies and peptides to nonhuman primates, this is not a situation that lends itself to the use of chronic renal biomarkers. [465][466][467] The rapidly progressive glomerulonephritis (RPGN) produced by anti-drug antibody-related immune complexes is too fulminant to require chronic dosing to observe a signal, and these preclinical immune reactions are not predictive in humans. 465 Also, most cases of immune-mediated glomerulonephritis due to drug or chemical treatment may have a rapid onset and fulminant course typical of human RPGN, thus human trials would not benefit from the addition of chronic renal biomarkers in longer term animal studies.…”

Spontaneous Background and Procedure-Related Microscopic Findings and Common Artifacts in Ocular Tissues of Laboratory Animals in Ocular Studies

“…20 An increase in the incidence and severity of uveal mononuclear cell infiltrates, especially if plasma cells are a prominent component, may indicate an immune response to an injected biotherapeutic. 21 Infiltrates of mononuclear cells may also be noted at the limbus in monkeys, dogs, and rabbits. 19,20,22 Mononuclear cell infiltrates in the conjunctiva 19,22 likely represent conjunctiva-associated lymphoid tissue.…”