Drug-induced Glomerulonephritis: The Spectre of Biotherapeutic and Antisense Oligonucleotide Immune Activation in the Kidney
| Autor: | Kendall S. Frazier, Leslie A. Obert |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Drug Evaluation Preclinical Toxicology Immune complex formation Pathology and Forensic Medicine Proinflammatory cytokine 03 medical and health sciences Glomerulonephritis 0302 clinical medicine Immune system Antigen Animals Humans Immune Complex Diseases Medicine Molecular Biology business.industry Cell Biology Oligonucleotides Antisense medicine.disease Immune complex Complement system Biological Therapy Disease Models Animal 030104 developmental biology 030220 oncology & carcinogenesis Immunology business Immune complex disease |
| Zdroj: | Toxicologic Pathology. 46:904-917 |
| ISSN: | 1533-1601 0192-6233 |
| Popis: | Prevalence of immune-mediated glomerulonephritis has increased in preclinical toxicity studies, with more frequent use of biotherapeutic agents (especially antigenic humanized molecules) and antisense oligonucleotide (ASO) therapies. Immune complex disease affects a small number of study monkeys, often correlates with antidrug antibody (ADA) titers, and occurs at a dose that favors immune complex formation or impedes clearance. While preclinical glomerulonephritis often fails to correlate with evidence of glomerular or vascular injury in human clinical trials and is not considered predictive, additional animal investigative immunohistochemical work may be performed to substantiate evidence for immune complex pathogenesis. While ADA is most commonly encountered as a predisposing factor with biotherapeutic agents, complement activation may occur without circulating complexes, and other mechanisms of non-ADA immune-mediated glomerulonephritis have been observed including nonendogenous immune aggregates and immunoregulatory pharmacology. Although glomerulonephritis associated with oligonucleotide therapies has been noted occasionally in preclinical studies and more rarely with human patients, pathophysiologic mechanisms involved appear to be different between species and preclinical cases are not considered predictive for humans. ADA is not involved in oligonucleotide-associated cases, and complement fixation plays a more important role in monkeys. Recent screening of ASOs for proinflammatory activity appears to have decreased glomerulonephritis incidence preclinically. |
| Databáze: | OpenAIRE |
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