Phenotypic validation of humanized IgA1 and CD89 transgenic mice as a model for IgA nephropathy 4633

Description Kaiyuan Zi1, Juan Liang1 1GemPharmatech Co. Ltd., 12 Xuefu Road, Nanjing, 210061, China The etiology of IgA nephropathy (IgAN) remains only partly understood, but the presence of IgA antibodies together with the myeloid IgA-receptor FcαRI/CD89 complexes in the circulation of patients is considered a specific pathogenic factor for mesangial deposition. To better understand these effects, we developed a transgenic mouse model expressing human IgA1 and CD89, in which CD89 was expressed under the control of an endogenous murine CD14 promotor specific for blood and tissue monocytes/macrophages. B6-Cd14-hCD89/hIGHA1 mice showed a higher spontaneous mortality rate in females. Compared to wild-type mice, B6-Cd14-hCD89/hIGHA1 female mice had consistent leakage of low urine total protein (UPCR) from 7 weeks of age. At 12 weeks of age, these female mice displayed human IgA glomerular deposits, a pathological feature of IgAN. More severe human IgA deposition was detected at 21 and 27 weeks. Histopathological analysis of the kidneys in 27-week-old female mice revealed various renal lesions, including fibrous tissue hyperplasia, thickening of the basement membrane of the renal corpuscle, and inflammatory cell infiltration. B6-Cd14-hCD89/hIGHA1 mice exhibited an IgAN-like phenotype. This novel model can contribute significantly to unraveling the mechanisms underlying IgAN and provide a clinically relevant mouse model to evaluate novel therapeutics against IgAN.