Systemic Lupus Erythematosus (SLE) And The Role Of Animal Models in Therapeutic Development

Systemic Lupus Erythematosus (SLE) is a chronic, multi-system inflammatory disease characterized by the production of autoantibodies and the deposition of immune complexes. Its clinical manifestations are diverse and complex, commonly including symptoms such as polyarthralgia and arthritis, Raynaud's phenomenon, rashes on the cheeks and other areas, pleuritis and pericarditis, renal or central nervous system involvement, and hematopoietic cell deficiencies.

The course of SLE is typically chronic, recurrent, and difficult to predict. However, with proper control of the initial acute phase-even in cases of severe disease such as cerebral thrombosis or severe nephritis-good long-term prognosis can still be achieved. The current treatment goals for SLE are to induce disease remission, prevent and manage organ damage, and improve both survival rates and the quality of life of patients. The limitations in treatment are largely due to the incomplete understanding of the pathogenesis of SLE and the restricted development of drugs based on the mechanisms of disease progression.

In the investigation of the pathogenesis of SLE and the search for effective therapeutic agents, animal models have played a crucial role. On the one hand, they provide a pathway for preclinical studies of the disease's pathogenesis; on the other hand, they serve as a platform for the preclinical development and evaluation of new SLE therapies.

In recent years, multiple SLE animal models have been developed worldwide. These models can broadly be divided into spontaneous models, which are genetically driven, and induced models, which are triggered by environmental factors. These models each simulate different aspects of human SLE and exhibit distinct characteristics.

There are two major viewpoints regarding the involvement of innate and adaptive immunity in the pathogenesis of SLE:

In innate immunity, Toll-like receptors (TLRs) are activated by extracellular DNA and RNA, leading to the downstream activation of interferon regulatory factors (IRF-3) and NF-κB. This activation triggers the production of interferon-alpha (IFN-α) and autoantibodies against RNA-binding proteins such as La and Sm.

Apoptotic and damaged cells serve as antigens, which are presented to T cells by antigen-presenting cells (APCs). This process stimulates the production of cytokines and CD40L binding, leading to excessive B cell activation and the production of large quantities of autoantibodies.

Recently, neutrophil ferroptosis has garnered attention in the pathogenesis of SLE. This process is induced by the synergistic action of autoantibodies and IFN-α, which promote the binding of the transcriptional repressor CREMα to the GPX4 promoter, downregulating GPX4 expression. During apoptosis, neutrophils release large amounts of antinuclear antibodies, which are immunogenic and activate plasmacytoid dendritic cells (pDCs). These pDCs, in turn, activate TLR7/9, releasing IFN-α and inducing the production of anti-DNA autoantibodies.

Due to their evolutionary homology with humans and genetic similarity, non-human primates (NHPs) play a critical role in scientific research, particularly in the fields of biomedical research, disease model development, drug testing, and neuroscience studies.

Pristane is a mineral oil component that primarily induces the SLE model by activating B cells in the immune system. The disease progression in this model more closely resembles the chronic onset of human SLE, but the modeling period is long. SLE symptoms generally become evident at least 6 months after Pristane injection.

IMQ, on the other hand, activates TLR7 and rapidly triggers immune responses, resulting in a faster onset of disease. Symptoms such as skin lesions can appear within a week, and the observation period usually lasts about 3 months. However, the systemic symptoms are generally less severe than those in the Pristane-induced model, with the disease primarily affecting the skin and early immune system activation stages.

Common evaluation parameters for SLE animal models include:

• Proteinuria Test: Urine samples are collected, and protein levels are measured using urine dipsticks or biochemical analyzers. The protein-to-creatinine ratio (UPCR) is a more accurate method for assessing the extent of proteinuria.
• Serum Creatinine and Urea Nitrogen Levels: These indicators reflect kidney function. Elevated levels are indicative of renal impairment.
• Autoantibody Detection: Anti-dsDNA antibody levels can be measured through enzyme-linked immunosorbent assay (ELISA) or indirect immunofluorescence (IIF). Higher antibody titers correlate with increased disease activity.
• Cell-Level Detection: Flow cytometry is used to detect changes in B cell and T cell subtypes.
• Renal Pathological Evaluation: This can assess tubular atrophy, interstitial inflammation, and fibrosis in the kidneys.

Considering the species dependence of bispecific and multispecific molecules, the following strategies are recommended for selecting animal models in drug efficacy evaluation:

• Non-Human Primates (NHPs): Choose NHPs with higher homology to human genomes for efficacy evaluation, as results from NHPs are more translatable to clinical settings and significantly enhance the potential value of the drug.
• Transgenic Mice with Dual Targets: Transgenic mice (often of the C57BL/6 strain) can be used for drug efficacy evaluation, especially when they express humanized targets or disease-related genes.
• Immunocompromised Mice: Immunodeficient mice, particularly those with reconstituted immune systems, can also be used for evaluating the immune-modulatory effects of dual or multispecific antibodies.