Session Type: Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: T cells are an important contributor to the pathogenesis of SLE and lupus nephritis, and thus present themselves as interesting therapeutic targets. CD6 is a co-stimulatory receptor, predominantly expressed on T cells, that binds to activated leukocyte cell adhesion molecule (ALCAM), a ligand expressed on antigen-presenting cells and various epithelial and endothelial tissues. The CD6-ALCAM pathway plays an integral role in modulating T cell activation and trafficking, and could potentially be targeted within the context of SLE and LN as a therapeutic avenue. In this study, we assessed the expression of CD6 and ALCAM within the context of a murine model of SLE, and then targeted this signaling axis to determine its role in the pathogenesis of disease.
Methods: The MRL/lpr mouse is a spontaneous murine model of SLE, which exhibits systemic autoimmunity, nephritis, and skin disease. In an initial experiment, kidneys from 6-month old MRL/lpr and B6 mice were analyzed for the presence of both ALCAM and CD6. Following the initial experiment, two separate cohorts of female MRL/lpr mice were aged to 9-10 weeks of age, at which point treatment was begun with either anti-CD6 monoclonal antibody (60 ug/dose, intraperitoneally twice per week), isotype control (60 ug/dose, twice per week), or cyclophosphamide (25 mg/kg, once per week). We also included a no treatment group, and a group of MRL/MpJ mice, a congenic control strain. Baseline levels of anti-DNA antibodies, weight, and proteinuria in the MRL/lpr groups were similar. Mice were monitored weekly for proteinuria, lymph node swelling, and macroscopic skin lesions.
Results: At 6 months, when disease is advanced, analysis of ALCAM and CD6 expression by both flow cytometry and immunofluorescence revealed increased levels of ALCAM in renal myeloid cell populations and within the glomeruli and tubules, and increased expression of CD6 on renal T cell subsets, in MRL/lpr compared to B6 healthy control mice. Subsequently, we blocked this signaling axis in MRL/lpr mice using a monoclonal antibody against CD6. Anti-CD6 treatment significantly improved proteinuria levels as measured by uristix and albumin:creatine ratios compared to isotype control treated mice. Blood urea nitrogen levels were also significantly improved (p< 0.05), and survival of anti-CD6 treated mice was significantly better than isotype control mice (p=0.05). Histology of renal tissue revealed an improvement with anti-CD6 treatment and immunofluorescence staining showed decreased accumulation of renal T cells and myeloid cells. Flow cytometry confirmed decreased renal infiltration T cells and myeloid cells, specifically activated and memory CD4+ T cells and memory CD8+ T cells. Interestingly, anti-CD6 treatment also decreased lymph node size and improved macroscopic skin lesions. The results were confirmed in two separate cohorts.
Conclusion: In a spontaneous model of SLE, anti-CD6 treatment ameliorated pathology in multiple end organs, namely the kidney and skin. Overall, these results indicate that targeting CD6-ALCAM interactions may have promising therapeutic potential within the context of different end organ pathologies of SLE.
To cite this abstract in AMA style:Chalmers S, Garcia S, Ayilam Ramachandran R, Mohan C, Herlitz L, Chu D, Ampudia J, Ng C, Connelly S, Putterman C. CD6 Modulation Ameliorates Kidney and Skin Disease in a Spontaneous Murine Lupus Model [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/cd6-modulation-ameliorates-kidney-and-skin-disease-in-a-spontaneous-murine-lupus-model/. Accessed April 17, 2021.
« Back to ACR Convergence 2020
ACR Meeting Abstracts - https://acrabstracts.org/abstract/cd6-modulation-ameliorates-kidney-and-skin-disease-in-a-spontaneous-murine-lupus-model/