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Abstract Number: 65

CD6 Modulation Ameliorates Skin and Kidney Disease in a Spontaneous Murine Model of SLE

Samantha Chalmers1, Sayra Garcia 1, Rajalakshmy Ayilam Ramachandran 2, Chandra Mohan 2, Jeanette Ampudia 3, Cherie Ng 3, Stephen Connelly 3 and Chaim Putterman 4, 1Albert Einstein College of Medicine, Bronx, NY, 2University of Houston, Houston, 3Equillium, Inc, San Diego, CA, 4Albert Einstein College of Medicine, New York, NY

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: cutaneous lupus, Lupus nephritis, SLE, T cells and Lupus

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Session Information

Date: Sunday, November 10, 2019

Session Title: SLE – Animal Models Poster

Session Type: Poster Session (Sunday)

Session Time: 9:00AM-11:00AM

Background/Purpose: T cells are an important contributor the pathogenesis of SLE and its various end organ manifestations. Thus, they present themselves as potential therapeutic targets; however, the optimal approach to targeting T cells in SLE still remains under investigation. 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 presentation cells and various epithelial and endothelial tissues.  The CD6-ALCAM pathway plays an integral role in modulating T cell activation, proliferation, differentiation and trafficking. In this study, we assessed the expression of CD6 and ALCAM within the context of a murine model of SLE, and then subsequently 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, 6 month old MRL/lpr mice and B6 kidneys were stained for the presence of both ALCAM and CD6. In a separate experiment, female MRL/lpr mice were aged to 9-10 weeks of age, and then treated with either anti-CD6 monoclonal antibody (60 ug/dose, IP 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 healthy 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: MRL/lpr mice at 6 months of age show increased levels of ALCAM expression in their kidneys, both within their tubules and glomeruli, compared to B6 healthy control mice (shown are images representative of 3 mice per group). Additionally, macrophages infiltrating into the glomeruli of MRL/lpr mice were ALCAM+ (white arrows, top panel) and were paired with a concomitant increase in CD6+ T cell infiltration (white arrows, bottom panel). Consequently, in a separate study, we blocked this signaling axis using a monocolonal antibody for CD6. At 19 weeks of age, mice treated with anti-CD6 show improved proteinuria compared to isotype control mice (p< 0.05). MRL/lpr mice develop lymphoproliferative disease which results in abnormally large lymph nodes. Assessing lymphadenopathy at 19 weeks of age, we noted a significant improvement in the anti-CD6 treated mice, compared to the isotype control (p< 0.05). MRL/lpr mice also develop severe skin lesions that have similar pathology to cutaneous lupus. Macroscopic scoring of these lesions showed a significant improvement in the skin disease of the anti-CD6 treated mice compared to the isotype control group (p< 0.05).

Conclusion: Within a spontaneous model of SLE, anti-CD6 treatment ameliorated multiple end organ pathologies, namely in the kidney and skin, while also significantly reducing the lymphoproliferative phenotype of this model. Overall, these results indicate that targeting the CD6-ALCAM pathway may have promising therapeutic potential for multiple end organ pathologies within SLE.

Upregulated expression of ALCAM -CD166, red-, is seen in the tubules of 6 month old MRL/lpr mice, compared to age matched B6 mice -top panel-. Looking more closely at the glomeruli, we note ALCAM expression is increased in lupus mice, including on macrophages -CD11b+, white arrows- infiltrating into the glomerulus -middle panel-. Finally, CD6+CD3+ T cells are also noted infiltrating the glomeruli of MRL/lpr mice -white arrow, bottom panel-. Shown are representative images from 3 mice per group.


Disclosure: S. Chalmers, Equillium, Inc, 2; S. Garcia, None; R. Ayilam Ramachandran, None; C. Mohan, Equillium, 5, Equillium, Inc, 5; J. Ampudia, Equillium, Inc, 3; C. Ng, Equillium, Inc, 3; S. Connelly, Equillium, Inc, 3, 6, Equillium, 3; C. Putterman, Equillium, 5, Equillium, Inc, 2, 5, Exagen, 2.

To cite this abstract in AMA style:

Chalmers S, Garcia S, Ayilam Ramachandran R, Mohan C, Ampudia J, Ng C, Connelly S, Putterman C. CD6 Modulation Ameliorates Skin and Kidney Disease in a Spontaneous Murine Model of SLE [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/cd6-modulation-ameliorates-skin-and-kidney-disease-in-a-spontaneous-murine-model-of-sle/. Accessed February 27, 2021.
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