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Abstract Number: 0840

Amelioration of Immune Complex-Mediated Glomerulonephritis via CD6 Modulation

Samantha Chalmers1, Sayra Garcia1, Leal Herlitz2, Jeanette Ampudia3, Cherie Ng4, Stephen Connelly3 and Chaim Putterman1, 1Albert Einstein College of Medicine, Bronx, NY, 2Cleveland Clinic, Cleveland, OH, 3Equillium, Inc, San Diego, CA, 4Equillium, Inc, La Jolla, CA

Meeting: ACR Convergence 2020

Keywords: Animal Model, Lupus nephritis, Systemic lupus erythematosus (SLE), T Cell, T-Lymphocyte

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Session Information

Date: Saturday, November 7, 2020

Session Title: SLE – Animal Models Poster

Session Type: Poster Session B

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

Background/Purpose: 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. T cells are important contributors to the pathogenesis of SLE, especially in the development of kidney disease (lupus nephritis, LN). The CD6-ALCAM pathway plays an integral role in T cell activation, differentiation, proliferation, and trafficking, and increased levels of CD6 are associated with pathogenic T cell responses. Thus, the CD6-ALCAM pathway is a potential contributor to disease pathogenesis and presents itself as a potential therapeutic target.

Methods: Nephrotoxic serum nephritis (NTN) is a validated, short-term model of LN. Disease was induced in two separate cohorts of female 129/svJ mice, both aged to 10 weeks. Mice were immunized with rabbit IgG and complete Freund’s adjuvant on day 0, followed by passive transfer of pre-formed rabbit anti-mouse glomerular antibodies intravenously (i.e. nephrotoxic serum) given on day 5, causing an antibody-mediated nephritis similar in pathology to LN. One group of mice was treated 3x per week with anti-CD6 monoclonal antibody (10D12) (60ug/dose, n=23), while control mice were treated with either vehicle control (n=23) or isotype control (cohort 2 only, n=12). Healthy mice (immunized with rabbit IgG, but not given nephrotoxic serum) were also included as a control (n=12). We monitored the progress of kidney disease to assess the effect of the anti-CD6 treatment on both cohorts, and completed flow cytometry, RT-PCR, immunofluorescent staining, and multiplexed gene expression analysis to assess the effect of treatment on kidney disease development.

Results: Mice treated with anti-CD6 displayed decreased levels of proteinuria as measured by uristix and albumin:creatine ratios compared to vehicle control (p< 0.0001, p< 0.0001, respectively) and isotype control treated mice (p< 0.05, p< 0.0001, respectively).  Blood urea nitrogen (BUN) levels were also significantly improved when comparing anti-CD6 to vehicle control treated mice  (p< 0.05). Anti-CD6 treatment ameliorated glomerular histopathology, and had a near significant improvement in tubular histology. Flow cytometric analysis of kidney tissue indicated decreased numbers of activated T cells (CD4+CD25+CD69+, p < 0.01) as well as decreased inflammatory macrophages (p< 0.05). Finally, we performed a PCR array to assess expression of a number of inflammatory genes. When comparing anti-CD6 treated mice to both the vehicle and isotype control groups, 13 genes were significantly decreased in both comparisons, including C3, CCL1, CCL2, CCL5, CCL7, CCL20, CSF1, CXCL3, CXCL2, CD14, CD40, CXCL5, and IL1rn.

Conclusion: Anti-CD6 treatment is beneficial in ameliorating the nephritis associated with nephrotoxic antibody administration, an inducible model of lupus nephritis. These results suggest a promising therapeutic option that is more selective than the immunosuppressive therapies currently offered.


Disclosure: S. Chalmers, None; S. Garcia, None; L. Herlitz, None; J. Ampudia, Equillium, Inc, 3; C. Ng, Equillium, Inc, 3; S. Connelly, Equillium, Inc, 3; C. Putterman, Equillium, 1, 2.

To cite this abstract in AMA style:

Chalmers S, Garcia S, Herlitz L, Ampudia J, Ng C, Connelly S, Putterman C. Amelioration of Immune Complex-Mediated Glomerulonephritis via CD6 Modulation [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/amelioration-of-immune-complex-mediated-glomerulonephritis-via-cd6-modulation/. Accessed April 11, 2021.
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