Attenuation of Murine Collagen‐Induced Arthritis by Targeting CD6

Abstract

Objective CD6 is an important regulator of T cell function that interacts with the ligands CD166 and CD318. To further clarify the significance of CD6 in rheumatoid arthritis (RA), we examined the effects of targeting CD6 in the mouse model of collagen‐induced arthritis (CIA), using CD6‐knockout (CD6‐KO) mice and CD6‐humanized mice that express human CD6 in lieu of mouse CD6 on their T cells. Methods We immunized wild‐type (WT) and CD6 gene–KO mice with a collagen emulsion to induce CIA. For treatment studies using CD6‐humanized mice, mice were immunized similarly and a mouse anti‐human CD6 IgG (UMCD6) or control IgG was injected on days 7, 14, and 21. Joint tissues were evaluated for tissue damage, leukocyte infiltration, and local inflammatory cytokine production. Collagen‐specific Th1, Th9, and Th17 responses and serum levels of collagen‐specific IgG subclasses were also evaluated in WT and CD6‐KO mice with CIA. Results The absence of CD6 reduced 1) collagen‐specific Th9 and Th17, but not Th1 responses, 2) the levels of many proinflammatory joint cytokines, and 3) serum levels of collagen‐reactive total IgG and IgG1, but not IgG2a and IgG3. Joint homogenate hemoglobin content was significantly reduced in CD6‐KO mice with CIA compared to WT mice with CIA (P < 0.05) (reduced angiogenesis). Moreover, treating CD6‐humanized mice with mouse anti‐human CD6 monoclonal antibody was similarly effective in reducing joint inflammation in CIA. Conclusion Taken together, these data suggest that interaction of CD6 with its ligands is important for the perpetuation of CIA and other inflammatory arthritides that are T cell driven.

CD6 is a target for cancer immunotherapy

“…Indeed, UCMD6 quickly led to capping of CD6, with subsequent clearing of CD6 from the cell membrane over 6 hours ( Supplemental Figure 4 ). UMCD6-treated lymphocytes remained CD6 – for several days, consistent with previous observations in vivo in CD6-humanized mice, in which a large population of CD6 – lymphocytes appeared after administration of UMCD6 ( 15 ).…”

“…In both CD6 –/– mice and in CD6-humanized mice treated with anti-CD6, robust protective effects were seen in mouse models of multiple sclerosis ( 13 ), autoimmune uveitis ( 14 ), and RA ( 15 ). The therapeutic benefit was manifested as amelioration of clinical indicators of disease, attenuation of the immune cell infiltrates into the target organs, and marked reduction of the Th1 and/or Th17 immune responses that are essential to these conditions.…”

“…The therapeutic benefit was manifested as amelioration of clinical indicators of disease, attenuation of the immune cell infiltrates into the target organs, and marked reduction of the Th1 and/or Th17 immune responses that are essential to these conditions. Initial stages of lymphocyte activation were not inhibited by genetic absence of CD6 or use of UMCD6 in the CD6-humanized mice, and these mice did not become lymphopenic when UMCD6 was administered ( 15 ). Lack of T cell depletion is attributable to the rapid internalization of CD6 upon binding of UMCD6 to the cell surface, and abundant CD3 + CD6 – T cells were therefore detected in vivo after treatment with anti-CD6.…”

“…We recently showed CD6 to be essential in murine models of multiple sclerosis (MS) ( 13 ), uveitis ( 14 ), and rheumatoid arthritis (RA) ( 15 ). In both CD6 –/– mice and CD6-humanized mice treated with the mouse anti–human CD6 mAb UMCD6, striking reductions in clinical signs of disease, pathogenic Th1/Th17 responses, and inflammatory cell infiltration into the target organs were observed ( 13 – 15 ). Both known CD6 ligands, CD318 and CD166, participate in adhesion of T cells to fibroblast-like synoviocytes (FLS) derived from RA synovial tissue by engagement of distinct domains on CD6.…”

Immunoprofiling of active and inactive systemic juvenile idiopathic arthritis reveals distinct biomarkers: a single-center study

“…Membrane-bound CD6 (mCD6) regulates T cell activity, and deficiency of mCD6 reduced both T cell activity and cytokine production in collagen-induced arthritis [ 27 , 28 ]. Soluble CD6 (sCD6) measured in this study is regarded as a decoy receptor.…”