Targeting CD6 for the treatment of experimental autoimmune uveitis

Zhang, Lingjun; Li, Yan; Qiu, Wen; Bell, Brent A.; Dvorina, Nina; Baldwin, William M.; Singer, Nora G.; Kern, Timothy S.; Caspi, Rachel R; Fox, David A.; Lin, Feng

doi:10.1016/j.jaut.2018.02.004

Cited by 27 publications

(35 citation statements)

References 27 publications

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“…CD6‐humanized mice provide a useful preclinical in vivo model for demonstrating the effectiveness of anti‐CD6 antibodies in the treatment of autoimmune conditions. UMCD6 significantly reduced inflammatory responses in the target organs of CIA, EAE, and experimental autoimmune uveitis in these mice . Further, UMCD6 is an effective agent in suppressing differentiation of autoreactive lymphocytes into pathogenic, cytokine‐producing Th1 and Th17 cells.…”

Section: Discussionmentioning

confidence: 87%

Attenuation of Murine Collagen‐Induced Arthritis by Targeting CD6

Ruth

Rasmussen

et al. 2020

Arthritis & Rheumatology

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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.

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Section: Discussionmentioning

confidence: 87%

Attenuation of Murine Collagen‐Induced Arthritis by Targeting CD6

Ruth

Rasmussen

et al. 2020

Arthritis & Rheumatology

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“…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 UMCD6, a mouse anti-human CD6 monoclonal antibody (mAb), striking reductions in clinical signs of disease, pathogenic Th1/Th17 responses and inflammatory cell infiltration into the target organs were observed (13)(14)(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.…”

Section: Introductionmentioning

confidence: 99%

“…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 ).…”

Section: Introductionmentioning

confidence: 99%

CD6 is a target for cancer immunotherapy

Ruth¹,

Gurrea-Rubio²,

Athukorala³

et al. 2021

JCI Insight

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Limitations of checkpoint inhibitor cancer immunotherapy include induction of autoimmune syndromes and resistance of many cancers. Since CD318, a novel CD6 ligand, is associated with aggressiveness and metastatic potential of human cancers, we tested the effect of an anti-CD6 monoclonal antibody, UMCD6, on killing of cancer cells by human lymphocytes. UMCD6 augmented killing of breast, lung or prostate cancer cells through direct effects on both CD8+ T cells and natural killer (NK) cells, increasing cancer cell death and lowering cancer cell survival in vitro more robustly than monoclonal antibody checkpoint inhibitors that interrupt the PD-1/PD-L1 axis. UMCD6 also augmented in vivo killing by human peripheral blood lymphocytes of a human breast cancer line xeno-transplanted into immunodeficient mice. Mechanistically, UMCD6 upregulated the expression of the activating receptor NKG2D and down-regulated expression of the inhibitory receptor NKG2A on both NK cells and CD8+ T cells, with concurrent increases in perforin and granzyme-B production. The combined capabilities of an anti-CD6 monoclonal antibody to control autoimmunity through effects on CD4+ lymphocyte differentiation, while enhancing killing of cancer cells through distinct effects on CD8+ and NK cells, opens a potential new approach to cancer immunotherapy that would suppress rather than instigate autoimmunity.

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“…Although most of these cytosolic effectors exert positive regulatory roles in T cell activation, CD6 has also been categorized as a negative regulator of T cell activation ( Gonçalves et al, 2018 ; Oliveira et al, 2012 ). Mice lacking CD6 are less prone than their WT counterpart to develop experimental autoimmune encephalomyelitis ( Li et al, 2017 ) and T cell–mediated autoimmune retinal destruction ( Zhang et al, 2018 ), suggesting that CD6 has a net costimulatory effect in the development of several autoimmune diseases.…”

Section: Introductionmentioning

confidence: 99%

The T cell CD6 receptor operates a multitask signalosome with opposite functions in T cell activation

Mori

Grégoire

Voisinne

et al. 2020

Journal of Experimental Medicine

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To determine the respective contribution of the LAT transmembrane adaptor and CD5 and CD6 transmembrane receptors to early TCR signal propagation, diversification, and termination, we describe a CRISPR/Cas9–based platform that uses primary mouse T cells and permits establishment of the composition of their LAT, CD5, and CD6 signalosomes in only 4 mo using quantitative mass spectrometry. We confirmed that positive and negative functions can be solely assigned to the LAT and CD5 signalosomes, respectively. In contrast, the TCR-inducible CD6 signalosome comprised both positive (SLP-76, ZAP70, VAV1) and negative (UBASH3A/STS-2) regulators of T cell activation. Moreover, CD6 associated independently of TCR engagement to proteins that support its implication in inflammatory pathologies necessitating T cell transendothelial migration. The multifaceted role of CD6 unveiled here accounts for past difficulties in classifying it as a coinhibitor or costimulator. Congruent with our identification of UBASH3A within the CD6 signalosome and the view that CD6 constitutes a promising target for autoimmune disease treatment, single-nucleotide polymorphisms associated with human autoimmune diseases have been found in the Cd6 and Ubash3a genes.

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Targeting CD6 for the treatment of experimental autoimmune uveitis

Cited by 27 publications

References 27 publications

Attenuation of Murine Collagen‐Induced Arthritis by Targeting CD6

Attenuation of Murine Collagen‐Induced Arthritis by Targeting CD6

CD6 is a target for cancer immunotherapy

The T cell CD6 receptor operates a multitask signalosome with opposite functions in T cell activation

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