Table 1.
Costimulatory pathway | Tissue expression | Expression levels | Clinical manifestations | Experimental blockade in SSc animal models | Experimental activation in SSc animal models | Clinical trials | Main results | |
---|---|---|---|---|---|---|---|---|
Positive costimulators | CD28-CD80/86 | Serum | Increased | None | None | None | ||
ICOS-B7RP1 | Serum, skin | Increased | Early dcSSc | None | None | |||
OX40L-OX40 | Serum, skin | Increased | Early onset, worsening of dermal fibrosis | Prevented and induced regression of established inflammation-driven dermal fibrosis in the bleomycin mouse model; Protected against interstitial lung disease and pulmonary hypertension in the Fra-2 model | Spontaneous ILD Production of antiDNA antibodies | |||
CD40L-CD40 | Serum, skin | Increased | Digital ulcers, PH, early/active NVC pattern | None | None | |||
CD112/155-DNAM-1 | Skin | Increased | Correlates with more severe dermal fibrosis and ILD | None | None | |||
Negative costimulators | CTLA-4-CD80/86 | Serum | Increased | dcSSc, correlates with disease activity and severity | None | Prevented induced dermal fibrosis; was effective in the treatment of established fibrosis | 1) Pilot study evaluating the clinical and molecular effects of Abatacept in dcSSc 2) Study of Subcutaneous Abatacept to Treat Diffuse Cutaneous Systemic Sclerosis (ASSET) trial (ClinicalTrials.gov identifier: NCT02161406) |
1) Trend toward improvement in mRSS 2) Estimated study completion date: September 2018 |
PD1-L-PD1 | Serum | Increased | Correlates with disease severity | None | None |
CD (cluster of differentiation), ICOS (inducible co-stimulatory molecule), B7RP1 (B7-related protein-1), DNAM-1 (DNAX Accessory Molecule-1), CTLA-4 (cytotoxic Tlymphocyte-associated protein 4), PD1 (programmed death 1), dcSSc (diffuse cutaneous systemic sclerosis), PH (pulmonary hypertension), NVC (nailfold vascular capillaroscopy), ILD (interstitial lung disease), mRSS (modified-Rodnan skin score)