Signal regulating proteins (SIRPs) participate in sarcoidosis granuloma formation by promoting immune cell...

Signal regulatory protein alpha (SIRPα) is an important regulator of innate and adaptive immune responses by promoting T cell and macrophage activation and macrophage adhesion (multi-nucleated giant cell formation) while preventing phagocytic cell death to sustain inflammatory responses.

We determined whether SIRPα is expressed in sarcoidosis tissue and whether ELA026, a humanized SIRP-blocking Ab, suppresses sarcoidosis granuloma formation by attenuating inflammation, promoting cell death, and suppressing adhesion during granuloma formation.

Based upon immunohistochemistry, SIRPα stained in greater abundance in giant cells, monocytes, macrophages and dendritic cells in sarcoidosis lung tissue than in normal lung, lung cancer, non-granulomatous lung diseases and non-sarcoidosis granulomatous diseases. All these differences were statistically significant except for non-sarcoidosis granulomatous lung diseases. We then leveraged an ex vivo human granuloma model, wherein PBMCs from sarcoidosis patients are activated to form granulomas within 7 days, to determine whether ELA026 attenuated granuloma formation, based upon MIPAR image analysis, and associated cytokine responses. A matching isotype antibody (ELA099) that does not bind SIRPs was a negative control; prednisone was a positive control. As hypothesized, pre-treatment (day 0) or post-treatment (day 4) with ELA026 or prednisone (not ELA099) caused dose-dependent suppression of sarcoidosis granuloma formation by day 7. Unexpectedly, ELA026 only modestly reduced TNFα production when used as a pre-treatment and did not suppress IL-1β release or promote cell death, as reflected by no LDH release.

SIRPα is robustly expressed in monocyte/macrophage lineages within human sarcoidosis tissues, and inhibition of SIRPs (ELA026) suppresses sarcoidosis granuloma formation by preventing macrophage adhesion/aggregation.