Respiratory research · 2025
Signal regulating proteins (SIRPs) participate in sarcoidosis granuloma formation by promoting immune cell aggregation.
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Judson Marc A, Julian Mark W, Foulke Llewellyn, Panicker Sandip, Arker Soe H, Feustel Paul J, Parry Graham, Bicer Sabahattin, Crouser Elliott D
Аннотация
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.