Pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I like receptors (RLRs) and cytosolic DNA sensors (cyclic GMP-AMP (cGAMP) synthetase (cGAS), stimulator of interferon genes (STING), absent in melanoma 2 (AIM2)) and others involved in pathogen recognition are critical for host defense. Furthermore, there is emerging evidence that PRRs including TLRs and NLRs can influence the development of acute graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), although the mechanisms governing this response remain poorly understood. Understanding the processes that help prevent GVHD while preserving graft-versus-tumor activity (GVT) against hematopoietic malignancies will allow for the clinical exploitation of strategies for improving allo-HSCT outcome.
We have provided recent evidence that activation of the NLRP3 inflammasome — a multiprotein complex that regulates the production of bioactive Interleukin-1beta (IL-1β) and IL-18 — in early conditioning contributes to the development of acute GVHD. Upon irradiation, pathogen-associated molecular patterns (PAMPs) such as enteric bacteria-derived LPS deliver the first signal necessary for pro-IL-1β synthesis. The second signal leading to inflammasome activation and subsequent secretion of bioactive IL-1β is provided by uric acid released from damaged cells. Secreted IL-1b then induces allogeneic Th17 differentiation that contributes to the development of acute GVHD.
Several interesting areas of future study have arisen from this initial discovery, including exploring the role of other innate immune pathways involved in the recognition of commensal microbiota in triggering GVHD, identifying factors that are induced by PRR activation that could selectively reduce GVHD, examining the role of PRRs on GVT activity, and the clinical translation of selective PRR activation as a potential regenerative therapy to boost immune function.
Awards
Feodor Lynen Scholar for Experienced Researchers (Alexander von Humboldt-Foundation)