Targeting the interleukin-1 pathway in patients with hematological disorders

Abstract

Interleukin-1α (IL-1α) and IL-1β are potent inflammatory cytokines that activate local and systemic inflammatory processes and are involved in protective immune responses against infections. However, their dysregulated production and signaling can aggravate tissue damage during infection, inflammatory diseases, and chemotherapy-induced intestinal mucositis. Additionally, cytokines of the IL-1 family play an important role in homeostatic as well as "emergency" hematopoiesis and are involved in the pathogenesis of several myeloid and lymphoid hematological malignancies. In the pathogenesis of intestinal mucositis and graft-versus-host disease (GVHD), these cytokines are considered pivotal during the initiation as well as propagation phase, and insights from animal studies suggest that targeting the IL-1 pathway can significantly ameliorate mucositis and GVHD. Moreover, IL-1α and IL-1β might prove to be valuable targets for both prevention and treatment of cancer and cancer therapy-related complications, and the first clinical studies have already been performed in the setting of hematological malignancies. In this review, we will discuss the role of cytokines of the IL-1 family in hematological malignancies, chemotherapy-induced intestinal mucositis, and GVHD, and speculate on possibilities of therapeutically targeting the IL-1 pathway in hematological patients.

Targeting JAK2 reduces GVHD and xenograft rejection through regulation of T cell differentiation

“…Tyk2 and JAK2 regulate p40 cytokine receptor signal transduction (36), and Tyk2 inhibition by pacritinib might also impact Th1 and Th17 differentiation beyond the effects of the JAK2 blockade. Additionally, suppression of IRAK1 and IL-1β receptor activity may modulate donor alloresponses (37). In comparison, ruxolitinib inhibits JAK1 and JAK2 equally (4).…”

Graft-versus-host disease propagation depends on increased intestinal epithelial tight junction permeability

“…Although efforts to reduce conditioning-associated intestinal damage for prevention of GVHD initiation have shown some efficacy, their utility is limited by the fact that intense antineoplastic therapies and bone marrow ablation are necessary for successful HSCT (2,3). We therefore focused on the lesswell-defined mechanisms by which barrier loss promotes ongoing attack of recipient tissues, i.e., GVHD propagation, which is associated with local T cell recruitment and apoptosis of intestinal crypt epithelial cells (5,6). Identification of these mech-anisms and means to prevent GVHD propagation could have tremendous therapeutic potential (7)(8)(9).…”

“…Sustained intestinal barrier loss has been proposed as a contributor to GVHD propagation based on the observation that the degree of intestinal barrier loss correlates with disease severity in patients and mice with GVHD (4,6,(8)(9)(10)(11)(12)(13). However, it remains unclear whether this increased permeability is a consequence of disease or a primary driver of disease propagation.…”

The emerging roles of inflammasome‐dependent cytokines in cancer development

“…While not being expressed under homeostatic conditions, the levels of IL-1b are elevated in numerous tumours, including melanoma, colon and breast cancer as well as in haematological malignancies [57][58][59][60][61][62][63]. Notably, clinical studies revealed that patients with IL-1b-producing tumours generally have poorer prognosis [56,59,62,64,65].…”

“…Recently, cell‐extrinsic factors such as infection and inflammation have been put forward as potential mechanisms that promote a selective competitive advantage to mutant cells to expand and survive . Furthermore, aberrant innate immune and cytokine signalling, as well as perturbed anti‐tumour immunity, seem to be pivotal in the pathogenesis of haematological malignancies .…”