Inhibition of IL-1 Receptor-Associated Kinase 1 Decreases Murine Acute Graft-versus-Host Disease While Preserving the Graft-versus-Lymphoma Effect

by Selleckchem | Nov 21 2023

Activation of antigen-presenting cells (APCs) is crucial in initiating inflammation and alloreaction during acute graft-versus-host disease (aGVHD), a common life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). IL-1 receptor-associated kinase 1 (IRAK1) regulates the activation of APCs in inflammatory settings, and inhibition of IRAK1 might decrease APC activation and aGVHD. This study was conducted to explore the impact of IRAK1 inhibition on APC activation and aGVHD in mice. We administered a selective IRAK1 inhibitor, Jh-X-119-01, to recipient mice undergoing allo-HCT or co-challenged by A20 lymphoma cells. We assessed aGVHD and the graft-versus-lymphoma (GVL) effect. T cell and APC activations were analyzed as well. Jh-X-119-01 was associated with increased survival and decreased aGVHD of recipients. Jh-X-119-01 decreased the proportions of Th1 cells and Tc1 cells in the aGVHD model and in the in vitro mixed lymphocyte reaction. The IRAK1 inhibitor reduced production of TNFα and IFNγ in macrophages of recipient mice. In in vitro cultured bone marrow dendritic cells (BMDCs), Jh-X-119-01 decreased productions of inflammatory cytokines, reduced expression levels of CD80 and CD86, and decreased protein levels of antiapoptotic Bcl2 and phosphorylated NF-κB p65. RNA-seq analysis showed that Jh-X-119-01 had an impact on several pathophysiologic processes of BMDCs, including reduction of GVHD-related genes and regulation of helper T cell differentiation. Importantly, IRAK1 inhibition did not impair cytotoxic function of T cells or the allo-HCT-related GVL effect against A20 lymphoma cells. In addition, the IRAK1 inhibitor did not retard recovery of hematopoietic cells in blood or bone marrow. Our findings show that selective IRAK1 inhibition ameliorates murine aGVHD but preserves the GVL effect. Our findings may have implications for the use of an IRAK1 inhibitor in allo-HCT.

Comments:

The study you described investigates the effects of a selective IRAK1 inhibitor, Jh-X-119-01, on acute graft-versus-host disease (aGVHD) in mice undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Here are the key findings and implications of the study:

1. **Increased Survival and Decreased aGVHD:** Administration of Jh-X-119-01 to recipient mice undergoing allo-HCT resulted in increased survival rates and decreased severity of aGVHD. This suggests that IRAK1 inhibition has a protective effect against aGVHD, a serious complication of allo-HCT.

2. **Modulation of T Cell and APC Activations:** Jh-X-119-01 reduced the proportions of Th1 cells and Tc1 cells in the aGVHD model. This indicates that IRAK1 inhibition affects T cell activation and differentiation. Additionally, the inhibitor decreased the production of pro-inflammatory cytokines (TNFα and IFNγ) in macrophages of recipient mice, suggesting a modulation of APC activation.

3. **Effects on Dendritic Cells:** In vitro experiments with bone marrow dendritic cells (BMDCs) showed that Jh-X-119-01 reduced the production of inflammatory cytokines, decreased expression levels of co-stimulatory molecules (CD80 and CD86), and affected proteins related to apoptosis and NF-κB signaling. These findings indicate that IRAK1 inhibition affects the function and activation of dendritic cells, crucial antigen-presenting cells involved in immune responses.

4. **Gene Expression Changes:** RNA-seq analysis revealed that Jh-X-119-01 influenced various biological processes in BMDCs, including the downregulation of GVHD-related genes and the regulation of helper T cell differentiation. This suggests a broad impact of IRAK1 inhibition on immune response pathways.

5. **Preservation of Graft-Versus-Lymphoma (GVL) Effect:** Importantly, IRAK1 inhibition did not impair the cytotoxic function of T cells or the GVL effect against A20 lymphoma cells. This means that while it mitigates aGVHD, it does not compromise the beneficial graft-versus-tumor response, which is crucial for eliminating cancer cells after allo-HCT.

6. **Hematopoietic Cell Recovery:** The IRAK1 inhibitor did not hinder the recovery of hematopoietic cells in the blood or bone marrow. This suggests that the treatment does not have a negative impact on the overall hematopoietic system.

**Implications:**

These findings have important implications for the field of allo-HCT and immunotherapy:

1. **Therapeutic Potential:** IRAK1 inhibition, as demonstrated by Jh-X-119-01, could be a potential therapeutic strategy to reduce the severity of aGVHD in patients undergoing allo-HCT. This could improve the overall success and safety of transplantation procedures.

2. **Preservation of GVL Effect:** The ability of IRAK1 inhibition to preserve the GVL effect is particularly promising. It means that this treatment approach could help prevent aGVHD without compromising the patient's ability to fight against residual or recurring cancer cells.

3. **Safety and Hematopoietic Recovery:** The study suggests that IRAK1 inhibition does not adversely affect normal hematopoietic cell recovery. This is crucial for ensuring the patient's overall health and immune function post-transplantation.

In summary, the selective IRAK1 inhibitor Jh-X-119-01 shows significant potential as a therapeutic agent in the context of allo-HCT, offering a way to manage aGVHD without compromising the essential immune responses against cancer cells.