Bone Marrow Transplantation Platform to Investigate the Role of Dendritic Cells in Graft-versus-Host Disease

Allogeneic hematopoietic stem cell transplantation (BMT) is an effective therapy to treat hematological malignancies^1,2 through the graft-versus-leukemia (GVL) effect³. However, donor lymphocytes always mount unwanted immunological attacks against recipient tissues, a process called graft-versus-host disease (GVHD)⁴.

Murine models of GVHD are an effective tool to study the biology of GVHD and the GVL response⁵. Mice are a cost-effective research animal model. They are small and efficiently dosed with molecules and biologics at early phases of development⁶. Mice are ideal research animals for genetic manipulation studies because they are genetically well defined, which is ideal for studying biological pathways and mechanisms⁶. Several mouse major histocompatibility complex (MHC) MHC-mismatched models of GVHD have been well established, such as C57BL/6 (H2^b) to BALB/c (H2^d) and FVB (H2^q)→C57BL/6 (H2^b)^5,7. These are particularly valuable models to determine the role of individual cell types, genes, and factors that affect GVHD. Transplantation from C57/BL/6 (H2^b) parental donors to recipients with mutations in MHC I (B6.C-H2^bm1) and/or MHC II (B6.C-H2b^m12) revealed that a mismatch in both MHC class I and class II is an important requirement for the development of acute GVHD. This suggests that both CD4⁺ and CD8⁺ T-cells are required for disease development^7,8. GVHD is also involved in an inflammatory cascade known as the 'pro-inflammatory cytokine storm'⁹. The most common conditioning method in murine models is total body irradiation (TBI) by X-ray or ¹³⁷Cs. This leads to the recipient's bone marrow ablation, thereby allowing donor stem cell engraftment and preventing rejection of the graft. This is done by limiting the proliferation of recipient T-cells in response to donor cells. Additionally, genetic disparities play an important role in disease induction, which also depends on minor MHC-mismatch¹⁰. Therefore, myeloablative irradiation dose varies in different mouse strains (e.g., BALB/c→C57BL/6).

Activation of donor T-cells by host antigen presenting cells (APCs) is essential for GVHD development. Among the APCs, dendritic cells (DCs) are the most potent. They are inheritably capable of inducing GVHD due to their superior antigen uptake, expression of T-cell co-stimulatory molecules, and production of pro-inflammatory cytokines that polarize T-cells into pathogenic subsets. Recipient DCs are critical for facilitating T-cell priming and GVHD induction after transplantation^11,12. Accordingly, DCs have become interesting targets in the treatment of GVHD¹².

TBI is required to enhance the donor cell engraftment. Due to the TBI effect, recipient DCs are activated and survive for a short time after the transplantation¹². Despite major advancements in the usage of bioluminescence or fluorescence, establishing an effective model to study the role of recipient DCs in GVHD is still challenging.

Because donor T-cells are the driving force for GVL activity, treatment strategies using immunosuppressive drugs such as steroids to suppress T-cell alloreactivity often cause tumor relapse or infection¹³. Therefore, targeting recipient DCs may provide an alternative approach to treat GVHD while preserving the GVL effect and avoiding infection.

In brief, the current study provides a platform to understand how different types of signaling in recipient DCs regulates GVHD development and the GVL effect after BMT.