A New Murine Model Of Chronic Graft Versus Host Disease

Chronic graft-versus-host-disease (cGVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), with highly variable clinical presentations. The pathophysiology of cGVHD remains to be further understood. The utilization of murine models to study cGVHD has contributed to the understanding of cGVHD, and highlights its mechanistic complexity. Here, we report a new murine cGVHD modle with obvious lung tissue damage in these mice resulted in the development of bronchiolitis obliterans (BO), which is pathopneumonic for cGVHD.

Recipients 8 weeks BALB/c (H-2^d) female mice, which irradiated with 700cGy dose of linear accelerator, then were injected with bone-marrow cells (1×10⁷) and spleen cells (5×10⁶) from (C57BL/6 x BALB/c) F1 donors (H-2^bd haplotype) male mice. The observed items post-transplantation included hematopoietic reconstruction, implant, and general condition. Clinical scores were assessed every 3 days after +14 d. At + 135 d, mice were killed to evaluate the pathological changes of major target organs.

Mice in transplantation groups were in hematopoietic reconstruction at +7 d, and all survived to the end point (+135 d). Chromosomes of recipient mice were in full donor chimera. Clinical scores of cGVHD group have been more than 0.6 since +90 d. These mice develop pathologic manifestations in several organs including lung, skin, and liver. Biopsy-proven BO incidence was 100%, and pathological scores of cGVHD group were 5.33±1.55, which significantly higher than those of transplantation control groups (P < 0.05).

To date, most models involve parent-into-F1 combinations the transfer of MHC-mismatched cells resulted in a phenotype that resembles clinical systemic lupus erythematosus (SLE), termed SLE-cGVHD. However, some of the models do not use any pretransplantation conditioning and no obvious lung tissue damage. We exchanged parent for recipients, and provide a total boby irradiation as pretransplantation conditioning. New MHC-mismatched murine cGVHD model was easily obtained, and more relevancy to the clinical features of cGVHD. This model provides an ideal study model of clinical cGVHD pathogenesis and treatment strategies.

NOTES: The project was sponsored by grants from National Natural Science Foundation (No. 81270648 and 30972790), National Public Health Grand Research Foundation (No.201202017), and Guangdong Natural Science Foundation (No. S2012010009560).