Dnase I Treatment Reduces Gvhd in Mice

Graft-versus-host-disease (GVHD) is an alloimmune response complicating allogeneic hematopoietic stem cell transplantation (allo-HSCT). The development of GVHD is thought to involve three phases: T cell activation, followed by proliferation and differentiation of allogeneic T cells into activated effector cells, and finally specific tissue damage. In the activation phase, donor T cells interact with host APCs, leading to activation and differentiation toward the effector pathway and migration of these cells to target tissues affected during acute GVHD. Although donor T lymphocytes and recipient antigen presenting cells (APCs) are the primarily mediators of GVHD, the molecular and cellular basis are not well understood. Thus, the prevention and treatment of GVHD remains a major challenge. Deoxyribonuclease I (DNaseI) is an endonuclease that facilitates chromatin breakdown of apoptotic and necrotic cells. The impaired activity of DNaseI has been associated with the pathogenesis of systemic lupus erythematosus (SLE) and inflammatory bowl diseases (IBD). Using the MHC class I and II disparate model, C57BL/6 (H-2^b) to BALB/c (H-2^d), our studies demonstrate that DNaseI treatment can reduce GVHD mortality and morbidity in mice. In comparison to PBS control, DNaseI-treated mice showed a lower mortality rate. Within 4 weeks post-transplantation, 80% of DNaseI-treated recipients survived, compared with only 30% of PBS control mice. Whereas control recipients had severe GVHD in the skin, intestine, liver, and lung, DNaseI-treated mice exhibited only mild changes in these organs, reflected in their significantly lower GVHD scores. Furthermore, we analyzed donor-derived T cells in mice 7 days post-transplant, and found a significantly lower number of donor-derived CD4⁺ and CD8⁺ subsets in the peripheral lymph node (pLN) and Peyer’s patches (PP) of DNaseI-treated mice compared to that of PBS control recipients. We further investigated the functional consequences of DNaseI treatment on inflammatory cytokine production in GVHD mice, and found the frequency of IFN-γ (Th1), IL-17 (Th17) and IL-2 producing donor CD4⁺ cells in the spleen was significantly reduced in DNaseI-treated mice compared to PBS control mice. The results have established the disease-modifying activity of DNaseI in mouse GVHD model, and thus raise the possibility for using this drug as a potential new therapeutic intervention.