The role of the innate immune system in acute Graft-versus-Host disease

Abstract

Acute Graft-versus-Host disease (aGvHD) remains a potentially lethal complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and an obstacle to curing blood cancer. A persistent challenge in finding new treatment options is the ambiguous role of allo-reactive donor T cells, which mediate both graft-versus-host but also graft-versus-leukemia (GvL) immunity. This thesis explores how the innate immune system contributes to aGvHD development and could be exploited for treatment. <br/> Here, we establish a common MHC-mismatched mouse model for aGvHD (C57BL6/N → BALB/c) using x-ray total body irradiation (TBI). Although considerably lower than previously reported target dosages, TBI with 5 Gy provides sufficient myeloablation and facilitates donor engraftment. Allo-HSCT with bone marrow and T cells results in non-lethal radiation sickness and subsequent clinical manifestation of aGvHD. <br/> Using this model, we investigate the potential of myeloperoxidase (MPO) inhibition as a means to target neutrophils. Our data show that preemptive inhibition of MPO through treatment with ABAH prior to the conditioning improves aGvHD severity and lethality. ABAH-treated mice present with decreased serum levels of pro-inflammatory cytokines (IL-1, TNFα, CXCL1), lipocalin-2, and liver enzymes shortly after allo-HSCT, indicating ameliorated early inflammation and tissue damage. Treatment with ABAH also reduced T cell infiltration and inflammation in liver and small intestine on day 21 after allo-HSCT. Interestingly, GvL activity remained unaffected by MPO inhibition, suggesting that the GvL effect is at least partially independent of the early events leading to aGvHD. Furthermore, ABAH treatment did not result in impaired bacterial clearance during urinary tract infection (UTI) with <em>E. coli</em>. <br/> We also investigated whether eosinophils contribute to aGvHD development but found that neither adoptive transfer nor antibody-mediated depletion of eosinophils in recipient mice altered aGvHD severity and lethality. <br/> In conclusion, our study provides evidence that neutrophil-derived MPO exacerbates conditioning-induced inflammation and tissue damage, which subsequently drives aGvHD pathogenesis, but is dispensable for GvL activity. Therefore, targeting the innate immune system, for example by inhibition of MPO, presents a promising prophylactic strategy for the prevention of aGvHD without increased risks of relapse or infection.