Allogeneic hematopoietic stem cell transplantation (HSCT) is often the only curative option for hematological malignancies such as acute myeloid leukemia (AML) and non-malignant blood disorders such as sickle cell disease. However, allogeneic HSCT is limited by acute graft- versus-host disease (GvHD), a common and potentially lethal complication that involves the destruction of host tissues and organs by alloreactive donor immune cells present in the transplanted graft. The aim of this project was to further elucidate the role of heme oxygenase-1 (HO-1) in disease, with the focus on acute graft-versus-host disease (GvHD). HO-1 has important anti-inflammatory functions. HO-1 is of great interest to us because its expression can be strongly induced by external stimuli, providing potential for therapeutic application.
We used plasma samples of allogeneic hematopoietic stem cell transplantation recipients with and without acute GvHD, as well as a humanized mouse model for acute GvHD to perform our experiments.
For all allogeneic HSCT recipients (n = 66) in our cohort we had samples available at baseline (just before allogeneic HSCT) and at several timepoints after allogeneic HSCT (1 month and 3 months). We measured plasma levels of HO-1 and of the scavenger proteins haptoglobin and hemopexin in both patient cohorts and in plasma samples of healthy controls. We found significantly higher plasma levels of HO-1 in all allogeneic HSCT recipients at 1 month after transplantation compared to healthy controls. At 3 months after transplantation, patients with early acute GvHD had significantly higher levels of HO-1 compared to patients with late acute GvHD and healthy controls. We found no differences in haptoglobin or hemopexin levels at any of the timepoints. Finally, we investigated the role of HO-1 in a humanized mouse model for acute GvHD. We then compared mice that we left untreated to mice that we treated with a compound named cobalt protoporphyrin IX chloride (CoPP), which is a potent inducer of HO-1 expression. We found that mice treated with CoPP showed better survival and significantly reduced weight loss and disease severity compared to untreated mice. Overall, our results indicate that HO-1 is involved in the development and progression of acute GvHD and that the induction of HO-1 in patients may be a valid treatment strategy.

THESIS 2023: Mediators of tissue damage and inflammation in acute graft-versus-host disease - Myrrdin Verheij