UC Irvine

Blood cells keep us alive by fighting off infection and providing oxygen to every cell in our body. Every blood cell is derived from hematopoietic stem cells (HSCs) which can self-renew to maintain a constant HSC pool throughout a lifetime, engraft long-term in a conditioned recipient, and give rise to all the lineage blood cells. These characteristics are key for carrying out the lifesaving therapy HSC transplantation (HSCT), also known as hematopoietic cell transplantation (HCT) or bone marrow transplantation (BMT). A form of HCT called allogeneic HCT (allo-HCT) is a therapeutic strategy that eradicates a defective blood system, often with radiation therapy or chemotherapy conditioning, then replaces it with a healthy one using non-identical donor HSCs. It is effective against hematological malignancies like leukemia, and lymphoma, the 7th and 8th leading cause of death among cancers. Unfortunately, allo-HCT is used as a last resort treatment due to the complications associated with it including suboptimal allo-HSC recipient engraftment and the major complication Graft-vs-Host disease (GvHD). Resolving these limitations could increase the shortage of much needed donor cells and expand the patient pool to patients with milder blood cancer cases and other diseases such as autoimmune diseases. GvHD occurs when donor immune cells, or graft cells, recognize the host as a foreign threat, thus engendering host tissue damage and organ failure. Many have strived to prevent GvHD after allo-HCT, however, there is still a high incidence of GvHD seen in the clinic. Currently, we face the complex challenge of minimizing GvHD while conserving the benefit of the Graft-vs-Leukemia (GvL) effect elicited by donor immune cells. There is currently no strategy that fully satisfies all these issues plaguing allo-HCT. There is a need for a new approach to safely and efficiently eliminate GvHD while preserving GvL and HSC engraftment in allo-HCT. Here we explore a new proof-of-principle method that prevents GvHD after allo-HCT by using the glucocorticoid fluticasone propionate (Flonase) on a mouse model. We treated donor cells isolated from spleen and bone marrow with the glucocorticoid fluticasone propionate (Flonase) then transplanted them into lethally irradiated fully major histocompatibility complex (MHC) mismatched allogeneic recipients to prevent GvHD. We provide evidence on Flonase efficacy that addresses multiple issues associated with allo-HCT. Here we show that Flonase treatment increases HSC chemotaxis to the bone marrow through increased C-X-C chemotactic receptor type 4 (CXCR4) expression. We also show that pre-treating donor cells with Flonase decreases GvHD in allo-HCT and creates donor T cell immune tolerance. Our results demonstrate a possible mechanism underlying Flonase-induced immune tolerance involving regulatory T cell suppression of alloreactive cells. We also utilize HCT to learn more about pre-HSCs, the HSC precursor. Altogether, we explore potential ways of improving HCT by shedding light on the pre-HSC and showing proof of concept that Flonase donor cell pre-treatment can prevent GvHD. We also investigate using HCT to treat the autoimmune disease Idiopathic Thrombocytopenic Purpura (ITP) by first developing a new mouse model to allow us to test HCT.