Allogeneic hematopoietic stem cell transplantation (HSCT) intends to cure high-risk hematological malignancies, immunodeficiencies, metabolic disease, or a life-threatening bone marrow failure syndrome. Despite substantial advances, graft-versus-host disease (GvHD) is a major contributor to morbidity and mortality after allogenic HSCT. The intestinal epithelial cells (IECs) in the gastrointestinal (GI) tract plays a critical role in driving the pathogenesis of acute GvHD, which occurs within the first few months following transplantation. Dr. Geoff Hill’s group has developed methods of reducing the risk of GvHD by (i) modulating the subject’s microbiome via administration of antibiotics, probiotics, or fecal transplant, and/or (ii) by reducing the activity of an inflammatory cytokine by administering cytokine inhibitor(s), and/or (iii) by reducing the expression of MHC II on intestinal epithelial cells in the subject by administering innate defense regulators and host defense peptides. These methods are developed based on the finding that IECs presented alloantigen to CD4+ T cells, which is crucial in initiating GvHD. Additional In vivo mouse experiments demonstrate that inhibition of microbiota-driven IL-12 pretransplant was sufficient to attenuate MHC class II expression by IECs and prevent acute GvHD lethality. In order to reduce the risk of GVHD in a transplant recipient, a composition addressing the above approaches can be administered to the subject before transplantation and preferably prior to conditioning therapy.
- Reduce risk of GvHD following allogenic HSCT, BMT
- Reduce risk of acuate GVHD following organ transplantation
- Multiple strategies can be applied together to maximize results
- Therapeutic Interventions target the underlying immunopathobiology without deleting macrophages or dendritic cells
- IECs drive pathogenies and can be controlled by soluble mediators in response to the microbiome
US Patent Application No. 17/298,312
Over 30,000 allogeneic HSCT transplants are carried out annually worldwide and are increasing each year. Acute GvHD will affect up to 70% of patients and approximately half of these patients will develop acute GvHD of the GI tract. Novel therapeutic interventions to mitigate the morbidity and mortality of transplantation are needed to improve the quality of life and survival after HSCT.
- Geoffrey Hill, M.D., FRACP, FRCPA, Clinical Research Division
Director, Hematopoietic Stem Cell Transplantation
Scientific Director, Immunotherapy Integrated Research Center
José Carreras/E. Donnall Thomas Endowed Chair for Cancer Research