Project Details
Projekt
Effects of intestinal microbiota and their metabolites on immune reconstitution and graft-versus-host disease in patients undergoing allogeneic hematopoietic stem cell transplantation
Applicant
Dr. Sarah Lindner
Subject Area
Hematology, Oncology
Term
from 2019 to 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 428031595
Allogeneic hematopoietic cell transplantation (allo-HCT) is for many hematological malignancies a curative treatment but graft-versus-host disease (GVHD), infections, and relapse remain a major cause of morbidity and mortality. GVHD results from the donor immune system recognizing host tissues as foreign, leading to life-threatening inflammation. The immune-suppression strategies currently in use to prevent and treat GVHD are only partially effective and simultaneously increase the risks for relapse and infections. One promising approach to reduce GVHD but leave immune function intact is to target the complex community of microbes that reside within our intestinal tracts, termed intestinal microbiota. In recent years, extensive next-generation sequencing studies determining the genomes of microbiota in mice and patients showed a significant relationship between intestinal microbiota and major complications of allo-HCT, but the mechanistic relationship is still not well understood. In our research project we will study in Aim 1 the recovery of microbiota after allo-HCT and its relationship with immune reconstitution. We will prioritize an in-depth analysis of mucosal-associated invariant T cells (MAITs) because of their critical role in coordinating immune response to microbial invasion within the lamina propria. We will use advanced fluorescence-activated cell sorting (FACS) analysis at multiple time points and will assess donor-host chimerism of FACS-purified MAITs at optimal timepoints using standard short tandem repeat polymerase chain reaction. In addition, we will correlate clinical, microbiota and metabolomic outcome data to assess the relationship of MAIT and immune cell reconstitution to transplant outcomes, microbiota and functional microbial pathways. In Aim 2 we will do comprehensive metabolomics and lipidomic profiling of stool samples of experimental mice with and without GVHD to identify the microbiota-derived metabolites that contribute to GVHD (Subaim 2.1). We will use algorithms to predict biosynthetic gene clusters that will point to specific organisms that we will then mono-associate into the germfree GVHD models (Subaim 2.2). In Aim 1 we expect to find associations between post-HCT reconstitution of MAITs and other immune populations with acute GVHD and other clinical transplant outcomes, and to discover associations between MAIT reconstitution and intestinal microbiota features, specifically α-diversity, individual taxa or functional metabolic pathways of gut microbes. In Aim 2 we expect that riboflavin-pathway intermediates will be found in decreased abundance in GVHD-affected mice as compared with non-GVHD control animals. In the colonized germ-free mice with candidate bacteria from Subaim 2.1 we expect to ameliorate or exacerbate GVHD. This research project will help to elucidate the mechanisms by which the microbiota can regulate immune reconstitution and GVHD and to define novel GVHD prevention and treatment strategies.
DFG Programme
Research Fellowships
International Connection
USA
