ImMiGeNe - Interplay of immune parameters, microbiota and host genetics during childhood stem cell transplantation

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The gut microbiota are thought to strongly influence human health and are regulated by innate (mediated, for example, by pattern recognition receptors (PRRs) via recognition of microbe-associated molecular patterns, MAMPs) and adaptive (mediated by antigens and soluble IgA) immune recognition and effector mechanisms. However, the interplay of microbiota, host immune system and host genetics have not always been studied systematically and longitudinally. Since microbiome studies in humans are usually non-interventional for ethical reasons, the relationships established so far have, for the major part, been based on observations in mouse models or purely correlative without establishing causalities. Stem cell transplantation (SCT) patients undergo significant interventions in terms of their microbiota, immune system, and host genetics, providing the unique opportunity to assess the impact of strong interventions on both the microbiota and the immune system in human subjects. But how donor immuno-genetics affect matching within a SCT recipient in terms of host factors beyond classical HLA (e.g. including so-called minor histocompatibility antigens, miHAs, e.g. coding SNPs, and non-typical HLAs) is not fully understood, and whether the donor immune system encounters ‘matching issues’ due to the recipient’s microbiota having been imprinted by the recipient immune system is unclear. Within the ImMiGeNe study (NCT02940093) longitudinal (nine time points) stool, urine, and blood samples as well as full clinical documentation have been acquired for 20 donor-recipient SCT pairs and fecal samples have already been subjected to metagenomics shotgun microbiome analysis. In order to correlate changes in the microbiome to changes in host genetics and immune system, we here propose to conduct whole-exome sequencing (WES) and transcriptomics of SCT donor and recipients via the Tübingen NGS hub. Using novel bioinformatics tools developed by us, we will explore whether differences between donor and recipient in terms of PRRs affect MAMP abundance and mutations at the level of the microbiota. The data will also be used to explore matching beyond classical HLA-A, -B, -C, DRB1 and DQB1 and include miHAs. Additionally, we will investigate microbiota shotgun metagenomics sequences for evidence of ‘imprinting’ by the recipient’s immune system, and whether changed immunogenicity of certain taxa leads to a change in microbiome composition post-SCT. All three questions will be related to well-documented and detailed clinical data in terms of graft versus host disease (GvHD) and long-term complications like diarrhea and malabsorption. Bringing our expertises in immunology and bioinformatics together, our joint aim is to discover host and microbial biomarkers for the prediction and subsequent reduction/prevention of SCT-associated adverse effects and to gain valuable insights into the interplay between microbiota and host via this unbiased multi-omics approach.