Allogeneic hematopoietic stem cell transplantation (HCT) is a potentially curative procedure for patients with hematologic malignancies; however, its success has been limited by the morbidity and mortality of post-transplant infection and graft versus host disease (GVHD) associated with perturbed immune reconstitution. Recent studies have demonstrated extraordinary diversity in the bacterial composition of the human gastrointestinal (GI) tract and have highlighted the capacity of the GI microbiota to modify innate and adaptive immune homeostasis. Prior to and during HCT, antibiotics, immune suppression, dietary alteration and mucosal injury alter the composition of the GI microbiota; however, relatively little is known in humans about the immunologic mediators that are responsive to changes in the GI microbiota and the mechanisms by which the microbiota might affect clinical outcomes after HCT. Recent characterization of non-conventional subsets of T cell receptor (TCR) ??+ T cells, such as mucosal-associated invariant T cells, invariant NKT cells, Th17 cells and Treg cells has shown that they are distinguished in part from conventional T cells by their remarkable dependence on the GI microbiota for differentiation and maintenance. These bacteria-responsive T cell subsets exhibit functional plasticity that enables pro-inflammatory or suppressive function, suggesting that alterations in the composition of the GI microbiota might affect their reconstitution after HCT and alter clinical outcomes. In this project, we will develop and interrogate a comprehensive microbiota, immunologic and clinical dataset to determine whether perturbation of the GI microbiota impacts reconstitution of non-conventional T cell subsets after allogeneic HCT, and establish the association of these T cell subsets with bacterial infection and GVHD. Identification of a link in these human studies between the composition of the GI microbiota, non-conventional T cell subset recovery, and clinical outcomes after HCT will be paradigm changing, and will guide future innovative approaches to investigate, prevent and treat delayed immune reconstitution and GVHD after HCT.
Allogeneic hematopoietic stem cell transplantation (HCT) is a potentially curative therapy for many blood and bone marrow diseases, immunodeficiencies, and metabolic disorders that are otherwise incurable with conventional therapies; however, the toxicities of transplantation have limited its success. Robust immune reconstitution after transplant may in part be guided by the bacterial composition of the gastrointestinal (GI) tract, which has recently been shown to impact the incidence of many human diseases, including blood disorders, obesity, diabetes, asthma, and cardiac disease. In this project, we will identify characteristics of the GI microbiota that are associated with recovery after HCT of subsets of immune system T cells that play an important role in defense against infections and regulation of inflammation. Our data may provide insight into characteristics of the GI microbiota that influence T cell homeostasis and promote or impair human health, and will guide future feasible strategies to modify the GI microbiota to improve outcomes of HCT and treat or prevent human blood, cardiac, pulmonary, autoimmune and metabolic diseases.
| Bhattacharyya, Abir; Hanafi, Laïla-Aïcha; Sheih, Alyssa et al. (2018) Graft-Derived Reconstitution of Mucosal-Associated Invariant T Cells after Allogeneic Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 24:242-251 |
