Allogeneic hematopoietic stem cell transplantation (HCT) represents a powerful curative therapy for a broad range of hematologic malignancies and non-malignant diseases. However, HCT is associated with multiple toxicities, one of the most deadly being acute Graft-versus-Host Disease (aGVHD). Despite decades-long investigation, current clinical practice still predominantly relies on non-specific pan-immunosuppression for aGVHD prevention and treatment, and a significant proportion of HCT patients continue to develop steroid-resistant aGVHD, which is associated with up to 50% mortality. Therefore, the identification of novel targeted approaches for controlling the pathologic alloimmunity that drives aGVHD, and their validation in a clinically-relevant model remains a critical unmet need.
To address this, in Dr. Kean’s laboratory we have developed a translational model of aGVHD in non-human primates (NHP), which allows mechanistic studies of immunity following transplantation in a setting, faithfully recapitulating HCT in patients, and enabling a rigorous interrogation of target organ-specific aGVHD mechanisms. Our current research projects are dedicated to the following areas:
Systems immunology of aGVHD. Our laboratory use systems biology approaches and gene editing technologies to identify and precisely target signaling pathways that are highly specific for pathogenic disease-causing T cells during aGVHD but spare physiologic immune reconstitution following aGVHD.
Mechanisms of tissue-specific alloimmunity. Our laboratory aim to discover the mechanisms of tissue-specific immunopathology that drives aGVHD with the particular interest to the role of donor- and recipient-derived tissue-resident T cells.
Co-stimulatory blockade for aGVHD control. We are studying the contribution of different co-stimulatory pathways to the pathogenic activation of donor T cells after allogeneic HCT and the translational potential of the novel immunosuppressive regimens utilizing targeted costimulatory blockade.