1. Immune dysregulation
My lab is studying the role of specific T cells subpopulations in regulating immune responses during severe allergic reactions, autoimmunity and exaggerated inflammation such as that observed among patients with Omenn’s syndrome [1,2] or following cell and organ transplantations.
2. Hematopoietic stem cell transplantation
Allogeneic hematopoietic stem cell transplantations (HSCT) have been used to treat many patients suffering from severe PIDD. We demonstrated that HSCT using HLA-matched unrelated donors result in better survival and immune reconstitution than HSCT using haplo-identical parents [3,4]. Currently my lab is investigating the best preparation for HSCT (myeloablative versus non-myeloablative chemotherapy), stem cell source (bone marrow versus umbilical cord blood) and management of graft-versus host disease, which is still the main cause for morbidity and mortality after HSCT for PIDD [5,6].
3. Inherited purine defects
Inherited defects in the purine enzymes adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) account for >25% of all profound T cells deficiencies [7,8]. We have recently demonstrated that ADA- and PNP- deficiency also cause neurological, pulmonary, hepatic and bone abnormalities in children [9, 10, 11, 12]. Using relevant ADA- and PNP- deficient animal models as well as induced pleuri-potent stem cells from patients, my lab has been able to better characterize the mechanisms contributing to the multi-organ damage. Understanding the pathogenesis of these conditions has allowed us to better appreciate the effects of HSCT , enzyme replacement [14, 15] and gene therapy [16, 17, 18] for ADA and PNP deficiency. Indeed, recognizing the limitation of current management options and the need to correct the neurological defects led my lab to develop novel treatments that deliver the missing purine enzymes into cells and across the blood brain barrier [19, 20, 21, 22], a strategy that my lab continues to explore.