Instructor, Pediatrics - Stem Cell Transplantation
Member, Maternal & Child Health Research Institute (MCHRI)
Preclinical Safety and Efficacy Validation of CD4(LVFOXP3) Cells as an Innovative Cell-Based Gene Therapy Approach for IPEX Syndrome
CELL PRESS. 2021: 340
View details for Web of Science ID 000645188700689
Human-engineered Treg-like cells suppress FOXP3-deficient T cells but preserve adaptive immune responses in vivo.
Clinical & translational immunology
2020; 9 (11): e1214
Genetic or acquired defects in FOXP3+ regulatory T cells (Tregs) play a key role in many immune-mediated diseases including immune dysregulation polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Previously, we demonstrated CD4+ T cells from healthy donors and IPEX patients can be converted into functional Treg-like cells by lentiviral transfer of FOXP3 (CD4LVFOXP3). These CD4LVFOXP3 cells have potent regulatory function, suggesting their potential as an innovative therapeutic. Here, we present molecular and preclinical in vivo data supporting CD4LVFOXP3 cell clinical progression.The molecular characterisation of CD4LVFOXP3 cells included flow cytometry, qPCR, RNA-seq and TCR-seq. The in vivo suppressive function of CD4LVFOXP3 cells was assessed in xenograft-versus-host disease (xeno-GvHD) and FOXP3-deficient IPEX-like humanised mouse models. The safety of CD4LVFOXP3 cells was evaluated using peripheral blood (PB) humanised (hu)- mice testing their impact on immune response against pathogens, and immune surveillance against tumor antigens.We demonstrate that the conversion of CD4+ T cells to CD4LVFOXP3 cells leads to specific transcriptional changes as compared to CD4+ T-cell transduction in the absence of FOXP3, including upregulation of Treg-related genes. Furthermore, we observe specific preservation of a polyclonal TCR repertoire during in vitro cell production. Both allogeneic and autologous CD4LVFOXP3 cells protect from xeno-GvHD after two sequential infusions of effector T cells. CD4LVFOXP3 cells prevent hyper-proliferation of CD4+ memory T cells in the FOXP3-deficient IPEX-like hu-mice. CD4LVFOXP3 cells do not impede in vivo expansion of antigen-primed T cells or tumor clearance in the PB hu-mice.These data support the clinical readiness of CD4LVFOXP3 cells to treat IPEX syndrome and other immune-mediated diseases caused by insufficient or dysfunctional FOXP3+ Tregs.
View details for DOI 10.1002/cti2.1214
View details for PubMedID 33304583
View details for PubMedCentralID PMC7688376
Immunoregulatory Cell Therapy with Lentiviral-Mediated FOXP3 Converted CD4+T Cells into Treg Cells: Towards the Proof-of-Concept Application in IPEX Syndrome
CELL PRESS. 2019: 311
View details for Web of Science ID 000464381003119
Tregopathies: Monogenic diseases resulting in regulatory T-cell deficiency.
The Journal of allergy and clinical immunology
2018; 142 (6): 1679–95
Monogenic diseases of the immune system, also known as inborn errors of immunity, are caused by single-gene mutations resulting in immune deficiency and dysregulation. More than 350 diseases have been described to date, and the number is rapidly expanding, with increasing availability of next-generation sequencing facilitating the diagnosis. The spectrum of immune dysregulation is wide, encompassing deficiencies in humoral, cellular, innate, and adaptive immunity; phagocytosis; and the complement system, which lead to autoinflammation and autoimmunity. Multiorgan autoimmunity is a dominant symptom when genetic mutations lead to defects in molecules essential for the development, survival, and/or function of regulatory T (Treg) cells. Studies of "Tregopathies" are providing critical mechanistic information on Treg cell biology, the role of Treg cell-associated molecules, and regulation of peripheral tolerance in human subjects. The pathogenic immune networks underlying these diseases need to be dissected to apply and develop immunomodulatory treatments and design curative treatments using cell and gene therapy. Here we review the pathogenetic mechanisms, clinical presentation, diagnosis, and current and future treatments of major known Tregopathies caused by mutations in FOXP3, CD25, cytotoxic Tlymphocyte-associated antigen 4 (CTLA4), LPS-responsive and beige-like anchor protein (LRBA), and BTB domain and CNC homolog 2 (BACH2) and gain-of-function mutations in signal transducer and activator oftranscription 3 (STAT3). We also discuss deficiencies in genesencoding STAT5b and IL-10 or IL-10 receptor aspotential Tregopathies.
View details for DOI 10.1016/j.jaci.2018.10.026
View details for PubMedID 30527062
FOXP3 Gene Transfer in T cells and FOXP3 Gene Editing in HSC as Novel Treatment Options for IPEX Syndrome
SPRINGER/PLENUM PUBLISHERS. 2018: 427
View details for Web of Science ID 000431311600212