Publication Date:
2016-12-02
Description:
INTRODUCTION Regulatory T cells (Treg) modulate allograft immune responses and Treg-based cellular therapies can be used for prevention of graft-versus-host disease (GvHD) following hematopoietic cell transplantation and for prevention of allograft rejection following tissue or organ transplantation. Treg adoptive transfer has limitations including that Treg do not necessarily home to sites where they are needed and can become inactivated in inflammatory milieus. METHODS We used new technologies of T cell engineering to force the expression of a chimeric antigen receptor on T cells and Treg that recognizes labeled therapeutic monoclonal antibodies (mabCAR), allowing for precise control of their localization in vivo. The mabCAR recognizes fluorescein isothiocyanate (FITC) through a FITC-specific single-chain variable fragment fused to a CD28 and TCRζ costimulatory domain. Any monoclonal antibody (mab) coupled to FITC within its Fc domain can be recognized. We tested this approach with T cells and Treg to ameliorate GvHD and induce tolerance to pancreatic islet grafts. RESULTS We first tested our mabCAR construct in conventional T cells (Tcon) which when transfected and stimulated with a FITC-mab become activated and expressed higher levels of CD44 (p=0.0003), CD25 (p=0.009) and produced more IFNγ (p=0.04). To test if mabCAR transient transfection alters Tcon homing after adoptive transfer, we injected luc+ mabCAR Tcon directed against MAdCAM1 (a gut and lymph node endothelial integrin) or SDF1 (a chemokine mainly expressed in the bone marrow) into allogeneic hosts. MAdCAM1-directed Tcon mainly homed to the gut and lymph nodes, while SDF1-directed Tcon homed to bones and spleen. SDF1-directed Tcon induced a milder GvHD (p
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
Permalink