In situ activation and expansion of host tregs: a new approach to enhance donor chimerism and stable engraftment in major histocompatibility complex-matched allogeneic hematopoietic cell transplantation.
Host antidonor effector T cells represent a major barrier to the successful engraftment of allogeneic donor hematopoietic progenitor and stem cells. Here, administration of a complex of IL-2 and anti-IL 2 antibodies (IAC) significantly enhanced donor chimerism early as well as long-term engraftment following reduced-intensity conditioning (RIC) and allogeneic major histocompatibility complex (MHC)-matched hematopoietic cell transplantion (HCT). Timing of administration of this complex was crucial: administration of IAC post-HCT more efficiently facilitated marrow engraftment than pre-HCT treatment. Donor chimerism persisted to >6 months post-HCT. Importantly, this approach clearly suppressed the emergence of host antidonor CD8 T cells 2 to 3 weeks post-HCT as assessed by tetramer staining. Following in vivo reactivation of IAC-treated and control recipients at >5 months post-HCT with donor antigen, only PBS-treated control marrow allograft recipients responded with tetramer-binding CD8 cells. In total, the present findings support the notion that the transient activation and expansion of host Tregs in situ post-HCT can be explored as a new approach to regulate host alloreactivity posttransplant. Interestingly, direct stimulation of recipient Treg cells in RIC recipients obviated a requirement for exogenous Treg cell transfusion in this model and may represent a viable alternative to, and/or complement the adaptive transfer of Treg populations in clinical HCT.
Shatry
Alwi
A
Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33101, USA. ashary@med.miami.edu
Levy
Robert B
RB
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D006649:Histocompatibility Antigens / Q000276:immunology*; D006789:Host vs Graft Reaction / Q000187:drug effects* / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D013997:Time Factors; D018183:Transplantation Chimera / Q000276:immunology*; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D006649:Histocompatibility Antigens; D007376:Interleukin-2