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

• Published in: Biology of blood and marrow transplantation 2009-07, Vol.15 (7), p.785-794
• Main Authors: Shatry, Alwi, Levy, Robert B
• Format: Article
• Language: English
• Subjects: Allogeneic HCT; Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; CD8-Positive T-Lymphocytes - immunology; Chimerism; Engraftment; Graft Survival - drug effects; Graft Survival - immunology; Hematology, Oncology and Palliative Medicine; Hematopoietic Stem Cell Transplantation; Histocompatibility Antigens - immunology; Host vs Graft Reaction - drug effects; Host vs Graft Reaction - immunology; Interleukin-2 - immunology; Interleukin-2 - pharmacology; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; MHC-matched; Mice; T-Lymphocytes, Regulatory - immunology; Time Factors; Tolerance; Transplantation Chimera - immunology; Transplantation, Homologous; Tregs
• ISSN: 1083-8791; 1523-6536
• DOI: 10.1016/j.bbmt.2009.03.011

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.