Submitted May 1, 2008
Accepted June 24, 2008
Graft rejection as a Th1-type process amenable to regulation by donor Th2-type cells through an IL-4/STAT6 pathway
Jacopo Mariotti*, Jason Foley, Kaitlyn Ryan, Nicole Buxhoeveden, Veena Kapoor, Shoba Amarnath, and Daniel H Fowler
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
* Corresponding author; email: mariottj{at}mail.nih.gov.
Graft rejection has been defined as the mirror image of graft-versus-host disease, which is biologically characterized primarily as a Th1-type process. As such, we reasoned that graft rejection would represent a Th1 response amenable to Th2 modulation. Indeed, adoptive transfer of host Th1-type cells mediated rejection of fully MHC-disparate murine bone marrow allografts more effectively than host Th2-type cells. Furthermore, STAT1-deficient host T cells did not differentiate into Th1-type cells in vivo and failed to mediate rejection. We next hypothesized that donor Th2 cell allograft augmentation would prevent rejection by modulation of the host Th1/Th2 balance. In the setting of donor Th2 cell therapy, host-anti-donor allospecific T cells acquired Th2 polarity, persisted post-transplant, and did not mediate rejection. Abrogation of rejection required donor Th2 cell IL-4 secretion and host T cell STAT6 signaling. In conclusion, T cell-mediated marrow graft rejection primarily resembles a Th1-type process that can be abrogated by donor Th2 cell therapy that promotes engraftment through a novel mechanism whereby cytokine polarization is transferred to host T cells.
