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Blood, 1 December 2008, Vol. 112, No. 12, pp. 4765-4775.
Prepublished online as a Blood First Edition Paper on July 14, 2008; DOI 10.1182/blood-2008-05-154278.


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TRANSPLANTATION

Graft rejection as a Th1-type process amenable to regulation by donor Th2-type cells through an interleukin-4/STAT6 pathway

Jacopo Mariotti1, Jason Foley1, Kaitlyn Ryan1, Nicole Buxhoeveden1, Veena Kapoor1, Shoba Amarnath1, and Daniel H. Fowler1

1 Experimental Transplantation and Immunology Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD

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 posttransplantation, 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.


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