Graft rejection as a Th1-type process amenable to regulation by donor Th2-type cells through an interleukin-4/STAT6 pathway.
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.
Mariotti
Jacopo
J
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. mariottj@mail.nih.gov
Foley
Jason
J
Ryan
Kaitlyn
K
Buxhoeveden
Nicole
N
Kapoor
Veena
V
Amarnath
Shoba
S
Fowler
Daniel H
DH
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D006086:Graft vs Host Disease / Q000276:immunology; D015847:Interleukin-4 / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D050800:STAT6 Transcription Factor / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology / Q000502:physiology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D014184:Transplantation, Homologous / Q000276:immunology; D014185:Transplantation, Isogeneic / Q000276:immunology
D050794:STAT1 Transcription Factor; D050800:STAT6 Transcription Factor; C494080:Stat1 protein, mouse; D015847:Interleukin-4