TGF-beta in allogeneic stem cell transplantation: friend or foe?
Donor treatment with granulocyte-colony-stimulating factor (G-CSF) attenuates the ability of donor T cells to induce acute graft-versus-host disease (aGVHD) but increases the severity of chronic GVHD (cGVHD). We investigated the role of the regulatory cytokine transforming growth factor beta (TGF-beta) in this paradox in well-established murine models of aGVHD and cGVHD wherein recipients undergo transplantation with splenocytes from donors treated with G-CSF. Neutralization of TGF-beta after stem-cell transplantation (SCT) significantly increased the severity of aGVHD, and the concurrent prevention of interleukin-10 (IL-10) production further exaggerated this effect. Early after SCT, donor T cells were the predominant source of TGF-beta and were able to attenuate aGVHD in a TGF-beta-dependent fashion. Although the neutralization of TGF-beta augmented the proliferation and expansion of donor T cells after SCT, it paradoxically impaired cellular cytotoxicity to host antigens and associated graft-versus-leukemia (GVL) effects. In cGVHD, neutralization of TGF-beta from day 14 after SCT attenuated histologic abnormalities, and CD11b+ mononuclear cells infiltrating sclerodermatous skin produced 50-fold more TGF-beta than corresponding T cells. Thus, though the production of TGF-beta by donor T cells early after transplantation attenuates aGVHD and is required for optimal GVL, the production of TGF-beta late after SCT is preferentially from mononuclear cells and mediates cGVHD. These data have important implications for the timing of therapeutic TGF-beta neutralization to prevent cGVHD after allogeneic SCT.
Banovic
Tatjana
T
Bone Marrow Transplantation Laboratory, Queensland Institute of Medical Research, 300 Herston Rd, Herston, QLD 4006, Australia.
MacDonald
Kelli P A
KP
Morris
Edward S
ES
Rowe
Vanessa
V
Kuns
Rachel
R
Don
Alistair
A
Kelly
Jane
J
Ledbetter
Steve
S
Clouston
Andrew D
AD
Hill
Geoffrey R
GR
D000208:Acute Disease; D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D006086:Graft vs Host Disease; D020544:Graft vs Leukemia Effect / Q000187:drug effects; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D051379:Mice; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental / Q000150:complications / Q000628:therapy; D013601:T-Lymphocytes / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology*; D014184:Transplantation, Homologous
D016212:Transforming Growth Factor beta