Absence of IL-23p19 in donor allogeneic cells reduces mortality from acute GVHD.
The p19 dimer of interleukin 23 (IL-23) has been reported to have a major role in the pathogenesis of many experimental and clinical autoimmune diseases and may also have a prominent role in transplantation. We reasoned that deficiency of p19 in the allogeneic donor transplant might reduce the inflammation caused by acute GVHD (aGVHD). The major histocompatibility complex-2 (H2(d)) BALB/c mice were subjected to 8.5 Gy TBI, followed by transplantation with 10 x 10(6) BM and 2.5 x 10(6) spleen cells from H2(d) BALB/c, H2(b) C57Bl/6 (B6) or H2(b) p19-/- donors. In all, 75% of the p19-/- transplanted mice survived, compared with only 12.5% of the B6 transplanted mice. This superior survival is correlated with significantly less severe aGVHD, absence of p19 after transplantation, less upregulation of mRNA and lower serum levels of IL-17 as compared with the B6 transplants. TBI alone significantly upregulated transforming growth factor-beta (TGF-beta), IL-6 and p19 mRNA levels in host BALB/c mice, possibly providing the milieu to induce IL-17 in p19-/- donor cells. IL-22, another cytokine, the induction of which in T-helper 17 (Th17) cells is supported by p19, was upregulated in BALB/c hosts but not in transplanted B6 or p19 donor cells, and may not have had a major role in modifying aGVHD.
Thompson
J S
JS
Veterans Affairs Medical Center, Department of Internal Medicine, University of Kentucky, Lexington, KY 40502, USA. jsthom1@uky.edu
Chu
Y
Y
Glass
J F
JF
Brown
S A
SA
D000818:Animals; D006086:Graft vs Host Disease / Q000378:metabolism*; D006650:Histocompatibility Testing; D020381:Interleukin-17 / Q000235:genetics* / Q000378:metabolism; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D033581:Stem Cell Transplantation; D016019:Survival Analysis; D014184:Transplantation, Homologous; D015854:Up-Regulation; D014916:Whole-Body Irradiation; D000097043:Interleukin-22
D020381:Interleukin-17; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D012333:RNA, Messenger; D000097043:Interleukin-22