Expression of chemokines in GVHD target organs is influenced by conditioning and genetic factors and amplified by GVHR.
Graft-versus-host disease (GVHD) is the most significant clinical problem that arises after allogeneic hematopoietic cell transplantation. Because chemokines induced by proinflammatory conditioning treatment may promote T-cell migration into GVHD target tissues, we addressed the influence of conditioning on chemokine expression in GVHD target organs. Our results showed that (1) conditioning leads to rapid and transient chemokine upregulation in GVHD target tissues before the time of GVHD-associated T-cell infiltration; (2) conditioning intensity and mouse strain influence chemokine expression in GVHD target organs; and (3) compared with syngeneic bone marrow transplantation, allogeneic bone marrow transplantation led to marked amplification of chemokine expression in GVHD target organs after myeloablative conditioning. This is also reflected by chemokine protein expression that is measured in the serum and colon. Intestines showed the greatest sensitivity to conditioning intensity, and chemokines affecting T-helper type 1 cells (eg, interferon gamma-inducible protein 10 [CXCL10]) were most strongly expressed there after conditioning and during GVHD. However, severity of GVHD was not significantly different between recipients of CXCR3+/+ or CXCR3-/- splenocytes, indicating that this chemokine pathway does not play a critical role. In summary, our data show that conditioning and recipient strain influence chemokine expression in GVHD target organs and that GVH alloreactivity markedly amplifies this expression, thus contributing to the inflammatory cascade associated with tissue GVHD.
Mapara
Markus Y
MY
Transplantation Biology Research Center, Bone Marrow Transplantation Section, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA.
Leng
Corinna
C
Kim
Yong-Mi
YM
Bronson
Roderick
R
Lokshin
Anna
A
Luster
Andrew
A
Sykes
Megan
M
D000818:Animals; D054357:Chemokine CXCL10; D018925:Chemokines / Q000235:genetics*; D019743:Chemokines, CXC / Q000235:genetics; D005260:Female; D006086:Graft vs Host Disease / Q000235:genetics / Q000503:physiopathology*; D006087:Graft vs Host Reaction; D007700:Kinetics; D008099:Liver / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000235:genetics; D012260:Ribonucleases; D012867:Skin / Q000382:microbiology; D033581:Stem Cell Transplantation / Q000379:methods*; D014184:Transplantation, Homologous
D054357:Chemokine CXCL10; D018925:Chemokines; D019743:Chemokines, CXC; C485433:Cxcl10 protein, mouse; C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D012260:Ribonucleases