Expression of Chemokines in GVHD Target Organs Is Influenced by Conditioning and Genetic Factors and Amplified by GVHR

Markus Y. Mapara, Corinna Leng, Yong-Mi Kim, Roderick Bronson, Anna Lokshin, Andrew Luster, Megan Sykes
2006 Biology of Blood and Marrow Transplantation  
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
more » ... 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 ␥-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. KEY WORDS Bone marrow transplantation • Graft-versus-host disease • Chemokine • CXCR3 • Knockout mouse frequently been linked to the development of GVHD [3] . This GVL reaction is primarily alloantigen driven but can occur in the absence of GVHD, as demonstrated in preclinical models [4, 5] and in patients [3] . However, GVL effects are counterbalanced by GVHD, often leading to failure of improved relapsefree survival to translate into improved overall sur-Biology of Blood and Marrow Transplantation 12:623-634 (
doi:10.1016/j.bbmt.2006.02.005 pmid:16737935 fatcat:ujpauzu5wvhprapkjoync4ze7q