Role of Th17 cells and interleukin 17 in graft-versushost disease and graft-versusleukemia reactivity - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 285

inflammation of the gut such as in Crohn's disease [113] . Since the colon is
one of the target organs in GVHD pathogenesis, several studies have exam-
ined whether IL-23 receptor (IL-23R) gene polymorphisms affect the sever-
ity of GVHD. The polymorphism in the IL-23R that has been studied is at
position 1142, at which guanine replaces adenine. This results in a protein
substitution at position 381 in which glutamine supplants arginine. In the
general population, it appears that ~10% of patients are heterozygous for
this polymorphism, whereas very few are homozygous (<1%). To date, there
have been a total of four studies in which the association between this spe-
cific IL-23R polymorphism and GVHD has been examined. Three of these
studies were performed in Germany, with two focused primarily on adults
and one on children [114-116] . The results from these studies were remark-
ably consistent. Specifically, all demonstrated that there was no effect on
the severity of GVHD when the recipient possessed the IL-23R polymor-
phism. In contrast, when the gene variant was present in the donor, there
was a significant decrease in the incidence and severity of acute GVHD. One
study also reported a significant reduction in transplant-related mortal-
ity, although this could not be confirmed in the other two reports. Despite
the observed reduction in acute GVHD, none of these studies were able to
document any improvement in overall survival. Moreover, there was no
difference in the incidence of chronic GVHD or relapse. Blockade of IL-23
signaling in experimental murine models has been associated with selec-
tive protection in the colon microenvironment [61] . None of these studies,
however, provided detailed information as to organ-specific responses in
this cohort, although it was noted parenthetically in one study that there
was no difference in organ-specific pathology.

288

It should be noted that there has been one study analyzing data from U.S.
transplant centers that differs from the above reports [117] . This study, facil-
itated by the National Marrow Donor Program, analyzed 390 primarily adult
patients. All patients in this study received stem cell grafts from unrelated
donors, which distinguished this study from the European reports in which
the majority of transplantations were performed with family donors. The
gene frequency for the IL-23R polymorphism was 13% in donors and 16%
in recipients, which is similar to that reported by the European groups. The
authors noted that the IL-23R donor genotype had no effect on the inci-
dence or severity of GVHD after transplantation. The reasons for the dif-
ference between these results and those reported in the other studies were
speculated to be attributable to different patient populations, racial diver-
sity, and less common use of gut decontamination. When viewed in the
aggregate, there is a foundation of preclinical and epidemiologic data that
support the continued investigation of the role of IL-23 in GVHD pathogen-
esis in humans.

Roles of other Th17 cytokines in GVHD biology
Interleukin 21

In addition to the signature cytokine, IL-17A, Th17 cells also secrete a num-
ber of other cytokines, which include IL-21, IL-22, and IL-17F. IL-21, which
is produced by CD4 + T cells, CD8 + T cells, and NKT cells, is the one that has