Role of Th17 cells and interleukin 17 in graft-versushost disease and graft-versusleukemia reactivity - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 288

cells may also contribute to the skin pathology observed in chronic GVHD.
Moreover, genetic polymorphism studies in humans support a role for IL-17
and IL-23 in the pathophysiology of GVHD. Ongoing examination of this
newest T-helper population is likely to yield new insights into GVHD biology
and potentially provide opportunities for translational strategies designed to
reduce complications from GVHD in humans.

Unanswered questions

The precise roles of Th17 cells and IL-17 in the pathophysiology of GVHD
are still an evolving issue. There remain many important questions that
need to be addressed before the contribution of these cells can be resolved.
Specifically, these include, but are not limited to, the following:
1. Does blockade of IL-17 augment or ameliorate acute GVHD severity?
While multiple studies clearly demonstrate the presence of these cells
during GVHD, the precise role of IL-17 in animal models of GVHD has
been inconclusive. Is this a rational approach to be considered in hu-
mans?
2. Is IL-17 responsible for some of the autoimmune-like manifestations
observed in chronic GVHD, particularly skin fibrosis? More specifically,
does IL-17 direct tissue-specific pathology within the context of GVHD?
3. What is the role of Th17 cells that coexpress IFN-γ and IL-17 in the de-
velopment of GVHD? Do they pose a higher pathogenic potential than
CD4 + IFN-γ + or CD4 + IL-17 + single-cytokine-producing T cells? Do they
represent a unique cell population or is this an intermediary stage of dif-
ferentiation?
4. In addition to the signature cytokine IL-17, what are the roles of other
Th17-associated proinflammatory cytokines, such as IL-22, in GVHD
pathogenesis?
5. What are the contributions of other IL-17-secreting cells (e.g., CD8 + T
cells, γδ T cells, and granulocytes) in GVHD biology?
6. What are the roles of other IL-17 cytokine family members (e.g., IL-17F)
in GVHD biology?
7. Given the differences in IL-17 family cytokine signaling between humans
and mice, to what extent do animal results replicate IL-17-mediated in-
flammatory processes in humans?

291

Acknowledgments
The work from the authors' laboratory was supported by NIH R01 HL64603, HL081650, and
DK083358 and by awards from the Midwest Athletes Against Childhood Cancer Fund.

References

[1] Mosmann TR, Coffman RL. T H 1 and T H 2 cells: different patterns of lymphokine secre-
tion lead to different functional properties. Annu Rev Immunol 1989;7:145-73.

[2] Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature
1996;383:787-93.

[3] Rouvier E, Luciani M-F, Mattei MG, Denizot F, Golstein P. CTLA-8, cloned from an acti-
vated T cell, bearing AU-rich messenger RNA instability sequences and homologous to
a herpesvirus saimiri gene. J Immunol 1993;150:5445-56.