T-cell costimulation in graftversus- host disease and graft-versus-leukemia effect - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 211

In the meantime, several other promising approaches to enhance Tregs to
promote tolerance induction are now emerging. For example, extrapolat-
ing from studies of OX40 costimulation discussed above, this pathway is
a particularly attractive target for therapeutic blockade. OX40 blockade
may inhibit Teffs and simultaneously augment Treg function. There may
be strategies that might specifically promote Treg homeostatic or antigen-
induced proliferation, resulting in preferential expansion of Tregs over
Teffs in vivo. The fact that homeostatic proliferation of Tregs is regulated
differently from that of conventional T cells and that at least some costim-
ulatory molecules exhibit distinct functions on Tregs compared with con-
ventional T cells suggests that research in this area will be fruitful. It is also
possible that agents targeting costimulatory pathways can be combined,
for example, by the use of agents that potently inhibit Teffs with other
agents that promote Tregs. This combination may also achieve the goal
of tipping the balance of Teffs and Tregs toward active immune regulation
to create transplant tolerance. However, particular caution must be paid
to the potential effect on the GVL activity of any strategy in the favor of
immune regulation and tolerance.
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Conclusions
T-cell costimulation has been one area of focus in GVHD research for
many years. It is clear that costimulatory pathways are central to regulat-
ing T-cell immunity, and therefore targeting these pathways represents
one of the most promising approaches for the prevention and treatment
of GVHD. In addition to the extensively studied B7/CD28/CTLA4 path-
way, other costimulatory pathways have been ultimately implicated in
GVHD. In particular, several members of the TNFR family, such as CD40,
OX-40, and 4-1BB, have been demonstrated to contribute to T-cell acti-
vation and the development of acute GVHD. Targeting costimulatory
receptors or ligands using genetically modified mice or various mAbs
specific for these molecules has been substantially studied in preclinical
GVHD models with promising results. However, modulating costimula-
tion to control GVHD in the clinic will undoubtedly give rise to new chal-
lenges. We have realized that costimulatory pathways regulate multiple
aspects of the alloimmune responses on Teffs and Tregs, and thus when
targeting costimulation to inhibit Teffs, preservation of Tregs should
be considered. Given potentially overlapping functions of costimula-
tory molecules, multiple positive costimulators may have to be blocked
to control GVHD. On the other hand, the better understanding of the
mechanisms of molecules involved in counter-regulation of T-cell acti-
vation (i.e., CTLA4 and PD-1) makes these molecules attractive targets
for GVHD therapy. It is likely that a CTLA4 fusion protein will be tested
in patients with acute GVHD soon, as it is already used in patients with
autoimmune diseases. In allogeneic HCT settings, a critical issue is to
develop therapeutic strategies that, while blocking alloreactivity, do not
compromise the GVT effect. Finally, researchers and clinicians will need
to collaborate with industry to develop reagents that can be converted
to drugs to promote the translation of knowledge acquired from animal
models to clinical application.