Biology Reference
In-Depth Information
the therapeutic benefit since IL-2 has pleiotropic effects and the patients
received additional immunosuppressants. Yet, these findings are encourag-
ing enough for the initiation of follow-up studies in larger patient cohorts.
As the lineage stability of Treg is in part regulated by epigenetic mechanisms
such as DNA methylation and histone modification
[11,42-45,176,177]
,
efforts to stabilize natural Treg or to induce Treg from Tconv using hypo-
methylating agents are now being pursued. In animal models, azacytidine
(AZA) has been shown to increase Treg cell numbers and to mitigate GVHD
[178]
and a transient increase in Treg frequencies has been observed in
patients treated with AZA after SCT
[179]
. Yet again, convincing evidence
for the therapeutic efficacy is still lacking and requires further trials using
this or other agents for epigenetic Treg modifications.
Many other pharmacologic or biologic agents have been described to
preferentially promote Treg survival or differentiation
in vivo,
such as the
HIV-derived glycoprotein 120
[180]
, TGF-β
[181]
, Flt3-ligand
[182]
, retinoic
acid
[183]
, vitamin D
[184]
, and others. Yet, thus far, none of these strategies
has been tested systematically in clinical trials in SCT and the best
in vivo
expansion strategy remains to be determined. The most promising
in vivo
expansion of donor Treg seems to be the transfer of pure Treg populations
into lymphopenic recipients, which promotes expansion by alloantigen- as
well as lymphopenia-driven mechanisms
[90,148]
.
262
Summary
The potent prevention of GVHD by adoptively transferred donor Treg in
animal models has now led to the initiation of the first clinical trials test-
ing such strategies in allogeneic SCT. These trials primarily focused on
the safety and feasibility of such therapies, whereas efficacy still remains
to be proven. Continuous improvements in Treg isolation and expansion
technologies will facilitate Treg applications in the future. Nevertheless,
such strategies are laborious, technically challenging, and expensive and
will be pursued further only if clinically relevant improvements in treat-
ment outcome can be confirmed. In the longer term, a better understand-
ing of GVHD pathophysiology and Treg-mediated suppressive mechanisms
may permit the selective augmentation of Treg function
in vivo
for the
(re-)establishment of peripheral tolerance after SCT.
References
[1] Asano M, Toda M, Sakaguchi N, Sakaguchi S. Autoimmune disease as a consequence of
developmental abnormality of a T cell subpopulation. J Exp Med 1996;184:387-96.
[2] Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the tran-
scription factor Foxp3. Science 2003;299:1057-61.
[3] Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function
of CD4+CD25+ regulatory T cells. Nat Immunol 2003;4:330-6.
[4] Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin in CD4+CD25+ T
regulatory cells. Nat Immunol 2003;4:337-42.
[5] Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, et al. Disruption
of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative
disorder of the scurfy mouse. Nat Genet 2001;27:68-73.
[6] Chatila TA, Blaeser F, Ho N, Lederman HM, Voulgaropoulos C, Helms C, et al. JM2,
encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic
disregulation syndrome. J Clin Invest 2000;106:R75-81.
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