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Therapy

HSCT—resetting immune tolerance by boosting TREG cell diversity

Nature Reviews Rheumatology volume 11, page 681 (2015)Cite this article

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“Although the underlying mechanisms [of successful HSCT therapies] are incompletely understood,” explains van Wijk, “we have previously shown that transplantation restores immune tolerance by renewal and modulation of the CD4+ T effector cell compartment in a mouse model, and that the presence of TREG cells after transplantation is crucial to prevent disease relapse.” With these previous findings in mind, van Wijk and colleagues analysed the TREG cell compartment in the proteoglycan-induced arthritis (PGIA) mouse model (in which arthritic disease is induced with two intraperitoneal injections of proteoglycan plus adjuvant) and in patients with juvenile idiopathic arthritis (JIA) or juvenile dermatomyositis (JDM) before and after HSCT.

The use of congenic markers enables the distinction between host and donor-derived TREG cells differentiated after lethal irradiation and bone marrow transplantation in mice. Using this approach, the researchers confirmed that the donor-derived thymic output of TREG cells after bone marrow transplantation was progressively replaced with those originating from the graft; by 7 weeks post-transfer, this reconstitution was virtually complete. Analysis of a TREG cell-specific demethylated region in the Foxp3 gene showed that donor-derived TREG cells were more stable (higher demethylation) than host TREG cells. Furthermore, donor TREG cells had greater capacity to inhibit the proliferation of effector T cells than host TREG cells as assessed in in vitro suppression assays.

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References

  1. Delemarre, E. M. et al. Autologous stem cell transplantation benefits autoimmune patients through functional renewal and TCR diversification of the regulatory T cell compartment. Blood doi:10.1182/blood-2015-06-649145

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  1. João H. Duarte
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Duarte, J. HSCT—resetting immune tolerance by boosting TREG cell diversity. Nat Rev Rheumatol 11, 681 (2015). https://doi.org/10.1038/nrrheum.2015.149

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