Research ArticleTransplantation

Functional Regulatory T Cells Produced by Inhibiting Cyclic Nucleotide Phosphodiesterase Type 3 Prevent Allograft Rejection

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Science Translational Medicine  18 May 2011:
Vol. 3, Issue 83, pp. 83ra40
DOI: 10.1126/scitranslmed.3002099

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Regulatory T cells Go cAMPing

As summer approaches, campers yearn to leave their homes and sleep out under the stars. However, camping isn’t as blissful at it seems from the comfort of a couch in an air-conditioned home: Bugs, heat, and lack of facilities all take their toll on the sensitive adventurer. Transplanted organs face similar challenges in a new host. Not only must they acclimatize to a new environment, but they have to avoid attack from the recipient’s immune system. One way to dodge damage is with the help of immunosuppressive regulatory T cells (Tregs). Feng et al. now find that stimulating these Tregs in the presence of PDE (phosphodiesterase 3) inhibition enriches functional allospecific Tregs, which then can prevent transplant rejection.

Adenosine 3′,5′-monophosphate (cAMP) not only directly inhibits effector T cells, it also promotes production of Tregs. Feng et al. hypothesize that inhibiting PDEs, which break down cAMP, would increase cAMP concentrations in Tregs in culture and promote expansion of these cells in the presence of allogeneic dendritic cells. In the mouse PDE3 inhibition with cilostamide in conjunction with allostimulation enriched for functional alloreactive Tregs; these cells inhibited effector T cell function in vitro and prevented graft rejection. PDE3 inhibition also generates human Tregs and these inhibit T cell proliferation and prevent the rejection of human vessel transplants in a humanized mouse transplant model. The ability to selectively enhance allospecific Treg proliferation using cilostamide, a clinically approved agent, should decrease the need for general immunosuppression in transplant recipients. Allospecific Tregs expanded with cilostamide may provide a transplanted organ with an environment that is less like the great outdoors and instead has most of the comforts of home.

Footnotes

  • Citation: G. Feng, S. N. Nadig, L. Bäckdahl, S. Beck, R. S. Francis, A. Schiopu, A. Whatcott, K. J. Wood, A. Bushell, Functional Regulatory T Cells Produced by Inhibiting Cyclic Nucleotide Phosphodiesterase Type 3 Prevent Allograft Rejection. Sci. Transl. Med. 3, 83ra40 (2011).

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