Dendritic cells loaded with FK506 kill T cells in an antigen-specific manner and prevent autoimmunity in vivo

Abstract

FK506 (Tacrolimus) is a potent inhibitor of calcineurin that blocks IL2 production and is widely used to prevent transplant rejection and treat autoimmunity. FK506 treatment of dendritic cells (FKDC) limits their capacity to stimulate T cell responses. FK506 does not prevent DC survival, maturation, or costimulatory molecule expression, suggesting that the limited capacity of FKDC to stimulate T cells may be due to inhibition of calcineurin signaling in the DC. Instead, we demonstrate that DC inhibit T cells by sequestering FK506 and continuously releasing the drug over several days. T cells encountering FKDC proliferate but fail to upregulate the survival factor bcl-xl and die, and IL2 restores both bcl-xl and survival. In mice, FKDC act in an antigen-specific manner to inhibit T-cell mediated autoimmune arthritis. This establishes that DCs can act as a cellular drug delivery system to target antigen specific T cells.DOI: http://dx.doi.org/10.7554/eLife.00105.001

Enhancement of the immunoregulatory potency of mesenchymal stromal cells by treatment with immunosuppressive drugs

“…FK506 (tacrolimus) binds to the same cellular target protein (FKBP12) as does rapamycin but acts through a different downstream mechanism [27]. Orange et al [28] have reported that FK506 is adsorbed rapidly and then released by dendritic cells in a manner analogous to our observations for rapamycin. Figure 3.…”

“…There are precedents for the loading of cells with hydrophobic drugs, with Pessina et al [35] reporting that sufficient amounts of the anti-cancer drug paclitaxel were adsorbed by MSCs in a 24-h incubation to reduce tumor growth in vivo and Orange et al [28] finding that FK-506eloaded dendritic cells could inhibit autoimmune arthritis. A rapid partition of ISDs into cells would appear to explain our observations of increased suppression by brief pretreatments of MSCs, fibroblasts, APCs and HUVECs and may explain at least part of the increased suppression reported for rapamycintreated endothelia and Tregs [30,36].…”

A Bioequivalence Test by the Direct Comparison of Concentration-versus-Time Curves Using Local Polynomial Smoothers

“…As shown on the simulation studies (in Supplementary Material available online at http://dx.doi.org/10.1155/2016/4680642), the permutation-based test provides a valid means for testing the difference of two curves, achieving the desired type I error rate. We applied this procedure to longitudinal data collected by Orange et al [21] and showed that the results obtained were consistent with those obtained by using a generalized estimating equation model [22, 23]. Therefore, the proposed procedure to test the difference between curves using LPS can be employed in a wide range of applications in longitudinal data analysis.…”

A destructive feedback loop mediated by CXCL10 in central nervous system inflammatory disease

“…Although the inhibition of calcineurin activity in T cells is a known effect of FK506, additional intracellular targets such as p38 and c‐Jun N‐terminal kinase have been suggested 33. Interestingly, our laboratory has recently shown that FK506 preferentially accumulates in DCs, thereby targeting T cells engaged in antigen‐specific T cell–APC interactions 34. It is possible that FK506 may similarly act upon APCs in the brain.…”