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The immunosuppressive drug FK778 induces regulatory activity in stimulated human CD4+ CD25- T cells.
Blood. 2007 Jan 01; 109(1):244-52.Blood

Abstract

The induction of transplantation tolerance involves a T-cell-mediated process of immune regulation. In clinical transplantation, the use of immunosuppressive drugs that promote or facilitate this process would be highly desirable. Here, we investigated the tolerance-promoting potential of the immunosuppressive drug FK778, currently under development for clinical therapy. Using a human allogeneic in vitro model we showed that, upon T-cell receptor (TCR) triggering, FK778 induced a regulatory phenotype in CD4+ CD25- T cells. Purified CD4+ CD25- T cells primed in the presence of FK778 showed hyporesponsiveness upon restimulation with alloantigen in the absence of the drug. This anergic state was reversible by exogenous interleukin-2 (IL-2) and was induced independent of naturally occurring CD4+ CD25+ regulatory T cells. Pyrimidine restriction was a crucial requirement for the de novo induction of regulatory activity by FK778. The FK778-induced anergic cells showed suppressor activity in a cell-cell contact-dependent manner; were CD25(high), CD45RO+, CD27-, and CD62L-; and expressed cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), glucocorticoid-induced tumor necrosis factor receptor (GITR), and FoxP3. The cells revealed delayed p27(kip1) degradation and enhanced phosphorylation of STAT3. In conclusion, the new drug FK778 shows tolerizing potential through the induction of a regulatory T-cell subset in CD4+ CD25- T cells.

Authors+Show Affiliations

Radboud University Nijmegen Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

16902146

Citation

Kreijveld, Ellen, et al. "The Immunosuppressive Drug FK778 Induces Regulatory Activity in Stimulated Human CD4+ CD25- T Cells." Blood, vol. 109, no. 1, 2007, pp. 244-52.
Kreijveld E, Koenen HJ, Hilbrands LB, et al. The immunosuppressive drug FK778 induces regulatory activity in stimulated human CD4+ CD25- T cells. Blood. 2007;109(1):244-52.
Kreijveld, E., Koenen, H. J., Hilbrands, L. B., van Hooff, H. J., & Joosten, I. (2007). The immunosuppressive drug FK778 induces regulatory activity in stimulated human CD4+ CD25- T cells. Blood, 109(1), 244-52.
Kreijveld E, et al. The Immunosuppressive Drug FK778 Induces Regulatory Activity in Stimulated Human CD4+ CD25- T Cells. Blood. 2007 Jan 1;109(1):244-52. PubMed PMID: 16902146.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The immunosuppressive drug FK778 induces regulatory activity in stimulated human CD4+ CD25- T cells. AU - Kreijveld,Ellen, AU - Koenen,Hans J P M, AU - Hilbrands,Luuk B, AU - van Hooff,Hans J P, AU - Joosten,Irma, Y1 - 2006/08/10/ PY - 2006/8/12/pubmed PY - 2007/2/21/medline PY - 2006/8/12/entrez SP - 244 EP - 52 JF - Blood JO - Blood VL - 109 IS - 1 N2 - The induction of transplantation tolerance involves a T-cell-mediated process of immune regulation. In clinical transplantation, the use of immunosuppressive drugs that promote or facilitate this process would be highly desirable. Here, we investigated the tolerance-promoting potential of the immunosuppressive drug FK778, currently under development for clinical therapy. Using a human allogeneic in vitro model we showed that, upon T-cell receptor (TCR) triggering, FK778 induced a regulatory phenotype in CD4+ CD25- T cells. Purified CD4+ CD25- T cells primed in the presence of FK778 showed hyporesponsiveness upon restimulation with alloantigen in the absence of the drug. This anergic state was reversible by exogenous interleukin-2 (IL-2) and was induced independent of naturally occurring CD4+ CD25+ regulatory T cells. Pyrimidine restriction was a crucial requirement for the de novo induction of regulatory activity by FK778. The FK778-induced anergic cells showed suppressor activity in a cell-cell contact-dependent manner; were CD25(high), CD45RO+, CD27-, and CD62L-; and expressed cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), glucocorticoid-induced tumor necrosis factor receptor (GITR), and FoxP3. The cells revealed delayed p27(kip1) degradation and enhanced phosphorylation of STAT3. In conclusion, the new drug FK778 shows tolerizing potential through the induction of a regulatory T-cell subset in CD4+ CD25- T cells. SN - 0006-4971 UR - https://www.unboundmedicine.com/medline/citation/16902146/The_immunosuppressive_drug_FK778_induces_regulatory_activity_in_stimulated_human_CD4+_CD25__T_cells_ L2 - https://ashpublications.org/blood/article-lookup/doi/&lo.doi; DB - PRIME DP - Unbound Medicine ER -