title: Low circulating regulatory T-cell levels after acute rejection in liver transplantation.
abstract: Immune regulatory CD4+CD25+ T cells play a crucial role in inducing and maintaining allograft tolerance in experimental models of transplantation (Tx). In humans, the effect of Tx and immunosuppression on the function and homeostasis of CD4+CD25+ regulatory T cells (Tregs) is not well characterized. In this study, the frequency of Tregs in liver transplant recipients was determined based on flow cytometric analysis of CD4, CD25, CD45RO, and cytotoxic T lymphocyte antigen (CTLA)-4 markers, and the suppressor activity of Tregs was assessed in a mixed-leukocyte reaction. A link between Tregs, acute rejection, and immune-suppressive treatment was investigated. Liver transplant recipients had significantly higher Treg levels in peripheral blood pre-Tx than healthy controls. After Tx, a significant drop in the Treg fraction was observed. This reduction of circulating Tregs was transient and was associated with immunosuppression. In recipients who did not develop rejection, a relative recovery of Treg levels was seen within the first year after Tx. Recipients who experienced an episode of steroid-treated acute rejection, however, had sustained low Treg levels. The suppressive activities of CD4+CD25+ Tregs from rejectors, nonrejectors, and healthy controls on proliferation and interferon (IFN)-gamma production were indistinguishable. In conclusion, the percentage of CD4+CD25+CD45RO+CTLA-4+ quadruple-positive Tregs in peripheral blood decreases significantly after liver Tx. Treatment with methylprednisolone during Tx and for acute rejection is associated with low circulating Tregs. Despite these quantitative differences between rejectors and nonrejectors, the suppressive quality of CD4+CD25+ Tregs is identical in both groups.
authors.affiliation: Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Demirkiran
authors.forename: Alice
authors.initials: A
authors.lastname: Kok
authors.forename: Jaap
authors.initials: J
authors.lastname: Kwekkeboom
authors.forename: Johannes G
authors.initials: JG
authors.lastname: Kusters
authors.forename: Herold J
authors.initials: HJ
authors.lastname: Metselaar
authors.forename: Hugo W
authors.initials: HW
authors.lastname: Tilanus
authors.forename: Luc J W
authors.initials: LJ
authors.lastname: van der Laan
mesh_terms: D000208:Acute Disease; D000328:Adult; D015415:Biomarkers / Q000097:blood; D015704:CD4 Antigens / Q000032:analysis / Q000276:immunology; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005434:Flow Cytometry; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007371:Interferon-gamma / Q000097:blood; D017493:Leukocyte Common Antigens / Q000032:analysis / Q000276:immunology; D017093:Liver Failure / Q000097:blood / Q000601:surgery; D016031:Liver Transplantation / Q000009:adverse effects* / Q000276:immunology*; D018655:Lymphocyte Count; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011336:Probability; D011379:Prognosis; D012016:Reference Values; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014181:Transplantation Immunology / Q000502:physiology*; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D015415:Biomarkers; D015704:CD4 Antigens; D007166:Immunosuppressive Agents; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens