title: Interleukin-21: an interleukin-2 dependent player in rejection processes.
abstract: BACKGROUND
  Interleukin (IL)-21 is the most recently described cytokine that signals via the common cytokine receptor (gammac), is produced by activated CD4+ T-cells, and regulates expansion and effector function of CD8+ T-cells.
  
  
  METHODS
  To explore the actions of IL-21 with other gammac-dependent cytokines in alloreactivity, mRNA expression of IL-21, IL-21R alpha-chain, and IL-2 proliferation and cytotoxicity was measured after stimulation in mixed lymphocyte reactions. Additionally, IL-21 and IL-21R alpha-chain expression was studied in biopsies of heart transplant patients.
  
  
  RESULTS
  Analysis of mRNA expression levels of allostimulated T-cells showed a 10-fold induction of IL-21 and IL-21R alpha-chain. Interestingly, induction of IL-21 was highly dependent on IL-2 (as in the presence of anti-IL-2, anti-IL-2R alpha-chain, and the immunosuppressive drugs cyclosporine A, tacrolimus, and rapamycin) the transcription of IL-21 was almost completely inhibited, whereas in the presence of exogenous IL-2 the mRNA expression of IL-21 was even more upregulated. IL-21 functioned as a costimulator for IL-2 to augment proliferation and cytotoxic responses, while blockade of the IL-2 route abrogated these functions of IL-21. Blockade of the IL-21 route by anti-IL-21R alpha-chain monoclonal antibodies inhibited the proliferation of alloactivated T-cells. Also, in vivo alloreactivity was associated with IL-21/IL-21R alpha-chain expression. After heart transplantation, the highest intragraft IL-21, IL-21R alpha-chain, and IL-2 mRNA expression levels were measured during acute rejection (P<0.001, P=0.01, P=0.03).
  
  
  CONCLUSIONS
  IL-21 is a critical cytokine for IL-2 dependent immune processes. Blockade of the IL-21 pathway may provide a new perspective for the treatment of allogeneic responses in patients after transplantation.
authors.affiliation: Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, the Netherlands. c.c.baan@erasmusmc.nl
authors.forename: Carla C
authors.initials: CC
authors.lastname: Baan
authors.forename: Aggie H M M
authors.initials: AH
authors.lastname: Balk
authors.forename: I Esmé
authors.initials: IE
authors.lastname: Dijke
authors.forename: Sander S
authors.initials: SS
authors.lastname: Korevaar
authors.forename: Annemiek M A
authors.initials: AM
authors.lastname: Peeters
authors.forename: Ronella P
authors.initials: RP
authors.lastname: de Kuiper
authors.forename: Mariska
authors.initials: M
authors.lastname: Klepper
authors.forename: Pieter E
authors.initials: PE
authors.lastname: Zondervan
authors.forename: Lex A P W M
authors.initials: LA
authors.lastname: Maat
authors.forename: Willem
authors.initials: W
authors.lastname: Weimar
mesh_terms: D049109:Cell Proliferation; D015331:Cohort Studies; D003602:Cytotoxicity, Immunologic; D004699:Endocardium / Q000378:metabolism; D006084:Graft Rejection / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D016027:Heart Transplantation; D006801:Humans; D007165:Immunosuppression Therapy; D007376:Interleukin-2 / Q000378:metabolism*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D007959:Lymphocyte Culture Test, Mixed; D009206:Myocardium / Q000378:metabolism; D011184:Postoperative Period; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D053655:Receptors, Interleukin-21 / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000473:pathology; D000098546:Interleukin-21
chemical_list: D007376:Interleukin-2; D007378:Interleukins; D020033:Protein Isoforms; D012333:RNA, Messenger; D053655:Receptors, Interleukin-21; D000098546:Interleukin-21