title: Intragraft overexpression of interleukin-4 is neither sufficient nor essential for tolerance induction to cardiac allografts in a high-responder strain combination.
abstract: BACKGROUND
  Recently we have demonstrated that the nondepleting anti-CD4 monoclonal antibody (mAb) RIB5/2 induces long-term acceptance of kidney and heart allografts in all rat strain combinations tested. Cytokine gene expression studies by reverse transcriptase-polymerase chain reaction revealed a reversed intragraft interleukin (IL)-4/interferon-gamma ratio. Whether IL-4 mediated immune deviation contributes to transplantation tolerance is not clear so far.
  
  
  METHODS
  To learn more about the functional relevance of the relative IL-4 up-regulation, IL-4 was overexpressed in rat heart allografts by using ex vivo adenoviral gene transfer. The efficiency of gene transfer was analyzed by reporter gene assays as well by reverse transcriptase-polymerase chain reaction analysis of IL-4 mRNA expression.
  
  
  RESULTS
  The intragraft overexpression of IL-4 did not prolong the allograft survival compared with controls. Moreover, neutralization of IL-4 by OX81 mAb did not prevent tolerance induction by RIB5/2 treatment.
  
  
  CONCLUSIONS
  Anti-CD4 mAb-induced tolerance is associated with an intragraft type1/type2 shift, however, the up-regulation of IL-4 alone is neither sufficient nor essential to induce tolerance to cardiac allografts in a high-responder strain combination.
authors.affiliation: Institute of Medical Immunology and Clinic of Nephrology & Internal Intensive Care, Charité, Humboldt-University Berlin, Germany. thomas.ritter@charite.de
authors.forename: T
authors.initials: T
authors.lastname: Ritter
authors.forename: K
authors.initials: K
authors.lastname: Risch
authors.forename: G
authors.initials: G
authors.lastname: Schroder
authors.forename: J
authors.initials: J
authors.lastname: Kolls
authors.forename: A
authors.initials: A
authors.lastname: Siegling
authors.forename: E
authors.initials: E
authors.lastname: Graser
authors.forename: P
authors.initials: P
authors.lastname: Reinke
authors.forename: J
authors.initials: J
authors.lastname: Brock
authors.forename: M
authors.initials: M
authors.lastname: Lehmann
authors.forename: H D
authors.initials: HD
authors.lastname: Volk
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D018014:Gene Transfer Techniques; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D007108:Immune Tolerance; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D015847:Interleukin-4