title: An antagonist mutant IL-15/Fc promotes transplant tolerance.
abstract: BACKGROUND
  IL-15 is a proinflammatory and antiapoptotic T-cell growth factor that plays an important role in a variety of autoimmune disorders and transplant rejection. To inhibit IL-15 function and to target IL-15 receptor (IL-15R) bearing cells, we have generated a unique lytic antagonistic mutant IL-15/Fc fusion protein (mIL-15/Fc).
  
  
  METHODS
  In this study, we further examined the efficacy of mIL-15/Fc in preventing allograft rejection cross minor and major histocompatibility barriers.
  
  
  RESULTS
  A short-course treatment with mIL-15/Fc fusion protein is sufficient to prevent cardiac allograft rejection and induce antigen-specific tolerance in minor histocompatibility complex-mismatched recipients, and permit prolonged cardiac allograft survival in fully MHC mismatched recipients. In addition, mIL-15/Fc treatment, in combination with a suboptimal dose of anti-CD154 antibody, confers permanent cardiac allograft engraftment in a fully MHC-mismatched mouse strain combination. In a murine islet allograft model, mIL-15/Fc monotherapy is capable to permit permanent allograft survival in 50% fully MHC-mismatched recipients.
  
  
  CONCLUSIONS
  Immunochemistry studies demonstrated that prolonged graft survival was accompanied by reduced intragraft mononuclear cell infiltration and pro-inflammatory cytokine gene expression in the mIL-15/Fc treated recipients. Moreover, parallel experiments employing a mutated nonlytic IgG2a Fc demonstrate that the Fc portion of mIL-15/Fc contributes to the overall efficacy of the molecule in vivo.
authors.affiliation: Department of Medicine, Harvard Medical School, Division of Immunology, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
authors.forename: Xin Xiao
authors.initials: XX
authors.lastname: Zheng
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.forename: Elina
authors.initials: E
authors.lastname: Donskoy
authors.forename: Manfred
authors.initials: M
authors.lastname: Neuberg
authors.forename: Manfred
authors.initials: M
authors.lastname: Ruediger
authors.forename: Terry B
authors.initials: TB
authors.lastname: Strom
authors.forename: Thomas
authors.initials: T
authors.lastname: Moll
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D015415:Biomarkers; D023201:CD40 Ligand / Q000276:immunology; D002460:Cell Line; D006224:Cricetinae; D005786:Gene Expression Regulation / Q000276:immunology; D006084:Graft Rejection / Q000188:drug therapy / Q000276:immunology; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D006649:Histocompatibility Antigens / Q000276:immunology; D007108:Immune Tolerance / Q000187:drug effects* / Q000235:genetics / Q000276:immunology*; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000378:metabolism; D019409:Interleukin-15 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018448:Models, Immunological; D009154:Mutation / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D000906:Antibodies; D015415:Biomarkers; D006649:Histocompatibility Antigens; D007141:Immunoglobulin Fc Fragments; D019409:Interleukin-15; D023201:CD40 Ligand