Document Detail


An antagonist mutant IL-15/Fc promotes transplant tolerance.
MedLine Citation:
PMID:  16421485     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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. CONCLUSION: 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:
Xin Xiao Zheng; Wei Gao; Elina Donskoy; Manfred Neuberg; Manfred Ruediger; Terry B Strom; Thomas Moll
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Transplantation     Volume:  81     ISSN:  0041-1337     ISO Abbreviation:  Transplantation     Publication Date:  2006 Jan 
Date Detail:
Created Date:  2006-01-19     Completed Date:  2006-02-16     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0132144     Medline TA:  Transplantation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  109-16     Citation Subset:  IM    
Affiliation:
Department of Medicine, Harvard Medical School, Division of Immunology, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antibodies / immunology,  pharmacology
Biological Markers
CD40 Ligand / immunology
Cell Line
Cricetinae
Gene Expression Regulation / immunology
Graft Rejection / drug therapy,  immunology
Graft Survival / drug effects,  immunology
Heart Transplantation / immunology*,  pathology
Histocompatibility Antigens / immunology
Immune Tolerance / drug effects*,  genetics,  immunology*
Immunoglobulin Fc Fragments / genetics,  immunology*,  pharmacology*,  therapeutic use
Inflammation / metabolism
Interleukin-15 / antagonists & inhibitors*,  genetics,  immunology*
Macrophages / immunology
Mice
Models, Immunological
Mutation / genetics
T-Lymphocytes / immunology
T-Lymphocytes, Cytotoxic / immunology,  metabolism
Transplantation, Homologous / immunology
Chemical
Reg. No./Substance:
0/Antibodies; 0/Biological Markers; 0/Histocompatibility Antigens; 0/Immunoglobulin Fc Fragments; 0/Interleukin-15; 147205-72-9/CD40 Ligand

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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