An antagonist mutant IL-15/Fc promotes transplant tolerance.
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.
Zheng
Xin Xiao
XX
Department of Medicine, Harvard Medical School, Division of Immunology, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Gao
Wei
W
Donskoy
Elina
E
Neuberg
Manfred
M
Ruediger
Manfred
M
Strom
Terry B
TB
Moll
Thomas
T
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
D000906:Antibodies; D015415:Biomarkers; D006649:Histocompatibility Antigens; D007141:Immunoglobulin Fc Fragments; D019409:Interleukin-15; D023201:CD40 Ligand