title: An antagonist IL-15/Fc protein prevents costimulation blockade-resistant rejection.
abstract: IL-15 is a powerful T cell growth factor (TCGF) with particular importance for the maintenance of CD8(+) T cells. Because costimulation blockade does not result in universal tolerance, we hypothesized that "escape" from costimulation blockade might represent a CD8(+) and IL-15/IL-15R(+)-dependent process. For this analysis, we have used an IL-15 mutant/Fcgamma2a protein, a potentially cytolytic protein that is also a high-affinity receptor site specific antagonist for the IL-15Ralpha receptor protein, as a therapeutic agent. The IL-15-related fusion protein was used as monotherapy or in combination with CTLA4/Fc in murine islet allograft models. As monotherapies, CTLA4/Fc and an IL-15 mutant/Fcgamma2a were comparably effective in a semiallogeneic model system, and combined treatment with IL-15 mutant/Fcgamma2a plus CTLA4/Fc produced universal permanent engraftment. In a fully MHC-mismatched strain combination known to be refractory to costimulation blockade treatment, combined treatment with both fusion proteins proved to be highly effective; >70% of recipients were tolerized. The analysis revealed that the IL-15 mutant/Fc treatment confers partial protection from both CD4(+) and CD8(+) T cell graft infiltration. In rejections occurring despite CTLA4/Fc treatment, concomitant treatment with the IL-15 mutant/Fcgamma2a protein blocked a CD8(+) T cell-dominated rejection processes. This protection was linked to a blunted proliferative response of alloreactive T cells as well silencing of CTL-related gene expression events. Hence, we have demonstrated that targeting the IL-15/IL-15R pathway represents a new and potent strategy to prevent costimulation blockade-resistant CD8(+) T cell-driven rejection.
authors.affiliation: Department of Medicine, Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ferrari-Lacraz
authors.forename: X X
authors.initials: XX
authors.lastname: Zheng
authors.forename: Y S
authors.initials: YS
authors.lastname: Kim
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: W
authors.initials: W
authors.lastname: Maslinski
authors.forename: X C
authors.initials: XC
authors.lastname: Li
authors.forename: T B
authors.initials: TB
authors.lastname: Strom
mesh_terms: D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D060908:CTLA-4 Antigen; D003433:Crosses, Genetic; D003921:Diabetes Mellitus, Experimental / Q000601:surgery; D004353:Drug Evaluation, Preclinical; D020868:Gene Silencing; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology; D006183:H-2 Antigens / Q000276:immunology; D007108:Immune Tolerance; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019409:Interleukin-15 / Q000235:genetics / Q000627:therapeutic use*; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000187:drug effects / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D013311:Streptozocin; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D006183:H-2 Antigens; C440611:IL-15-Fcgamma2a protein, human; C508024:IL15RA protein, human; C508025:Il15ra protein, mouse; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D019409:Interleukin-15; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D011993:Recombinant Fusion Proteins; D013311:Streptozocin; D000069594:Abatacept