title: Anti-Leukocyte Function-Associated Antigen 1 Therapy in a Nonhuman Primate Renal Transplant Model of Costimulation Blockade-Resistant Rejection.
abstract: Costimulation blockade with the fusion protein belatacept provides a desirable side effect profile and improvement in renal function compared with calcineurin inhibition in renal transplantation. This comes at the cost of increased rates of early acute rejection. Blockade of the integrin molecule leukocyte function-associated antigen 1 (LFA-1) has been shown to be an effective adjuvant to costimulation blockade in a rigorous nonhuman primate (NHP) model of islet transplantation; therefore, we sought to test this combination in an NHP renal transplant model. Rhesus macaques received belatacept maintenance therapy with or without the addition of LFA-1 blockade, which was achieved using a murine-derived LFA-1-specific antibody TS1/22. Additional experiments were performed using chimeric rhesus IgG1 (TS1/22R1) or IgG4 (TS1/22R4) variants, each engineered to limit antibody clearance. Despite evidence of proper binding to the target molecule and impaired cellular egress from the intravascular space indicative of a therapeutic effect similar to prior islet studies, LFA-1 blockade failed to significantly prolong graft survival. Furthermore, evidence of impaired protective immunity against cytomegalovirus was observed. These data highlight the difficulties in translating treatment regimens between organ models and suggest that the primarily vascularized renal model is more robust with regard to belatacept-resistant rejection than the islet model.
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA.
authors.forename: D J
authors.identifier: 0000-0002-8919-2445
authors.initials: DJ
authors.lastname: Anderson
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Lo
authors.affiliation: Department of Surgery, Duke University, Durham, NC.
authors.forename: F
authors.initials: F
authors.lastname: Leopardi
authors.affiliation: Department of Surgery, Duke University, Durham, NC.
authors.forename: M
authors.initials: M
authors.lastname: Song
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA.
authors.forename: N A
authors.initials: NA
authors.lastname: Turgeon
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA.
authors.forename: E A
authors.initials: EA
authors.lastname: Strobert
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA.
authors.forename: J B
authors.initials: JB
authors.lastname: Jenkins
authors.affiliation: MassBiologics, University of Massachusetts Medical School, Boston, MA.
authors.forename: R
authors.initials: R
authors.lastname: Wang
authors.affiliation: MassBiologics, University of Massachusetts Medical School, Boston, MA.
authors.forename: K A
authors.initials: KA
authors.lastname: Reimann
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA.
authors.forename: C P
authors.initials: CP
authors.lastname: Larsen
authors.affiliation: Emory Transplant Center, Emory University, Atlanta, GA.|Department of Surgery, Duke University, Durham, NC.
authors.forename: A D
authors.initials: AD
authors.lastname: Kirk
mesh_terms: D000069594:Abatacept / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000276:immunology*; D007156:Immunologic Memory; D007676:Kidney Failure, Chronic / Q000276:immunology* / Q000601:surgery; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000009:adverse effects*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000008:administration & dosage / Q000276:immunology*; D008253:Macaca mulatta; D014184:Transplantation, Homologous
chemical_list: D016169:Lymphocyte Function-Associated Antigen-1; D000069594:Abatacept