title: Selective Targeting of High-Affinity LFA-1 Does Not Augment Costimulation Blockade in a Nonhuman Primate Renal Transplantation Model.
abstract: Costimulation blockade (CoB) via belatacept is a lower-morbidity alternative to calcineurin inhibitor (CNI)-based immunosuppression. However, it has higher rates of early acute rejection. These early rejections are mediated in part by memory T cells, which have reduced dependence on the pathway targeted by belatacept and increased adhesion molecule expression. One such molecule is leukocyte function antigen (LFA)-1. LFA-1 exists in two forms: a commonly expressed, low-affinity form and a transient, high-affinity form, expressed only during activation. We have shown that antibodies reactive with LFA-1 regardless of its configuration are effective in eliminating memory T cells but at the cost of impaired protective immunity. Here we test two novel agents, leukotoxin A and AL-579, each of which targets the high-affinity form of LFA-1, to determine whether this more precise targeting prevents belatacept-resistant rejection. Despite evidence of ex vivo and in vivo ligand-specific activity, neither agent when combined with belatacept proved superior to belatacept monotherapy. Leukotoxin A approached a ceiling of toxicity before efficacy, while AL-579 failed to significantly alter the peripheral immune response. These data, and prior studies, suggest that LFA-1 blockade may not be a suitable adjuvant agent for CoB-resistant rejection.
authors.affiliation: Department of Surgery, Duke University School of Medicine, Durham, NC.
authors.forename: K P
authors.initials: KP
authors.lastname: Samy
authors.affiliation: Emory Transplant Center, Emory University School of Medicine, Atlanta, GA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Anderson
authors.affiliation: Emory Transplant Center, Emory University School of Medicine, Atlanta, GA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Lo
authors.affiliation: Department of Surgery, Duke University School of Medicine, Durham, NC.
authors.forename: M S
authors.initials: MS
authors.lastname: Mulvihill
authors.affiliation: Department of Surgery, Duke University School of Medicine, Durham, NC.
authors.forename: M
authors.initials: M
authors.lastname: Song
authors.affiliation: Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA.
authors.forename: A B
authors.initials: AB
authors.lastname: Farris
authors.affiliation: Department of Surgery, Duke University School of Medicine, Durham, NC.
authors.forename: B S
authors.initials: BS
authors.lastname: Parker
authors.affiliation: Department of Surgery, Duke University School of Medicine, Durham, NC.
authors.forename: A L
authors.initials: AL
authors.lastname: MacDonald
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA.
authors.forename: C
authors.initials: C
authors.lastname: Lu
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA.
authors.forename: T A
authors.initials: TA
authors.lastname: Springer
authors.affiliation: School of Medicine, Rutgers University, Newark, NJ.|Actinobac Biomed, Inc., Kendall Park, NJ.
authors.forename: S C
authors.initials: SC
authors.lastname: Kachlany
authors.affiliation: Mass-Biologics, University of Massachusetts Medical School, Boston, MA.
authors.forename: K A
authors.initials: KA
authors.lastname: Reimann
authors.affiliation: Department of Surgery, Duke University School of Medicine, Durham, NC.
authors.forename: T
authors.initials: T
authors.lastname: How
authors.affiliation: Department of Surgery, Duke University School of Medicine, Durham, NC.
authors.forename: F V
authors.initials: FV
authors.lastname: Leopardi
authors.affiliation: Division of Laboratory Animal Resources, Duke University, Durham, NC.
authors.forename: K S
authors.initials: KS
authors.lastname: Franke
authors.affiliation: Division of Laboratory Animal Resources, Duke University, Durham, NC.
authors.forename: K D
authors.initials: KD
authors.lastname: Williams
authors.affiliation: Department of Surgery, Duke University School of Medicine, Durham, NC.
authors.forename: B H
authors.initials: BH
authors.lastname: Collins
authors.affiliation: Department of Surgery, Duke University School of Medicine, Durham, NC.|Emory Transplant Center, Emory University School of Medicine, Atlanta, GA.
authors.forename: A D
authors.initials: AD
authors.lastname: Kirk
mesh_terms: D000069594:Abatacept / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D006085:Graft Survival / Q000187:drug effects / Q000276:immunology*; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007677:Kidney Function Tests; D016030:Kidney Transplantation / Q000009:adverse effects*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry* / Q000378:metabolism; D008253:Macaca mulatta; D011183:Postoperative Complications; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology
chemical_list: D007166:Immunosuppressive Agents; D016169:Lymphocyte Function-Associated Antigen-1; D000069594:Abatacept
keywords: animal models: nonhuman primate; costimulation; fusion proteins and monoclonal antibodies: belatacept; immunobiology; immunosuppressant; immunosuppression/immune modulation; lymphocyte biology: trafficking; macrophage/monocyte biology: activation; translational research/science