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Am J Transplant ; 17(5): 1193-1203, 2017 May.
Article in English | MEDLINE | ID: mdl-27888551

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.


Subject(s)
Abatacept/pharmacology , Graft Rejection/drug therapy , Graft Survival/immunology , Immunologic Memory/immunology , Kidney Transplantation/adverse effects , Lymphocyte Function-Associated Antigen-1/chemistry , T-Lymphocytes/immunology , Animals , Disease Models, Animal , Glomerular Filtration Rate , Graft Rejection/etiology , Graft Rejection/pathology , Graft Survival/drug effects , Immunologic Memory/drug effects , Immunosuppressive Agents/pharmacology , Kidney Function Tests , Lymphocyte Function-Associated Antigen-1/metabolism , Macaca mulatta , Postoperative Complications , T-Lymphocytes/drug effects , T-Lymphocytes/pathology
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