Selective Targeting of High-Affinity LFA-1 Does Not Augment Costimulation Blockade in a Nonhuman Primate Renal Transplantation Model.
Am J Transplant
; 17(5): 1193-1203, 2017 May.
Article
in En
| 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.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
T-Lymphocytes
/
Lymphocyte Function-Associated Antigen-1
/
Kidney Transplantation
/
Abatacept
/
Graft Rejection
/
Graft Survival
/
Immunologic Memory
Type of study:
Etiology_studies
Limits:
Animals
Language:
En
Journal:
Am J Transplant
Journal subject:
TRANSPLANTE
Year:
2017
Type:
Article
Affiliation country:
New Caledonia