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Selective Targeting of High-Affinity LFA-1 Does Not Augment Costimulation Blockade in a Nonhuman Primate Renal Transplantation Model.

Publication ,  Journal Article
Samy, KP; Anderson, DJ; Lo, DJ; Mulvihill, MS; Song, M; Farris, AB; Parker, BS; MacDonald, AL; Lu, C; Springer, TA; Kachlany, SC; Reimann, KA ...
Published in: Am J Transplant
May 2017

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.

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Published In

Am J Transplant

DOI

EISSN

1600-6143

Publication Date

May 2017

Volume

17

Issue

5

Start / End Page

1193 / 1203

Location

United States

Related Subject Headings

  • T-Lymphocytes
  • Surgery
  • Postoperative Complications
  • Macaca mulatta
  • Lymphocyte Function-Associated Antigen-1
  • Kidney Transplantation
  • Kidney Function Tests
  • Immunosuppressive Agents
  • Immunologic Memory
  • Graft Survival
 

Citation

APA
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ICMJE
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Samy, K. P., Anderson, D. J., Lo, D. J., Mulvihill, M. S., Song, M., Farris, A. B., … Kirk, A. D. (2017). 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. https://doi.org/10.1111/ajt.14141
Samy, K. P., D. J. Anderson, D. J. Lo, M. S. Mulvihill, M. Song, A. B. Farris, B. S. Parker, et al. “Selective Targeting of High-Affinity LFA-1 Does Not Augment Costimulation Blockade in a Nonhuman Primate Renal Transplantation Model.Am J Transplant 17, no. 5 (May 2017): 1193–1203. https://doi.org/10.1111/ajt.14141.
Samy KP, Anderson DJ, Lo DJ, Mulvihill MS, Song M, Farris AB, et al. Selective Targeting of High-Affinity LFA-1 Does Not Augment Costimulation Blockade in a Nonhuman Primate Renal Transplantation Model. Am J Transplant. 2017 May;17(5):1193–203.
Samy, K. P., et al. “Selective Targeting of High-Affinity LFA-1 Does Not Augment Costimulation Blockade in a Nonhuman Primate Renal Transplantation Model.Am J Transplant, vol. 17, no. 5, May 2017, pp. 1193–203. Pubmed, doi:10.1111/ajt.14141.
Samy KP, Anderson DJ, Lo DJ, Mulvihill MS, Song M, Farris AB, Parker BS, MacDonald AL, Lu C, Springer TA, Kachlany SC, Reimann KA, How T, Leopardi FV, Franke KS, Williams KD, Collins BH, Kirk AD. Selective Targeting of High-Affinity LFA-1 Does Not Augment Costimulation Blockade in a Nonhuman Primate Renal Transplantation Model. Am J Transplant. 2017 May;17(5):1193–1203.
Journal cover image

Published In

Am J Transplant

DOI

EISSN

1600-6143

Publication Date

May 2017

Volume

17

Issue

5

Start / End Page

1193 / 1203

Location

United States

Related Subject Headings

  • T-Lymphocytes
  • Surgery
  • Postoperative Complications
  • Macaca mulatta
  • Lymphocyte Function-Associated Antigen-1
  • Kidney Transplantation
  • Kidney Function Tests
  • Immunosuppressive Agents
  • Immunologic Memory
  • Graft Survival