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LFA-1 - Specific therapy prolongs allograft survival in rhesus macaques

Publication ,  Journal Article
Badell, IR; Russell, MC; Thompson, PW; Turner, AP; Weaver, TA; Robertson, JM; Avila, JG; Cano, JA; Johnson, BE; et al.,
Published in: Journal of Clinical Investigation
2010

Outcomes in transplantation have been limited by suboptimal long-term graft survival and toxicities associated with current immunosuppressive approaches. T cell costimulation blockade has shown promise as an alternative strategy to avoid the side effects of conventional immunosuppressive therapies, but targeting CD28-mediated costimulation alone has proven insufficient to prevent graft rejection in primates. Donor-specific memory T (T M ) cells have been implicated in costimulation blockade - resistant transplant rejection, due to their enhanced effector function and decreased reliance on costimulatory signaling. Thus, we have tested a potential strategy to overcome T M cell - driven rejection by targeting molecules preferentially expressed on these cells, such as the adhesion molecule lymphocyte function - associated antigen 1 (LFA-1). Here, we show that short-term treatment (i.e., induction therapy) with the LFA-1 - specific antibody TS-1/22 in combination with either basiliximab (an IL-2Rα - specific mAb) and sirolimus (a mammalian target of rapamycin inhibitor) or belatacept (a high-affinity variant of the CD28 costimulation - blocker CTLA4Ig) prolonged islet allograft survival in nonhuman primates relative to control treatments. Moreover, TS-1/22 masked LFA-1 on T M cells in vivo and inhibited the generation of alloproliferative and cytokine-producing effector T cells that expressed high levels of LFA-1 in vitro. These results support the use of LFA-1 - specific induction therapy to neutralize costimulation blockade - resistant populations of T cells and further evaluation of LFA-1 - specific therapeutics for use in transplantation.

Duke Scholars

Published In

Journal of Clinical Investigation

DOI

ISSN

0021-9738

Publication Date

2010

Volume

120

Issue

12

Start / End Page

4520 / 4531

Related Subject Headings

  • Transplantation, Homologous
  • Tissue Donors
  • T-Lymphocyte Subsets
  • Macaca mulatta
  • Lymphocyte Function-Associated Antigen-1
  • Islets of Langerhans Transplantation
  • Immunosuppression Therapy
  • Immunosuppression
  • Immunology
  • Immunologic Memory
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Badell, I. R., Russell, M. C., Thompson, P. W., Turner, A. P., Weaver, T. A., Robertson, J. M., … et al., . (2010). LFA-1 - Specific therapy prolongs allograft survival in rhesus macaques. Journal of Clinical Investigation, 120(12), 4520–4531. https://doi.org/10.1172/JCI43895
Badell, I. R., M. C. Russell, P. W. Thompson, A. P. Turner, T. A. Weaver, J. M. Robertson, J. G. Avila, J. A. Cano, B. E. Johnson, and B. E. et al. “LFA-1 - Specific therapy prolongs allograft survival in rhesus macaques.” Journal of Clinical Investigation 120, no. 12 (2010): 4520–31. https://doi.org/10.1172/JCI43895.
Badell IR, Russell MC, Thompson PW, Turner AP, Weaver TA, Robertson JM, et al. LFA-1 - Specific therapy prolongs allograft survival in rhesus macaques. Journal of Clinical Investigation. 2010;120(12):4520–31.
Badell, I. R., et al. “LFA-1 - Specific therapy prolongs allograft survival in rhesus macaques.” Journal of Clinical Investigation, vol. 120, no. 12, 2010, pp. 4520–31. Manual, doi:10.1172/JCI43895.
Badell IR, Russell MC, Thompson PW, Turner AP, Weaver TA, Robertson JM, Avila JG, Cano JA, Johnson BE, et al. LFA-1 - Specific therapy prolongs allograft survival in rhesus macaques. Journal of Clinical Investigation. 2010;120(12):4520–4531.

Published In

Journal of Clinical Investigation

DOI

ISSN

0021-9738

Publication Date

2010

Volume

120

Issue

12

Start / End Page

4520 / 4531

Related Subject Headings

  • Transplantation, Homologous
  • Tissue Donors
  • T-Lymphocyte Subsets
  • Macaca mulatta
  • Lymphocyte Function-Associated Antigen-1
  • Islets of Langerhans Transplantation
  • Immunosuppression Therapy
  • Immunosuppression
  • Immunology
  • Immunologic Memory