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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; Song, M; Leopardi, FV ...
Published in: J Clin Invest
December 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 (TM) 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 TM 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 TM 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.

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Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

December 2010

Volume

120

Issue

12

Start / End Page

4520 / 4531

Location

United States

Related Subject Headings

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

Citation

APA
Chicago
ICMJE
MLA
NLM
Badell, I. R., Russell, M. C., Thompson, P. W., Turner, A. P., Weaver, T. A., Robertson, J. M., … Larsen, C. P. (2010). LFA-1-specific therapy prolongs allograft survival in rhesus macaques. J Clin Invest, 120(12), 4520–4531. https://doi.org/10.1172/JCI43895
Badell, Idelberto R., Maria C. Russell, Peter W. Thompson, Alexandra P. Turner, Tim A. Weaver, Jennifer M. Robertson, Jose G. Avila, et al. “LFA-1-specific therapy prolongs allograft survival in rhesus macaques.J Clin Invest 120, no. 12 (December 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. J Clin Invest. 2010 Dec;120(12):4520–31.
Badell, Idelberto R., et al. “LFA-1-specific therapy prolongs allograft survival in rhesus macaques.J Clin Invest, vol. 120, no. 12, Dec. 2010, pp. 4520–31. Pubmed, doi:10.1172/JCI43895.
Badell IR, Russell MC, Thompson PW, Turner AP, Weaver TA, Robertson JM, Avila JG, Cano JA, Johnson BE, Song M, Leopardi FV, Swygert S, Strobert EA, Ford ML, Kirk AD, Larsen CP. LFA-1-specific therapy prolongs allograft survival in rhesus macaques. J Clin Invest. 2010 Dec;120(12):4520–4531.

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

December 2010

Volume

120

Issue

12

Start / End Page

4520 / 4531

Location

United States

Related Subject Headings

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