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Belatacept and sirolimus prolong nonhuman primate islet allograft survival: adverse consequences of concomitant alefacept therapy.

Publication ,  Journal Article
Lowe, MC; Badell, IR; Turner, AP; Thompson, PW; Leopardi, FV; Strobert, EA; Larsen, CP; Kirk, AD
Published in: Am J Transplant
February 2013

Calcineurin inhibitors (CNI) and steroids are known to promote insulin resistance, and their avoidance after islet transplantation is preferred from a metabolic standpoint. Belatacept, a B7-specific mediator of costimulation blockade (CoB), is clinically indicated as a CNI alternative in renal transplantation, and we have endeavored to develop a clinically translatable, belatacept-based regimen that could obviate the need for both CNIs and steroids. Based on the known synergy between CoB and mTOR inhibition, we studied rhesus monkeys undergoing MHC-mismatched islet allotransplants treated with belatacept and the mTOR inhibitor, sirolimus. To extend prior work on CoB-resistant rejection, some animals also received CD2 blockade with alefacept (LFA3-Ig). Nine rhesus macaques were rendered diabetic with streptozotocin and underwent islet allotransplantation. All received belatacept and sirolimus; six also received alefacept. Belatacept and sirolimus significantly prolonged rejection-free graft survival (median 225 days compared to 8 days in controls receiving basiliximab and sirolimus; p = 0.022). The addition of alefacept provided no additional survival benefit, but was associated with Cytomegalovirus reactivation in four of six animals. No recipients produced donor-specific alloantibodies. The combination of belatacept and sirolimus successfully prevents islet allograft survival in rhesus monkeys, but induction with alefacept provides no survival benefit and increases the risk of viral reactivation.

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Published In

Am J Transplant

DOI

EISSN

1600-6143

Publication Date

February 2013

Volume

13

Issue

2

Start / End Page

312 / 319

Location

United States

Related Subject Headings

  • Transplantation, Homologous
  • Surgery
  • Steroids
  • Sirolimus
  • Recombinant Fusion Proteins
  • Macaca mulatta
  • Islets of Langerhans Transplantation
  • Islets of Langerhans
  • Immunosuppressive Agents
  • Immunoconjugates
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Lowe, M. C., Badell, I. R., Turner, A. P., Thompson, P. W., Leopardi, F. V., Strobert, E. A., … Kirk, A. D. (2013). Belatacept and sirolimus prolong nonhuman primate islet allograft survival: adverse consequences of concomitant alefacept therapy. Am J Transplant, 13(2), 312–319. https://doi.org/10.1111/j.1600-6143.2012.04341.x
Lowe, M. C., I. R. Badell, A. P. Turner, P. W. Thompson, F. V. Leopardi, E. A. Strobert, C. P. Larsen, and A. D. Kirk. “Belatacept and sirolimus prolong nonhuman primate islet allograft survival: adverse consequences of concomitant alefacept therapy.Am J Transplant 13, no. 2 (February 2013): 312–19. https://doi.org/10.1111/j.1600-6143.2012.04341.x.
Lowe MC, Badell IR, Turner AP, Thompson PW, Leopardi FV, Strobert EA, et al. Belatacept and sirolimus prolong nonhuman primate islet allograft survival: adverse consequences of concomitant alefacept therapy. Am J Transplant. 2013 Feb;13(2):312–9.
Lowe, M. C., et al. “Belatacept and sirolimus prolong nonhuman primate islet allograft survival: adverse consequences of concomitant alefacept therapy.Am J Transplant, vol. 13, no. 2, Feb. 2013, pp. 312–19. Pubmed, doi:10.1111/j.1600-6143.2012.04341.x.
Lowe MC, Badell IR, Turner AP, Thompson PW, Leopardi FV, Strobert EA, Larsen CP, Kirk AD. Belatacept and sirolimus prolong nonhuman primate islet allograft survival: adverse consequences of concomitant alefacept therapy. Am J Transplant. 2013 Feb;13(2):312–319.
Journal cover image

Published In

Am J Transplant

DOI

EISSN

1600-6143

Publication Date

February 2013

Volume

13

Issue

2

Start / End Page

312 / 319

Location

United States

Related Subject Headings

  • Transplantation, Homologous
  • Surgery
  • Steroids
  • Sirolimus
  • Recombinant Fusion Proteins
  • Macaca mulatta
  • Islets of Langerhans Transplantation
  • Islets of Langerhans
  • Immunosuppressive Agents
  • Immunoconjugates