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Alefacept promotes co-stimulation blockade based allograft survival in nonhuman primates

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Abstract

Memory T cells promote allograft rejection particularly in co-stimulation blockade–based immunosuppressive regimens. Here we show that the CD2-specific fusion protein alefacept (lymphocyte function–associated antigen-3–Ig; LFA -3–Ig) selectively eliminates memory T cells and, when combined with a co-stimulation blockade–based regimen using cytotoxic T lymphocyte antigen-4 (CTLA-4)-Ig, a CD80- and CD86-specific fusion protein, prevents renal allograft rejection and alloantibody formation in nonhuman primates. These results support the immediate translation of a regimen for the prevention of allograft rejection without the use of calcineurin inhibitors, steroids or pan–T cell depletion.

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Figure 1: The effect of LFA-3–Ig on renal allograft survival and memory T cells in rhesus macaques.
Figure 2: Studies investigating the relationship between CD2 expression and alloresponsiveness in MLC as measured by proliferation and cytokine production.

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Acknowledgements

This study was funded in part by the Division of Intramural Research, National Institute of Diabetes, Digestive and Kidney Disease, NIH (Z01 DK062007-06). Salary support for T.A.W. was provided by the Howard Hughes Medical Institute through the NIH Research Scholars Program. A.D.K. is supported by the National Institutes of Health (1U01AI079223-01A1), the Georgia Research Alliance and the McKelvey Foundation. We gratefully acknowledge the expert assistance of J. Bacher and the staff of the NIH Veterinary Pathology Department.

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Authors and Affiliations

  1. Department of Health and Human Services, Transplantation Branch, National Institute of Diabetes, Digestive and Kidney Diseases, US National Institutes of Health (NIH), Bethesda, Maryland, USA

    Tim A Weaver, Ali H Charafeddine, Avinash Agarwal, Alexandra P Turner, Maria Russell, Frank V Leopardi, Robert L Kampen, Linda Stempora, Mingqing Song & Allan D Kirk

  2. Emory Transplant Center, Emory University, Atlanta, Georgia, USA

    Tim A Weaver, Ali H Charafeddine, Frank V Leopardi, Robert L Kampen, Christian P Larsen & Allan D Kirk

Authors
  1. Tim A Weaver
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  2. Ali H Charafeddine
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  3. Avinash Agarwal
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  4. Alexandra P Turner
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  5. Maria Russell
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  6. Frank V Leopardi
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  7. Robert L Kampen
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  8. Linda Stempora
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  9. Mingqing Song
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  10. Christian P Larsen
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  11. Allan D Kirk
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Contributions

T.A.W. performed surgical procedures, cared for experimental macaques, conducted in vitro experiments, interpreted data and prepared the manuscript; A.H.C. performed surgical procedures and cared for experimental macaques; A.A. performed surgical procedures, cared for experimental macaques, conducted in vitro experiments and interpreted data; A.P.T. performed surgical procedures, cared for experimental macaques, conducted in vitro experiments and interpreted data; M.R. cared for experimental macaques, conducted in vitro experiments and interpreted data; F.V.L. performed surgical procedures and cared for experimental macaques; R.L.K. conducted in vitro experiments and interpreted data; L.S. conducted in vitro experiments and interpreted data;, M.S. performed histology and immunohistochemistry, interpreted data and prepared the manuscript; C.P.L. interpreted data and prepared the manuscript; A.D.K. conceived of experimental design, performed surgical procedures, cared for experimental macaques, interpreted data and prepared the manuscript.

Corresponding author

Correspondence to Allan D Kirk.

Supplementary information

Supplementary Text and Figures

Supplementary Table 1, Supplementary Figs. 1–4 and Supplementary Methods (PDF 6015 kb)

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Weaver, T., Charafeddine, A., Agarwal, A. et al. Alefacept promotes co-stimulation blockade based allograft survival in nonhuman primates. Nat Med 15, 746–749 (2009). https://doi.org/10.1038/nm.1993

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  • DOI: https://doi.org/10.1038/nm.1993

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