Interleukin-15 receptor blockade in non-human primate kidney transplantation

Silke Haustein, Jean Kwun, John Fechner, Ayhan Kayaoglu, Jean Pierre Faure, Drew Roenneburg, Jose Torrealba, Stuart J. Knechtle

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Background. Interleukin (IL)-15 is a chemotactic factor to T cells. It induces proliferation and promotes survival of activated T cells. IL-15 receptor blockade in mouse cardiac and islet allotransplant models has led to long-term engraftment and a regulatory T-cell environment. This study investigated the efficacy of IL-15 receptor blockade using Mut-IL-15/Fc in an outbred non-human primate model of renal allotransplantation. Methods. Male cynomolgus macaque donor-recipient pairs were selected based on ABO typing, major histocompatibility complex class I typing, and carboxy-fluorescein diacetate succinimidyl ester-based mixed lymphocyte responses. Once animals were assigned to one of six treatment groups, they underwent renal transplantation and bilateral native nephrectomy. Serum creatinine level was monitored twice weekly and as indicated, and protocol biopsies were performed. Rejection was defined as a increase in serum creatinine to 1.5 mg/dL or higher and was confirmed histologically. Complete blood counts and flow cytometric analyses were performed periodically posttransplant; pharmacokinetic parameters of Mut-IL-15/Fc were assessed. Results. Compared with control animals, Mut-IL-15/Fc-treated animals did not demonstrate increased graft survival despite adequate serum levels of Mut-IL-15/Fc. Flow cytometric analysis of white blood cell subgroups demonstrated a decrease in CD8+ T-cell and natural killer cell numbers, although this did not reach statistical significance. Interestingly, two animals receiving Mut-IL-15/Fc developed infectious complications, but no infection was seen in control animals. Renal pathology varied widely. Conclusions. Peritransplant IL-15 receptor blockade does not prolong allograft survival in non-human primate renal transplantation; however, it reduces the number of CD8+ T cells and natural killer cells in the peripheral blood.

Original languageEnglish (US)
Pages (from-to)937-944
Number of pages8
JournalTransplantation
Volume89
Issue number8
DOIs
StatePublished - Apr 2010

Fingerprint

Interleukin-15 Receptors
Interleukin-15
Kidney Transplantation
Primates
T-Lymphocytes
Natural Killer Cells
Creatinine
Serum
Kidney
Blood Cell Count
Chemotactic Factors
Macaca
Graft Survival
Regulatory T-Lymphocytes
Major Histocompatibility Complex
Nephrectomy
Allografts
Esters
Leukocytes
Pharmacokinetics

Keywords

  • Interleukin-15
  • Memory T cells
  • NK cells
  • Non-human primate
  • Transplantation

ASJC Scopus subject areas

  • Transplantation

Cite this

Haustein, S., Kwun, J., Fechner, J., Kayaoglu, A., Faure, J. P., Roenneburg, D., ... Knechtle, S. J. (2010). Interleukin-15 receptor blockade in non-human primate kidney transplantation. Transplantation, 89(8), 937-944. https://doi.org/10.1097/TP.0b013e3181d05a58

Interleukin-15 receptor blockade in non-human primate kidney transplantation. / Haustein, Silke; Kwun, Jean; Fechner, John; Kayaoglu, Ayhan; Faure, Jean Pierre; Roenneburg, Drew; Torrealba, Jose; Knechtle, Stuart J.

In: Transplantation, Vol. 89, No. 8, 04.2010, p. 937-944.

Research output: Contribution to journalArticle

Haustein, S, Kwun, J, Fechner, J, Kayaoglu, A, Faure, JP, Roenneburg, D, Torrealba, J & Knechtle, SJ 2010, 'Interleukin-15 receptor blockade in non-human primate kidney transplantation', Transplantation, vol. 89, no. 8, pp. 937-944. https://doi.org/10.1097/TP.0b013e3181d05a58
Haustein S, Kwun J, Fechner J, Kayaoglu A, Faure JP, Roenneburg D et al. Interleukin-15 receptor blockade in non-human primate kidney transplantation. Transplantation. 2010 Apr;89(8):937-944. https://doi.org/10.1097/TP.0b013e3181d05a58
Haustein, Silke ; Kwun, Jean ; Fechner, John ; Kayaoglu, Ayhan ; Faure, Jean Pierre ; Roenneburg, Drew ; Torrealba, Jose ; Knechtle, Stuart J. / Interleukin-15 receptor blockade in non-human primate kidney transplantation. In: Transplantation. 2010 ; Vol. 89, No. 8. pp. 937-944.
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abstract = "Background. Interleukin (IL)-15 is a chemotactic factor to T cells. It induces proliferation and promotes survival of activated T cells. IL-15 receptor blockade in mouse cardiac and islet allotransplant models has led to long-term engraftment and a regulatory T-cell environment. This study investigated the efficacy of IL-15 receptor blockade using Mut-IL-15/Fc in an outbred non-human primate model of renal allotransplantation. Methods. Male cynomolgus macaque donor-recipient pairs were selected based on ABO typing, major histocompatibility complex class I typing, and carboxy-fluorescein diacetate succinimidyl ester-based mixed lymphocyte responses. Once animals were assigned to one of six treatment groups, they underwent renal transplantation and bilateral native nephrectomy. Serum creatinine level was monitored twice weekly and as indicated, and protocol biopsies were performed. Rejection was defined as a increase in serum creatinine to 1.5 mg/dL or higher and was confirmed histologically. Complete blood counts and flow cytometric analyses were performed periodically posttransplant; pharmacokinetic parameters of Mut-IL-15/Fc were assessed. Results. Compared with control animals, Mut-IL-15/Fc-treated animals did not demonstrate increased graft survival despite adequate serum levels of Mut-IL-15/Fc. Flow cytometric analysis of white blood cell subgroups demonstrated a decrease in CD8+ T-cell and natural killer cell numbers, although this did not reach statistical significance. Interestingly, two animals receiving Mut-IL-15/Fc developed infectious complications, but no infection was seen in control animals. Renal pathology varied widely. Conclusions. Peritransplant IL-15 receptor blockade does not prolong allograft survival in non-human primate renal transplantation; however, it reduces the number of CD8+ T cells and natural killer cells in the peripheral blood.",
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AU - Roenneburg, Drew

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