Interleukin-15 receptor blockade in non-human primate kidney transplantation.
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.
Haustein
Silke
S
Division of Transplantation, Department of Surgery, Clinical Science Center, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Kwun
Jean
J
Fechner
John
J
Kayaoglu
Ayhan
A
Faure
Jean-Pierre
JP
Roenneburg
Drew
D
Torrealba
Jose
J
Knechtle
Stuart J
SJ
D000818:Animals; D000961:Antilymphocyte Serum / Q000494:pharmacology; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D003404:Creatinine / Q000097:blood; D004359:Drug Therapy, Combination; D005434:Flow Cytometry; D006084:Graft Rejection / Q000097:blood / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D016030:Kidney Transplantation / Q000009:adverse effects; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D018655:Lymphocyte Count; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D023421:Models, Animal; D009173:Mycophenolic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D053647:Receptors, Interleukin-15 / Q000037:antagonists & inhibitors* / Q000276:immunology; D013997:Time Factors; D014184:Transplantation, Homologous
D000961:Antilymphocyte Serum; D015415:Biomarkers; D007141:Immunoglobulin Fc Fragments; D007166:Immunosuppressive Agents; D053647:Receptors, Interleukin-15; D003404:Creatinine; D009173:Mycophenolic Acid