TY - JOUR
T1 - Dynamic quantification of host Schwann cell migration into peripheral nerve allografts
AU - Whitlock, Elizabeth L.
AU - Myckatyn, Terence M.
AU - Tong, Alice Y.
AU - Yee, Andrew
AU - Yan, Ying
AU - Magill, Christina K.
AU - Johnson, Philip J.
AU - Mackinnon, Susan E.
N1 - Funding Information:
This work was funded by a grant from the National Institute of Health (5RO1NS033406) and ELW was supported by the Howard Hughes Medical Institute as a Medical Research Fellow.
PY - 2010/10
Y1 - 2010/10
N2 - Host Schwann cell (SC) migration into nerve allografts is the limiting factor in the duration of immunosuppression following peripheral nerve allotransplantation, and may be affected by different immunosuppressive regimens. Our objective was to compare SC migration patterns between clinical and experimental immunosuppression regimens both over time and at the harvest endpoint. Eighty mice that express GFP under the control of the Schwann cell specific S100 promoter were engrafted with allogeneic, nonfluorescent sciatic nerve grafts. Mice received immunosuppression with either tacrolimus (FK506), or experimental T-cell triple costimulation blockade (CSB), consisting of CTLA4-immunoglobulin fusion protein, anti-CD40 monoclonal antibody, and anti-inducible costimulator monoclonal antibody. Migration of GFP-expressing host SCs into wild-type allografts was assessed in vivo every 3. weeks until 15. weeks postoperatively, and explanted allografts were evaluated for immunohistochemical staining patterns to differentiate graft from host SCs. Immunosuppression with tacrolimus exhibited a plateau of SC migration, characterized by significant early migration (< 3. weeks) followed by a constant level of host SCs in the graft (15. weeks). At the endpoint, graft fluorescence was decreased relative to surrounding host nerve, and donor SCs persisted within the graft. CSB-treated mice displayed gradually increasing migration of host SCs into the graft, without the plateau noted in tacrolimus-treated mice, and also maintained a population of donor SCs at the 15-week endpoint. SC migration patterns are affected by immunosuppressant choice, particularly in the immediate postoperative period, and the use of a single treatment of CSB may allow for gradual population of nerve allografts with host SCs.
AB - Host Schwann cell (SC) migration into nerve allografts is the limiting factor in the duration of immunosuppression following peripheral nerve allotransplantation, and may be affected by different immunosuppressive regimens. Our objective was to compare SC migration patterns between clinical and experimental immunosuppression regimens both over time and at the harvest endpoint. Eighty mice that express GFP under the control of the Schwann cell specific S100 promoter were engrafted with allogeneic, nonfluorescent sciatic nerve grafts. Mice received immunosuppression with either tacrolimus (FK506), or experimental T-cell triple costimulation blockade (CSB), consisting of CTLA4-immunoglobulin fusion protein, anti-CD40 monoclonal antibody, and anti-inducible costimulator monoclonal antibody. Migration of GFP-expressing host SCs into wild-type allografts was assessed in vivo every 3. weeks until 15. weeks postoperatively, and explanted allografts were evaluated for immunohistochemical staining patterns to differentiate graft from host SCs. Immunosuppression with tacrolimus exhibited a plateau of SC migration, characterized by significant early migration (< 3. weeks) followed by a constant level of host SCs in the graft (15. weeks). At the endpoint, graft fluorescence was decreased relative to surrounding host nerve, and donor SCs persisted within the graft. CSB-treated mice displayed gradually increasing migration of host SCs into the graft, without the plateau noted in tacrolimus-treated mice, and also maintained a population of donor SCs at the 15-week endpoint. SC migration patterns are affected by immunosuppressant choice, particularly in the immediate postoperative period, and the use of a single treatment of CSB may allow for gradual population of nerve allografts with host SCs.
KW - Composite tissue allotransplantation
KW - Costimulation blockade
KW - FK-506
KW - Immunomodulation
KW - Immunosuppression
KW - Nerve allograft
KW - Nerve transplantation
KW - Tacrolimus
UR - http://www.scopus.com/inward/record.url?scp=77956446775&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2010.07.001
DO - 10.1016/j.expneurol.2010.07.001
M3 - Article
C2 - 20633557
AN - SCOPUS:77956446775
SN - 0014-4886
VL - 225
SP - 310
EP - 319
JO - Experimental Neurology
JF - Experimental Neurology
IS - 2
ER -