Differential response of sensory and motor axons in nerve allografts after withdrawal of immunosuppressive therapy.
OBJECTIVE
Rejection of nerve allografts and loss of regenerated host axons after withdrawal of immunosuppressive therapy poses an ongoing challenge in peripheral nerve repair. The present report is of a blinded prospective controlled study in which an established rat model of nerve allotransplantation is used to examine the effect of fiber type on survival and degeneration of nerve allografts after discontinuation of immunosuppression. The authors hypothesized that sensory axons will selectively resist a rejection response, whereas motor axons will degenerate.


METHODS
Four-centimeter nerve segments from ACI rats were grafted into peroneal and sural (mixed) or saphenous (sensory) nerve gaps in Lewis rats. In some rats, L4-6 dorsal root ganglia were ablated before grafting, creating pure motor sural and peroneal nerves. All rats received 12 weeks of immunosuppressive therapy to support nerve regeneration into allografts. Immunosuppression with cyclosporin was then withdrawn. At planned death (12-18 weeks postsurgery), graft tissue was subjected to histomorphometric analysis for evaluation of axon survival and loss. Graft rejection led to loss of all axons in approximately 60% of the allograft segments. The mixed nerve group was most prone to complete rejection, with significantly lowered axon counts at Weeks 16 and 18 compared with the Week 12 baseline. Axons from the sensory nerve were least likely to degenerate. The pure motor nerve group axons demonstrated intermediate sensitivity, with a selective loss of larger axons at Week 16 and a significant decrease in axon counts from the Week 12 baseline at Week 18.


CONCLUSIONS
Whereas the majority of axons are lost after withdrawal of immunosuppressive therapy from nerve allografts, there is a selective survival of axons from cutaneous sensory nerves and smaller-diameter motor fibers. The biological and molecular mechanisms that make some axons impervious to injury remain to be determined.
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Department of Surgery, Sunnybrook and Women 's College Health Sciences Centre, University of Toronto, Ontario, Canada. rajiv.midha@swchsc.on.ca
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D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival; D016572:Cyclosporine / Q000008:administration & dosage* / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000601:surgery; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000494:pharmacology; D008297:Male; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D009417:Nerve Tissue / Q000187:drug effects / Q000473:pathology / Q000637:transplantation*; D009475:Neurons, Afferent / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D012867:Skin / Q000294:innervation; D013997:Time Factors; D014184:Transplantation, Homologous
D007166:Immunosuppressive Agents; D016572:Cyclosporine