An evaluation of nerve repair with nerve allografts in normal and immunologically tolerant rats

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✓ Schwann cells survive longer in allografts of ganglia that contain minor, rather than major and minor, transplantation antigens. The authors have investigated whether a nerve allograft with minor antigens would be superior to one with major and minor incompatibilities in aiding in the repair of injured nerve. A segment of host peroneal nerve was removed from rats and replaced with a peroneal nerve allograft that contained either minor or major and minor antigens. The results showed that in normal rats, host nerve fibers could functionally regenerate through (that is, grow through and reinnervate muscle) nerve allografts 2 cm but not 4 cm in length, irrespective of the antigens the allografts contained. Host nerve fibers could, however, regenerate through 4-cm nerve allografts if the hosts were rendered immunologically tolerant of the transplantation antigens of the nerve donors. Furthermore, when sensitized lymphoid cells were injected into tolerant rats bearing functional nerve allografts, Schwann cell rejection and demyelination occurred in the graft but host nerve fibers remained. It is concluded that minor antigens alone are as potent as major and minor antigens together in evoking an immune response that prevents functional regeneration through long lengths of nerve allografts. Host nerve fibers can, however, regenerate through such nerve allografts if the hosts are immunosuppressed.

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Address reprint requests to: Andrew A. Zalewski, M.D., Building 36, Room 4D-25, National Institutes of Health, Bethesda, Maryland 20205.

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    Appearance of cross sections of normal (A–C), grafted (D,H), and distal host (E–G) peroneal nerve. Many nerve fibers are present in a nerve allograft (D) and distal host nerve (E) after 120 days in a rat with reinnervated muscle. The regenerated nerve fibers in the graft and as illustrated here in the distal host nerve are thinner (F) and more variably myelinated (G) than normal (compare F to B and G to C, respectively). Only a few regenerated nerve fibers are present in a nerve allograft (bounded by arrows) after 120 days in a rat with nonreinnervated muscle (H). A, B, D–F, and H stained with silver; A, D, E, and H: × 80, B and F, × 350. C and G stained with PAS-hematoxylin, × 350.

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    Longitudinal sections through LE nerve grafts 4 weeks after injecting LE-sensitized FR lymphoid cells into normal (A) or LE-tolerant (B–D) FR rats that had successful 2-cm LE nerve grafts. In the normal rat (A), note in the nerve the presence of myelinated nerve fibers, and the perineural sheath (the location of the latter is indicated by the arrows). In contrast, note that the nerve in the tolerance-abolished rat (B) is infiltrated by mononuclear cells (arrows), extensive demyelination has occurred, and the perineural sheath is absent. Nerve fibers, however, are present in the region of demyelination (C, arrows indicate innermost region of nerve where myelin was seen in B). Frequently, a myelinated nerve fiber was seen to abruptly lose its myelin and continue distally unmyelinated (arrows in D indicate point on a nerve fiber where myelin ceases). A and B: PAS-hematoxylin, × 80; C and D: silver stain, × 350.

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    Appearance of cross sections of EDL muscle: normal (A and B), reinnervated (C–E), nonreinnervated (F and G), and denervated for 2 weeks (H). The normal EDL contains muscle fibers of various diameter which can be grouped into three fiber types after staining with actomyosin ATPase (A, fibers designated α, αβ, and β) or SDH (B, fibers called A, B, and C). It can be seen that reinnervated muscle (E) has fibers with nearly normal diameter (compare E to B), a typical neuromuscular junction (D, the short arrow points to the nerve while the long arrow indicates the muscle end-plate), and all fiber types (E). Note that while the normal EDL has few β fibers (A), the reinnervated one has more (C), which indicates that fiber type conversion has occurred. Fibers in nonreinnervated muscle are thinner (F) than normal (A), and SDH typing is lost in almost all fibers (G, arrow indicates an identifiable B fiber). No fiber conversion was found in nonreinnervated muscle, as these had few β fibers (see arrow in F). The findings in nonreinnervated muscle were similar to those of denervated muscle of rats, which did not receive any nerve graft. In H, it can be seen that A-type fibers atrophy and lose their histochemical identity (arrow) 2 weeks after nerve transection. These findings were not observed in any of the rats injected with sensitized cells. EDL = extensor digitorum longus; SDH = succinic dehydrogenase. A, C, and F: actomyosin ATPase stain, × 220; B, E, G, and H: SDH stain, × 350; D: silver stain, × 350.

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