Peripheral Nerve Transplantation: The Role of Chemical Acellularization in Eliminating Allograft Antigenicity

Jason M. Rovak; D. Keith Bishop; Leslie K. Boxer; Sherri C. Wood; Anil K. Mungara; Paul S. Cederna

doi:10.1055/s-2005-869828

Journal of Reconstructive Microsurgery, Table of Contents

J Reconstr Microsurg 2005; 21(3): 207-213
DOI: 10.1055/s-2005-869828

BASIC SCIENCE REVIEW

Peripheral Nerve Transplantation: The Role of Chemical Acellularization in Eliminating Allograft Antigenicity

Jason M. Rovak¹ ^, ² , D. Keith Bishop³ ^, ⁴ , Leslie K. Boxer⁵ , Sherri C. Wood³ , Anil K. Mungara⁵ , Paul S. Cederna² ^, ⁵

¹Division of Plastic and Reconstructive Surgery, Washington University, St. Louis, MO
²Institute of Gerontology, University of Michigan, Ann Arbor, MI
³Transplant Immunology Research Laboratories, Section of General Surgery, Department of Surgery, University of Michigan Health Systems, Ann Arbor, MI
⁴Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI
⁵Section of Plastic and Reconstructive Surgery, Department of Surgery, University of Michigan Health Systems, Ann Arbor, MI

Abstract

ABSTRACT

This study tests the hypothesis that a chemically acellularized peripheral nerve allograft is as immunologically inactive as a peripheral nerve isograft. Cellular and acellular sciatic nerves were transplanted from BALB/c into C57BL/6 mice. C57BL/6 sciatic nerves were also transplanted into C57BL/6 recipients as isograft controls. Fourteen days post-transplantation, recipient splenocytes were isolated, stimulated with donor alloantigens, and IL-2, IL-4, IL-5, and γ-IFN production was quantified using the ELISPOT technique. Cellular peripheral nerve allografts stimulated robust Th1 and Th2 systemic immune responses, whereas acellular peripheral nerve allografts elicited a response that is comparable to or lower than that quantified following peripheral nerve isograft transplantation. Chemical acellularization of peripheral nerve allografts dramatically reduces the cellular and humoral immunologic responses. These data indicate that chemically acellularized peripheral nerve constructs are relatively non-antigenic and may be a readily available source of nerve for peripheral nerve reconstruction.

KEYWORDS

Nerve - immunology - transplantation

Full Text

References

REFERENCES

1 Terzis J K, Sun D D, Thanos P K. Historical and basic science review: past, present, and future of nerve repair. J Reconstr Microsurg. 1997; 13 215-225
2 Watchmaker G P, Mackinnon S E. Advances in peripheral nerve repair. Clin Plast Surg. 1997; 24 63-73
3 Evans P J, Midha R, Mackinnon S E. The peripheral nerve allograft: a comprehensive review of regeneration and neuroimmunology. Prog Neurobiol. 1994; 43 187-233
4 Mackinnon S E, Dellon A L. Clinical nerve reconstruction with a bioabsorbable polyglycolic acid tube. Plast Reconstr Surg. 1990; 85 419-424
5 Weber R A, Breidenbach W C, Brown R E, Jabaley M E, Mass D P. A randomized prospective study of polyglycolic acid conduits for digital nerve reconstruction in humans. Plast Reconstr Surg. 2000; 106 1036-1045
6 Walton R L, Brown R E, Matory Jr W E, Borah G L, Dolph J L. Autogenous vein graft repair of digital nerve defects in the finger: a retrospective clinical study. Plast Reconstr Surg. 1989; 84 944-949
7 Chiu D T, Lovelace R E, Yu L T et al.. Comparative electrophysiologic evaluation of nerve grafts and autogenous vein grafts as nerve conduits: an experimental study. J Reconstr Microsurg. 1988; 4 303-309
8 Bunge M B, Clark M B, Dean A C, Eldridge C F, Bunge R P. Schwann cell function depends upon axonal signals and basal lamina components. Ann N Y Acad Sci. 1990; 580 281-287
9 Rodriguez F J, Verdu E, Ceballos D, Navarro X. Nerve guides seeded with autologous Schwann cells improve nerve regeneration. Exp Neurol. 2000; 161 571-584
10 Sondell M, Lundborg G, Kanje M. Regeneration of the rat sciatic nerve into allografts made acellular through chemical extraction. Brain Res. 1998; 795 44-54
11 Argall K G, Armati P J, Pollard J D, Watson E, Bonner J. Interactions between CD4+ T-cells and rat Schwann cells in vitro. 1. Antigen presentation by Lewis rat Schwann cells to P2-specific CD4+ T- cell lines. J Neuroimmunol. 1992; 40 1-18
12 Kingston A E, Bergsteinsdottir K, Jessen K R, Van der Meide P H, Colston M J, Mirsky R. Schwann cells co-cultured with stimulated T cells and antigen express major histocompatibility complex (MHC) class II determinants without interferon-gamma pretreatment: synergistic effects of interferon-gamma and tumor necrosis factor on MHC class II induction. Eur J Immunol. 1989; 19 177-183
13 Argall K G, Armati P J, Pollard J D, Bonner J. Interactions between CD4+ T-cells and rat Schwann cells in vitro. 2. Cytotoxic effects of P2-specific CD4+ T-cell lines on Lewis rat Schwann cells. J Neuroimmunol. 1992; 40 19-29
14 Stoll G, Muller H W. Nerve injury, axonal degeneration and neural regeneration: basic insights. Brain Pathol. 1999; 9 313-325
15 Funakoshi H, Frisen J, Barbany G et al.. Differential expression of mRNAs for neurotrophins and their receptors after axotomy of the sciatic nerve. J Cell Biol. 1993; 123 455-465
16 Dennis R G, Kuzon W M, Cederna P S. U.S. Serial No. 09/896,651, Method For Chemically Acellularizing a Biological Tissue Sample: Continuation in Part of U.S. Serial No. 09/709,890. U.S Patent No. 6,448,076, September 10. 2002
17 Matesic D, Lehmann P V, Heeger P S. High-resolution characterization of cytokine-producing alloreactivity in naive and allograft-primed mice. Transplantation. 1998; 65 906-914
18 Kramer H. The metachromatic staining reaction. J Histochem. 1955; 3 227-232
19 Chan S Y, DeBruyne L A, Goodman R E, Eichwald E J, Bishop D K. In vivo depletion of CD8+ T cells results in Th2 cytokine production and alternate mechanisms of allograft rejection. Transplantation. 1995; 59 1155-1161
20 Bishop D K, Shelby J, Eichwald E J. Mobilization of T lymphocytes following cardiac transplantation: evidence the CD4-positive cells are required for cytotoxic T lymphocyte activation, inflammatory endothelial development, graft infiltration, and acute allograft rejection. Transplantation. 1992; 53 849-857
21 Piccotti J R, Chan S Y, VanBuskirk A M, Eichwald E J, Bishop D. Are Th2 helper T lymphocytes beneficial, deleterious, or irrelevant in promoting allograft survival?. Transplantation. 1997; 63 619-624
22 Bishop D K, ChanWood S, Eichwald E J, Orosz C G. Immunobiology of allograft rejection in the absence of IFNγ: CD8+ effector cells develop independently of CD4+ cells and CD40-CD40 ligand interactions. J Immunol. 2001; 166 3248-3255
23 Bishop D K, Li W, Chan S Y, Ensley R D, Shelby J, Eichwald E J. Helper T lymphocyte unresponsiveness to cardiac allografts following transient depletion of CD4-positive cells. Implications for cellular and humoral responses. Transplantation. 1994; 58 576-584
24 Fu S Y, Gordon T. The cellular and molecular basis of peripheral nerve regeneration. Mol Neurobiol. 1997; 14 67-116
25 Piccotti J R, Chan S Y, Eichwald E J, Bishop D K. Differential effects of IL-12 receptor blockade with IL-12 p40 homodimer on the induction of CD4+ and CD8+ IFN-γ-producing cells. J Immunol. 1997; 158 643-648
26 Krams S M, Falco D A, Villanueva J C et al.. Cytokine and T cell receptor gene expression at the site of allograft rejection. Transplantation. 1992; 53 151-156
27 Martinez O M, Villanueva J C, Lake J, Roberts J P, Ascher N L, Krams S M. IL-2 and IL-5 gene expression in response to alloantigen in liver allograft recipients and in vitro. Transplantation. 1993; 55 1159-1166
28 VanBuskirk A M, Wakely M E, Orosz C G. Transfusion of polarized TH2-like cell populations into SCID mouse cardiac allograft recipients results in acute allograft rejection. Transplantation. 1996; 62 229-238
29 Strom T B, Roy-Chaudhury P, Manfro R et al.. The Th1/Th2 paradigm and the allograft response. Curr Opin Immunol. 1996; 8 688-693
30 Baumgarth N. A two-phase model of B-cell activation. Immunol Rev. 2000; 176 171-180
31 Haase S C, Rovak J M, Dennis R G, Kuzon W M, Cederna P S. Recovery of muscle contractile function following peripheral nerve gap repair with an acellularized peripheral nerve graft. J Reconstr Microsurg. 2005; , in press
32 Haase S C, Cederna P S, Dennis R G, Kuzon W M. Peripheral nerve reconstruction using acellular nerve grafts. Surg Forum. 2000; 51 607-609

Paul S CedernaM.D. F.A.C.S.

University of Michigan Health Systems, Department of Surgery, Section of Plastic Surgery

1500 East Medical Center Drive, 2130 Taubman Center

Ann Arbor, MI 48109-0340