Chimerism after Vascularized Limb Versus Bone Marrow Transplantation

Michael Cohen; Thalachallour Mohanakumar; Susan E. Mackinnon; Thomas H. Tung

doi:10.1055/s-2006-946716

Journal of Reconstructive Microsurgery, Table of Contents

J Reconstr Microsurg 2006; 22(5): 375-384
DOI: 10.1055/s-2006-946716

Chimerism after Vascularized Limb Versus Bone Marrow Transplantation

Michael Cohen¹ , Thalachallour Mohanakumar² , Susan E. Mackinnon¹ , Thomas H. Tung¹

¹Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St. Louis, Missouri
²Section of Transplantation, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri

Abstract

ABSTRACT

This study used quantitative PCR in the murine model to compare the ability of a limb allograft vs. a comparable dose of marrow suspension to induce chimerism. Female C57Bl/6 mice received a vascularized hindlimb allograft, a comparable dose of 5 × 10⁶ donor bone marrow cells, or a standard dose (20 × 10⁶) of marrow suspension from male Balb/c donors. All recipients were treated with a regimen based on CD40 costimulation blockade and T cell depletion. Y chromosome-specific quantitative PCR was used to measure chimerism. Most recipients of limb allografts demonstrated low levels of chimerism after 1 week (3/4) and 1 month (3/4). Most recipients of 5 × 10⁶ marrow cells had low levels of chimerism at 1 week (4/6) and only 1/5 after 1 month. All recipients of 20 × 10⁶ cells except one demonstrated either low or high levels of chimerism after 1 week (5/5) and 1 month (5/6). The marrow component of a limb allograft is thus more effective at inducing microchimerism compared to a comparable dose of bone marrow suspension.

KEYWORDS

Limb transplantation - costimulation blockade - chimerism - quantitative PCR - bone marrow transplantation

Full Text

References

REFERENCES

1 Jones J W, Gruber S A, Barker J H, Breidenbach W C. Successful hand transplantation: one-year follow-up. New Eng J Med. 2000; 343 468-473
2 Francois C G, Breidenbach W C, Maldonado C et al.. Hand transplantation: comparisons and observations of the first four clinical cases. Microsurgery. 2000; 20 360-371
3 Hettiaratchy S, Butler P E, Lee W P. Lessons from hand transplantations. Lancet. 2001; 357 494-495
4 Dubernard J M, Owen E, Herzberg G et al.. Human hand allograft: report on first 6 months. Lancet. 1999; 353 1315-1320
5 Nagano H, Tilney N L. Chronic allograft failure: the clinical problem. Am J Med Sci. 1997; 313 305-309
6 Monaco A P, Burke J F, Ferguson R M et al.. Current thinking on chronic renal allograft rejection: issues, concerns, and recommendations from a 1997 roundtable discussion. Am J Med Sci. 1999; 33 150-160
7 Halloran P F, Melk A, Barth C. Rethinking chronic allograft nephropathy: the concept of accelerated senescence. J Am Soc Nephrol. 1999; 10 167-181
8 Suzuki H, Hewitt C W, Tran H S et al.. Composite tissue/vascularized bone marrow transplantation: a hierarchy of tissue tolerogenicity. Graft. 1999; 2 111-115
9 Nikolic B, Sykes M. Bone marrow chimerism and transplantation tolerance. Curr Opin Immunol. 1997; 9 634-640
10 Starzl T E, Demetris A J, Murase N, Trucco M, Thomson A W, Rao A S. The lost chord: microchimerism and allograft survival. Immunol Today. 1996; 17 577-584
11 Wood K J, Sachs D H. Chimerism and transplantation tolerance: cause and effect. Immunol Today. 1996; 17 584-588
12 Starzl T E, Demetris A J, Murase N et al.. The future of transplantation: with particular references to chimerism and xenotransplantation. Transplant Proc. 1997; 29 19-27
13 Durham M M, Bingaman A W, Adams A B et al.. Administration of anti-CD40 ligand and donor bone marrow leads to hemopoietic chimerism and donor-specific tolerance without cytoreductive conditioning. J Immunol. 2000; 165 1-4
14 Wekerle T, Sayegh M H, Hill J et al.. Extrathymic T cell deletion and allogeneic stem cell engraftment induced with costimulatory blockade is followed by central T cell tolerance. J Exp Med. 1998; 187 2037-2044
15 Wekerle T, Sykes M. Mixed chimerism as an approach for the induction of transplantation tolerance. Transplantation. 1999; 68 459-467
16 Denton M D, Reul R M, Dharnidharka V R, Fang J C, Ganz P, Briscoe D M. Central role for CD40/CD40 ligand (CD154) interactions in transplant rejection. Pediatric Transplantation. 1998; 2 6-15
17 Grewal I S, Xu J, Flavell R A. Impairment of antigen-specific T-cell priming in mice lacking CD40 ligand. Nature. 1995; 378 617-620
18 Larsen C P, Pearson T C. The CD40 pathway in allograft rejection, acceptance, and tolerance. Curr Opin Immunol. 1997; 9 641-647
19 Ito H, Kurtz J, Shaffer J, Sykes M. CD4 T cell-mediated alloresistance to fully MHC-mismatched allogeneic bone marrow engraftment is dependent on CD40-CD40 ligand interactions, and lasting T cell tolerance is induced by bone marrow transplantation with initial blockade of this pathway. J Immunol. 2001; 166 2970-2981
20 Wekerle T, Sayegh M H, Ito H et al.. Anti-CD154 or CTLA4Ig obviates the need for thymic irradiation in a non-myeloablative conditioning regimen for the induction of mixed hemopoietic chimerism and tolerance. Transplantation. 1998; 68 1348-1355
21 Sykes M, Szot G L, Swenson K A, Pearson D A. Induction of high levels of allogeneic hematopoietic reconstitution and donor-specific tolerance without myelosuppressive conditioning. Nature Medicine. 1997; 3 783-787
22 Cobbold S P, Martin G, Qin S, Waldmann H. Monoclonal antibodies to promote marrow engraftment and tissue graft tolerance. Nature. 1986; 323 164-166
23 Tomita Y, Sachs D H, Sykes M. Myelosuppressive conditioning is required to achieve engraftment of pluripotent stem cells contained in moderate doses of syngeneic bone marrow. Blood. 1994; 83 939-948
24 Tomita Y, Sachs D H, Khan A, Sykes M. Additional mAb injections can replace thymic irradiation to allow induction of mixed chimerism and tolerance in mice receiving bone marrow transplantation after conditioning with anti-T cell mAbs and 3 Gy whole body irradiation. Tranplantation. 1996; 61 469-477
25 Tomita Y, Khan A, Sykes M. Mechanism by which additional monoclonal antibody injections overcome the requirement for thymic irradiation to achieve mixed chimerism in mice receiving bone marrow transplantation after conditioning with anti-T cell mAbs and 3 Gy whole body irradiation. Tranplantation. 1996; 61 477-485
26 Prabhune K A, Gorantla V S, Maldonado C, Perez-Abadia G, Barker J H, Ildstad S T. Mixed allogeneic chimerism and tolerance to composite tissue allografts. Microsurgery. 2000; 20 441-447
27 Exner B G, Acholonu I, Ildstad S T. Hematopoietic chimerism, tolerance induction and graft-versus-host disease: considerations for composite tissue transfer. Transplant Proc. 1998; 30 2718-2720
28 Wekerle T, Sachs D H, Sykes M. Mixed chimerism for the induction of tolerance: potential applicability in clinical composite tissue grafting. Transplant Proc. 1998; 30 2708-2710
29 Black K S, Hewitt C W, Frazer L A, Howard E B, Martin D C, Achauer B M, Furnas D W. Composite tissue (limb) allografts in rats. II. Indefinite survival using low-dose cyclosporine. Transplantation. 1985; 39 365-368
30 Hewitt C W, Black K S, Dowdy S F et al.. Composite tissue (limb) allografts in rats. III. Development of donor-host lymphoid chimeras in long-term survivors. Transplantation. 1986; 41 39-43
31 Hewitt C W, Ramsamooj R, Patel M P, Yazdi B, Achauer B M, Black K S. Development of stable mixed T cell chimerism and transplantation tolerance without immune modulation in recipients of vascularized bone marrow allografts. Transplantation. 1990; 50 766-772
32 Schuster K M, Hewitt C W. Basic science foundation for clinical composite tissue transplantation. Transplant Proc. 2001; 33 1717-1719
33 Tung T H, Mohanakumar T, Mackinnon S E. Development of a mouse model for heterotopic limb and composite-tissue transplantation. J Reconstr Microsurg. 2001; 17 267-273
34 Tung T H, Mohanakumar T, Mackinnon S E. A subcutaneous heterotopic limb transplantation model in the mouse for prolonged allograft survival. Microsurgery. 2001; 21 298-305
35 Tung T H, Mackinnon S E, Mohanakumar T. Long-term limb allograft survival using anti-CD40L antibody in a murine model. Transplantation. 2003; 75 644-650
36 Russell P S, Chase C M, Sykes M, Ito H, Shaffer J, Colvin R B. Tolerance, mixed chimerism, and chronic transplant arteriopathy. J Immunol. 2001; 167 5731-5740
37 Barber W H, Mankin J A, Laskow D A et al.. Long-term results of a controlled prospective study with transfusion of donor-specific bone marrow in 57 cadaveric renal allograft recipients. Transplantation. 1991; 51 70-75
38 Ciancio G, Miller J, Garcia-Morales R O et al.. Six-year clinical effect of donor bone marrow infusions in renal transplant patients. Transplantation. 2001; 71 827-835
39 Zeevi A, Pavlick M, Banas R et al.. Three years of follow-up of bone marrow-augmented organ transplant recipients: the impact on donor-specific immune modulation. Transplant Proc. 1997; 29 1205-1206
40 Fontes P, Rao A S, Demetris A J et al.. Bone marrow augmentation of donor-cell chimerism in kidney, liver, heart, and pancreas islet transplantation. Lancet. 1994; 344 151-155
41 Ajiki T, Takahashi M, Inoue S et al.. Generation of donor hematolymphoid cells after rat-limb composite grafting. Transplantation. 2003; 75 631-636
42 Donckier V, Toungouz M, Goldman M. Transplantation tolerance and mixed chimerism: at the frontier of clinical application. Transplant Int. 2001; 14 1-5
43 Muramatsu K, Bishop A T. Microchimerism following vascularized bone allotransplantation. Transplant Proc. 2002; 34 2722-2724
44 Talmor M, Steinman R M, Codner M A et al.. Bone marrow-derived chimerism in non-irradiated, cyclosporin-treated rats receiving microvascularized limb transplants: evidence for donor-derived dendritic cells in recipient lymphoid tissues. Immunology. 1995; 86 448-455
45 Siemionow M, Ulusal B G, Ozmen S, Ulusal A E, Ozer K. Composite vascularized skin/bone graft model: a viable source for vascularized bone marrow transplantation. Microsurgery. 2004; 24 200-206
46 Ozer K, Oke R, Gurunluoglu R et al.. Induction of tolerance to hind limb allografts in rats receiving cyclosporine A and antilymphocyte serum: effect of duration of the treatment. Transplantation. 2003; 75 31-36
47 Ozer K, Izycki D, Zielinski M, Siemionow M. Development of donor-specific chimerism and tolerance in composite tissue allografts under alphabeta-T-cell receptor monoclonal antibody and cyclosporine A treatment protocols. Microsurgery. 2004; 24 249-254
48 Muramatsu K, Bishop A T, Sunagawa T, Valenzuela R G. Fate of donor cells in vascularized bone grafts: identification of systemic chimerism by the polymerase chain reaction. Plast Reconstr Surg. 2003; 111 763-772
49 Bourget J L, Mathes D W, Nielsen G P et al.. Tolerance to musculoskeletal allografts with transient lymphocyte chimerism in miniature swine. Transplantation. 2001; 71 851-856
50 Mathes D W, Randolph M A, Bourget J L et al.. Recipient bone marrow engraftment in donor tissue after long-term tolerance to a composite tissue allograft. Transplantation. 2002; 73 1880-1885
51 Bemelman F, Honey K, Adams E, Cobbold S, Waldmann H. Bone marrow transplantation induces either clonal deletion or infectious tolerance depending on the dose. J Immunol. 1998; 160 2645-2648
52 Granger D K, Briedenbach W C, Pidwell D J, Jones J W, Baxter-Lowe L A, Kaufman C L. Lack of donor hyporesponsiveness and donor chimerism after clinical transplantation of the hand. Transplantation. 2002; 74 1624-1630

Thomas H TungM.D.

Division of Plastic and Reconstructive Surgery, Washington University School of Medicine

660 S. Euclid Avenue, Suite 5401, St. Louis, MO 63110