Survival of pig-to-rhesus corneal xenografts prolonged by prior donor bone marrow transplantation

Jie,Ying; Liu,Limin; Pan,Zhiqiang; Wang,Li

doi:10.3892/mmr.2013.1294

Survival of pig-to-rhesus corneal xenografts prolonged by prior donor bone marrow transplantation

Authors:
- Ying Jie
- Limin Liu
- Zhiqiang Pan
- Li Wang
View Affiliations

Affiliations: Beijing Ophthalmology and Visual Science Laboratory, Beijing Tongren Eye Centre, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, P.R. China
Published online on: January 28, 2013 https://doi.org/10.3892/mmr.2013.1294
Pages: 869-874

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The aim of the present study was to explore the survival of pig-rhesus corneal xenografts following donor bone marrow transplantation (BMT). Wuzhishan pigs were used as donors and rhesus monkeys as recipients for corneal xenotransplantation. Twelve rhesus monkeys were divided into two groups. Group 1 received intravenous injection of cyclophosphamide (CP) followed by pig bone marrow cell transplantation, while group 2 was used as a control and only received intravenous CP injection. All xenografts were evaluated using a slit-lamp microscope. The immunological status of the recipients following transplantation, including the formation of chimerism, mixed lymphocyte reaction (MLR) and immunoglobulin and complement in the serum, was analyzed. Two rhesus monkeys in each group were sacrificed for corneal histopathology examination. The mean survival time was 36.0±4.7 days in group 1 and 17.7±3.2 days in group 2. The mean chimerism percentage in group 1 at week 1 was 5.20±1.02%, but decreased with time and was <1% after week 3. MLR demonstrated that immune reactivity to donor spleen cells in group 1 was decreased following surgery. Immunoglobulin and complement levels in the serum revealed a decreasing trend. Histopathological examination demonstrated that the corneal xenografts in group 1 had minimal inflammatory cell infiltration and no eosinophil infiltration. Survival of corneal xenografts may be prolonged by prior BMT, suggesting that immune reactivity to donors is suppressed, and is highly dependent on chimerism formation.

View Figures

View References

1	Lan P, Wang L, Diouf B, et al: Induction of human T-cell tolerance to porcine xenoantigens through mixed hematopoietic chimerism. Blood. 103:3964–3969. 2004. View Article : Google Scholar : PubMed/NCBI
2	Ross JR, Howell DN and Sanfilippo FP: Characteristics of corneal xenograft rejection in a discordant species combination. Invest Ophthalmol Vis Sci. 34:2469–2476. 1993.PubMed/NCBI
3	Zhiqiang P, Cun S, Ying J, Ningli W and Li W: WZS-pig is a potential donor alternative in corneal xenotransplantation. Xenotransplantation. 14:603–611. 2007. View Article : Google Scholar : PubMed/NCBI
4	Wekerle T and Sykes M: Mixed chimerism and transplantation tolerance. Ann Rev Med. 52:353–370. 2001. View Article : Google Scholar : PubMed/NCBI
5	Sachs DH: Mixed chimerism as an approach to transplantation tolerance. Clin Immunol. 95:S63–S68. 2000. View Article : Google Scholar : PubMed/NCBI
6	Wekerle T: Transplantation tolerance induced by mixed chimerism. J Heart Lung Transplant. 20:816–823. 2001. View Article : Google Scholar : PubMed/NCBI
7	Sykes M: Mixed chimerism and transplant tolerance. Immunity. 14:417–424. 2001. View Article : Google Scholar : PubMed/NCBI
8	Pham SM, Mitruka SN, Youm W, et al: Mixed hematopoietic chimerism induces donor-specific tolerance for lung allografts in rodents. Am J Respir Crit Care Med. 159:199–205. 1999. View Article : Google Scholar : PubMed/NCBI
9	Huang CA, Fuchimoto Y, Scheier-Dolberg R, Murphy MC, Neville DM Jr and Sachs DH: Stable mixed chimerism and tolerance using a nonmyeloablative preparative regimen in a large animal model. J Clin Invest. 105:173–181. 2000. View Article : Google Scholar : PubMed/NCBI
10	Abe M, Qi J, Sykes M and Yang YG: Mixed chimerism induces donor-specific T cell tolerance across a highly disparate xenogeneic barrier. Blood. 99:3823–3829. 2002. View Article : Google Scholar : PubMed/NCBI
11	Beschorner WE, Sudan DL, Radio SJ, et al: Heart xenograft survival with chimeric pig donors and modest immune suppression. Ann Surg. 237:265–272. 2003. View Article : Google Scholar : PubMed/NCBI
12	Murakami M, Ito H, Harada E, Enoki T, Sykes M and Hamano K: Long-term survival of xenogeneic heart grafts achieved by costimulatory blockade and transient mixed chimerism. Transplantation. 82:275–281. 2006. View Article : Google Scholar : PubMed/NCBI
13	Lee PW, Cina RA, Randolph MA, et al: Stable multilineage chimerism across full MHC barriers without graft-versus-host disease following in utero bone marrow transplantation in pigs. Exp Hematol. 33:371–379. 2005. View Article : Google Scholar : PubMed/NCBI
14	Kawai T, Cosimi AB, Wee SL, et al: Effect of mixed hematopoietic chimerism on cardiac allograft survival in cynomolgus monkeys. Transplantation. 73:1757–1764. 2002. View Article : Google Scholar : PubMed/NCBI
15	Iwai T, Tomita Y, Zhang QW, Shimizu I, Nomoto K and Yasui H: Requirement of a higher degree of chimerism for skin allograft tolerance in cyclophosphamide-induced tolerance. Transplant Int. 17:795–803. 2005. View Article : Google Scholar : PubMed/NCBI
16	Kimikawa M, Sachs DH, Colvin RB, Bartholomew A, Kawai T and Cosimi AB: Modifications of the conditioning regimen for achieving mixed chimerism and donor-specific tolerance in cynomolgus monkeys. Transplantation. 64:709–716. 1997. View Article : Google Scholar : PubMed/NCBI
17	Sablinski T, Emery DW, Monroy R, et al: Long-term discordant xenogeneic (porcine-to-primate) bone marrow engraftment in a monkey treated with porcine-specific growth factors. Transplantation. 67:972–977. 1999. View Article : Google Scholar : PubMed/NCBI
18	Kozlowski T, Shimizu A, Lambrigts D, et al: Porcine kidney and heart transplantation in baboons undergoing a tolerance induction regimen and antibody adsorption. Transplantion. 67:18–30. 1999. View Article : Google Scholar : PubMed/NCBI
19	Chen D, Cao R, Guo H, et al: Pathogenesis and pathology of delayed xenograft rejection in pig-to-rhesus monkey cardiac transplantation. Transplant Proc. 36:2480–2482. 2004. View Article : Google Scholar
20	Yang YG: Application of xenogeneic stem cells for induction of transplantation tolerance: present state and future directions. Springer Semin Immunopathol. 26:187–200. 2004. View Article : Google Scholar : PubMed/NCBI
21	Millan MT, Shizuru JA, Hoffmann P, et al: Mixed chimerism and immunosuppressive drug withdrawal after HLA-mismatched kidney and hematopoietic progenitor transplantation. Transplantation. 73:1386–1391. 2002. View Article : Google Scholar : PubMed/NCBI
22	Cobbold SP, Martin G, Qin S and Waldmann H: Monoclonal antibodies to promote marrow engraftment and tissue graft tolerance. Nature. 323:164–166. 1986. View Article : Google Scholar : PubMed/NCBI
23	Li A, Pan Z, Jie Y, Sun Y, Luo F and Wang L: Comparison of immunogenicity and porcine-to-rhesus lamellar corneal xenografts survival between fresh preserved and dehydrated porcine corneas. Xenotransplantation. 18:46–55. 2011. View Article : Google Scholar
24	Tanaka K, Yamagami S and Streilein JW: Evidence that T-helper type 2 cell-derived cytokines and eosinophils contribute to acute rejection of orthotopic corneal xenografts in mice. Transplantation. 79:1317–1323. 2005. View Article : Google Scholar : PubMed/NCBI