Bone marrow was recently proposed as an alternative and potentially immune-privileged site for pancreatic islet transplantation. The aim of the present study was to assess the survival and rejection mechanisms of free and encapsulated xenogeneic islets transplanted into the medullary cavity of the femur, or under the kidney capsule of streptozotocin-induced diabetic C57BL/6 mice. The median survival of free rat islets transplanted into the bone marrow or under the kidney capsule was 9 and 14 days, respectively, whereas that of free human islets was shorter, 7 days (bone marrow) and 10 days (kidney capsule). Infiltrating CD8+ T cells and redistributed CD4+ T cells, and macrophages were detected around the transplanted islets in bone sections. Recipient mouse splenocytes proliferated in response to donor rat stimulator cells. One month after transplantation under both kidney capsule or into bone marrow, encapsulated rat islets had induced a similar degree of fibrotic reaction and still contained insulin positive cells. In conclusion, we successfully established a small animal model for xenogeneic islet transplantation into the bone marrow. The rejection of xenogeneic islets was associated with local and systemic T cell responses and macrophage recruitment. Although there was no evidence for immune-privilege, the bone marrow may represent a feasible site for encapsulated xenogeneic islet transplantation.
References
[1]
Aanstoot HJ, Anderson BJ, Daneman D, Danne T, Donaghue K, et al. (2007) The global burden of youth diabetes: perspectives and potential. Pediatr Diabetes 8 Suppl 81–44. doi: 10.1111/j.1399-5448.2007.00326.x
[2]
Incidence and trends of childhood Type 1 diabetes worldwide 1990–1999. Diabet Med 23: 857–866. doi: 10.1111/j.1464-5491.2006.01925.x
[3]
Basta G, Montanucci P, Luca G, Boselli C, Noya G, et al. (2011) Long-term metabolic and immunological follow-up of nonimmunosuppressed patients with type 1 diabetes treated with microencapsulated islet allografts: four cases. Diabetes Care 34: 2406–2409. doi: 10.2337/dc11-0731
[4]
Elliott RB, Escobar L, Tan PL, Muzina M, Zwain S, et al. (2007) Live encapsulated porcine islets from a type 1 diabetic patient 9.5 yr after xenotransplantation. Xenotransplantation 14: 157–161. doi: 10.1111/j.1399-3089.2007.00384.x
[5]
Vaithilingam V, Tuch BE (2011) Islet transplantation and encapsulation: an update on recent developments. Rev Diabet Stud 8: 51–67. doi: 10.1900/rds.2011.8.51
[6]
Carlsson PO, Palm F, Andersson A, Liss P (2001) Markedly decreased oxygen tension in transplanted rat pancreatic islets irrespective of the implantation site. Diabetes 50: 489–495. doi: 10.2337/diabetes.50.3.489
[7]
Siebers U, Horcher A, Bretzel RG, Klock G, Zimmermann Uet al (1993) Transplantation of free and microencapsulated islets in rats: evidence for the requirement of an increased islet mass for transplantation into the peritoneal site. Int J Artif Organs 16: 96–99.
Maffi P, Balzano G, Ponzoni M, Nano R, Sordi Vet al. (2013) Autologous Pancreatic Islet Transplantation in Human Bone Marrow. Diabetes.
[10]
Ciceri F, Piemonti L (2010) Bone marrow and pancreatic islets: an old story with new perspectives. Cell Transplant 19: 1511–1522. doi: 10.3727/096368910x514279
[11]
Cantarelli E, Melzi R, Mercalli A, Sordi V, Ferrari Get al (2009) Bone marrow as an alternative site for islet transplantation. Blood 114: 4566–4574. doi: 10.1182/blood-2009-03-209973
[12]
Luo JZ, Xiong F, Al-Homsi AS, Ricordi C, Luo L (2013) Allogeneic bone marrow cocultured with human islets significantly improves islet survival and function in vivo. Transplantation 95: 801–809. doi: 10.1097/tp.0b013e31828235c7
[13]
Bell GI, Broughton HC, Levac KD, Allan DA, Xenocostas A, et al. (2012) Transplanted human bone marrow progenitor subtypes stimulate endogenous islet regeneration and revascularization. Stem Cells Dev 21: 97–109. doi: 10.1089/scd.2010.0583
[14]
Oh BJ, Oh SH, Jin SM, Suh S, Bae JC, et al. (2013) Co-transplantation of bone marrow-derived endothelial progenitor cells improves revascularization and organization in islet grafts. Am J Transplant 13: 1429–1440. doi: 10.1111/ajt.12222
[15]
Karaoz E, Genc ZS, Demircan PC, Aksoy A, Duruksu G (2010) Protection of rat pancreatic islet function and viability by coculture with rat bone marrow-derived mesenchymal stem cells. Cell Death Dis 1: e36. doi: 10.1038/cddis.2010.14
[16]
Salazar-Banuelos A, Wright JRJ, Sigalet D, Benitez-Bribiesca L (2008) Pancreatic islet transplantation into the bone marrow of the rat. Am J Surg 195: 674–8 discussion 678. doi: 10.1016/j.amjsurg.2007.12.040
[17]
Bosco D, Armanet M, Morel P, Niclauss N, Sgroi A, et al. (2010) Unique arrangement of alpha- and beta-cells in human islets of Langerhans. Diabetes 59: 1202–1210. doi: 10.2337/db09-1177
[18]
Niclauss N, Sgroi A, Morel P, Baertschiger R, Armanet M, et al. (2008) Computer-assisted digital image analysis to quantify the mass and purity of isolated human islets before transplantation. Transplantation 86: 1603–1609. doi: 10.1097/tp.0b013e31818f671a
[19]
Muller YD, Mai G, Morel P, Serre-Beinier V, Gonelle-Gispert C, et al. (2010) Anti-CD154 mAb and rapamycin induce T regulatory cell mediated tolerance in rat-to-mouse islet transplantation. PLoS One 5: e10352. doi: 10.1371/journal.pone.0010352
[20]
Bosco D, Armanet M, Morel P, Niclauss N, Sgroi A, et al. (2010) Unique arrangement of alpha- and beta-cells in human islets of Langerhans. Diabetes 59: 1202–1210. doi: 10.2337/db09-1177
[21]
Pepper AR, Gall C, Mazzuca DM, Melling CW, White DJ (2009) Diabetic rats and mice are resistant to porcine and human insulin: flawed experimental models for testing islet xenografts. Xenotransplantation 16: 502–510. doi: 10.1111/j.1399-3089.2009.00548.x
[22]
Loganathan G, Graham ML, Radosevich DM, Soltani SM, Tiwari M, et al. (2013) Factors affecting transplant outcomes in diabetic nude mice receiving human, porcine, and nonhuman primate islets: analysis of 335 transplantations. Transplantation 95: 1439–1447. doi: 10.1097/tp.0b013e318293b7b8
[23]
Merani S, Schur C, Truong W, Knutzen VK, Lakey JR, et al. (2006) Compaction of islets is detrimental to transplant outcome in mice. Transplantation 82: 1472–1476. doi: 10.1097/01.tp.0000243166.64244.3d
[24]
Toso C, Mathe Z, Morel P, Oberholzer J, Bosco D, et al. (2005) Effect of microcapsule composition and short-term immunosuppression on intraportal biocompatibility. Cell Transplant 14: 159–167. doi: 10.3727/000000005783983223
[25]
Muller YD, Golshayan D, Ehirchiou D, Wyss JC, Giovannoni L, et al. (2011) Immunosuppressive effects of streptozotocin-induced diabetes result in absolute lymphopenia and a relative increase of T regulatory cells. Diabetes 60: 2331–2340. doi: 10.2337/db11-0159
[26]
Nilsson B, Ekdahl KN, Korsgren O (2011) Control of instant blood-mediated inflammatory reaction to improve islets of Langerhans engraftment. Curr Opin Organ Transplant 16: 620–626. doi: 10.1097/mot.0b013e32834c2393
[27]
Toso C, Oberholzer J, Ceausoglu I, Ris F, Rochat B, et al. (2003) Intra-portal injection of 400- microm microcapsules in a large-animal model. Transpl Int 16: 405–410. doi: 10.1111/j.1432-2277.2003.tb00321.x
[28]
Goto M, Tjernberg J, Dufrane D, Elgue G, Brandhorst D, et al. (2008) Dissecting the instant blood-mediated inflammatory reaction in islet xenotransplantation. Xenotransplantation 15: 225–234. doi: 10.1111/j.1399-3089.2008.00482.x
Yi S, Hawthorne WJ, Lehnert AM, Ha H, Wong JK, et al. (2003) T cell-activated macrophages are capable of both recognition and rejection of pancreatic islet xenografts. J Immunol 170: 2750–2758. doi: 10.4049/jimmunol.170.5.2750
[31]
Friedman T, Smith RN, Colvin RB, Iacomini J (1999) A critical role for human CD4+ T-cells in rejection of porcine islet cell xenografts. Diabetes 48: 2340–2348. doi: 10.2337/diabetes.48.12.2340
[32]
Wren SM, Wang SC, Thai NL, Conrad B, Hoffman RA, et al. (1993) Evidence for early Th 2 T cell predominance in xenoreactivity. Transplantation 56: 905–911. doi: 10.1097/00007890-199310000-00025
[33]
Yi S, Feng X, Hawthorne W, Patel A, Walters S, O’Connell PJ (2000) CD8+ T cells are capable of rejecting pancreatic islet xenografts. Transplantation 70: 896–906. doi: 10.1097/00007890-200009270-00007
[34]
Mirenda V, Golshayan D, Read J, Berton I, Warrens AN, et al. (2005) Achieving permanent survival of islet xenografts by independent manipulation of direct and indirect T-cell responses. Diabetes 54: 1048–1055. doi: 10.2337/diabetes.54.4.1048
[35]
Muller YD, Ehirchiou D, Golshayan D, Buhler LH, Seebach JD (2012) Potential of T-regulatory cells to protect xenografts. Curr Opin Organ Transplant 17: 155–161. doi: 10.1097/mot.0b013e3283508e17
[36]
Muller YD, Seebach JD, Buhler LH, Pascual M, Golshayan D (2011) Transplantation tolerance: Clinical potential of regulatory T cells. Self Nonself 2: 26–34. doi: 10.4161/self.2.1.15422
[37]
Vaithilingam V, Fung C, Ratnapala S, Foster J, Vaghjiani V, et al. (2013) Characterisation of the xenogeneic immune response to microencapsulated fetal pig islet-like cell clusters transplanted into immunocompetent C57BL/6 mice. PLoS One 8: e59120. doi: 10.1371/journal.pone.0059120
[38]
Hobbs HA, Kendall WFJ, Darrabie M, Opara EC (2001) Prevention of morphological changes in alginate microcapsules for islet xenotransplantation. J Investig Med 49: 572–575. doi: 10.2310/6650.2001.33722
[39]
Karsten V, Lencioni C, Tritschler S, Marchetti P, Belcourt A, et al. (1999) Chemotactic activity of culture supernatants of free and encapsulated pancreatic rat islets towards peritoneal macrophages. Horm Metab Res 31: 448–454. doi: 10.1055/s-2007-978773
[40]
Teramura Y, Iwata H (2009) Islet encapsulation with living cells for improvement of biocompatibility. Biomaterials 30: 2270–2275. doi: 10.1016/j.biomaterials.2009.01.036
[41]
Mahou R, Tran NM, Dufresne M, Legallais C, Wandrey C (2012) Encapsulation of Huh-7 cells within alginate-poly(ethylene glycol) hybrid microspheres. J Mater Sci Mater Med 23: 171–179. doi: 10.1007/s10856-011-4512-3
[42]
Li S, Waer M, Billiau AD (2009) Xenotransplantation: role of natural immunity. Transpl Immunol 21: 70–74. doi: 10.1016/j.trim.2008.10.004
[43]
Wolf LA, Coulombe M, Gill RG (1995) Donor antigen-presenting cell-independent rejection of islet xenografts. Transplantation 60: 1164–1170. doi: 10.1097/00007890-199511270-00018
[44]
Andres A, Toso C, Morel P, Bosco D, Bucher P, et al. (2005) Macrophage depletion prolongs discordant but not concordant islet xenograft survival. Transplantation 79: 543–549. doi: 10.1097/01.tp.0000151764.39095.ca
