Survival of Free and Encapsulated Human and Rat Islet Xenografts Transplanted into the Mouse Bone Marrow

Abstract

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.

Xenotransplantation: back to the future?

“…Indeed, the use of transgenic pigs led to comparable results in vascularized heterotopic heart xenografts . Another potential strategy, namely encapsulation of pig islets , should also benefit from further development of genetically modified pigs. Of note, islet xenotransplantation from nongenetically modified pig‐to‐human achieved islet survival but no significant clinical improvement .…”

Immunological aspects of allogeneic pancreatic islet transplantation: a comparison between mouse and human

“…Investigators have looked at the kidney capsule, omental pouch, gastric submucosa, peritoneal space, spleen, bone, and muscle among other potential sites for islet transplantation, some of which have been tested in humans . The advantages and disadvantages of several islet transplantation sites have been cataloged and compared between humans and other animal species and efforts to improve engraftment in easily accessible islet graft sites are warranted .…”

Current status of hepatocyte xenotransplantation

“…2) are most frequently used in cell microencapsulation. Sodium alginate has a great biological acceptance and permeability upon ionotropic gelation with divalent cations [45,46], but it has the disadvantage of relatively low physical resistance and stability [47]. Variants of sodium alginate have been tested including barium alginate microbeads [48], ornithine alginate [49], carrageenan alginate [50], synthetic methacrylate-based polymers [51], poly-L-lysine [52], agarose [53], sodium cellulose sulfate [54] or poly(ethylene glycol) [55].…”