Evaluation of Graft‐Host Response for Various Tissue Sources and Animal Models

Abstract

The efficacy of pancreatic islet transplants in correcting hyperglycemia and slowing the progression of complications in diabetics has been confirmed by many experimental and clinical studies. Unfortunately, the availability of human islets is extremely limited and, therefore, treatment of large numbers of human diabetic patients will almost certainly require either the use of islets harvested from animals (xenografts) or the use of insulin-secreting genetically modified cells of either human or animal origin. There is currently no effective regimen which will allow long-term survival of xenogeneic islets from widely unrelated donor-recipient combinations, such as pig-to-rodent, pig-to-dog, or pig-to-primate. There is considerable interest in the development of immunoisolation techniques for protection of donor islets. However, most materials used in immunoisolation devices are relatively bio-incompatible. Poly-L-lysine-alginate microcapsules are biocompatible and provide an optimal geometry for transmembrane diffusion of insulin and nutrients. Microcapsules allow long-term survival of xenogeneic islets in diabetic rodents or dogs with induced diabetes. However, mice and rats with spontaneous diabetes destroy encapsulated islet grafts within 2 to 3 weeks. Biopsies reveal large numbers of macrophages, immunoglobulins and limited numbers of helper and cytotoxic T-cells in the peri-microcapsule environment of the peritoneal cavity. Cytokines have been identified in peritoneal fluid from mice with islet grafts and may play a role in encapsulated islet destruction. Targeted immunomodulation by treatment of recipients with either anti-helper T-cell antibodies, or fusion proteins which block costimulatory interactions between antigen presenting cells and host T-cells have demonstrated synergy in significant prolongation of encapsulated islet xenograft survival in NOD mice with spontaneous diabetes. Technical improvements in microcapsule design also have contributed to prolonged graft survival. "Double-wall" microencapsulation provides a more durable microcapsule and islet pretreatment prior to encapsulation reduces the frequency of defective capsules with islets entrapped in the membrane. Long-term durability of encapsulated islet grafts remains a concern and further improvements in microcapsule design are a prerequisite to clinical trials.

In Vivo Noninvasive Monitoring of Dissolved Oxygen Concentration Within an Implanted Tissue-Engineered Pancreatic Construct

“…Shed antigens can combine with antibodies to form complexes which bind to the receptors on peritoneal macrophages. 9,11 If the antigen load is sufficiently high, the recruitment of host peritoneal cells could be significant, possibly contributing to the observed reduction in peritoneal DO.…”

“…9,[11][12][13] Rejection due to an immune response can be related to direct cytokine-mediated damage, not prevented by the encapsulation material; it could also be related to a significant inflammatory or fibrotic reaction toward the implant, which hampers the transport of nutrients, including oxygen, toward the implanted cells. 7,9,14 The problem of limited construct oxygenation may be exacerbated by the low oxygen at the implantation site, and, in many cases, the absence of vascularization around these implants. 7,15,16 Currently, assessment of the in vivo function of a pancreatic construct relies on measurements of blood glucose and insulin or C-peptide levels during oral glucose challenges.…”

“…[5][6][7][8] Immune rejection is a main obstacle in successfully transplanting allogeneic or xenogeneic cells even with the current encapsulation systems available. 7,9,10 Several investigators have reported on the infiltration of large numbers of host immune cells in the peritoneal cavities of rats and mice during the rejection of encapsulated allografts and xenografts. 9,[11][12][13] Rejection due to an immune response can be related to direct cytokine-mediated damage, not prevented by the encapsulation material; it could also be related to a significant inflammatory or fibrotic reaction toward the implant, which hampers the transport of nutrients, including oxygen, toward the implanted cells.…”

“…7,9,10 Several investigators have reported on the infiltration of large numbers of host immune cells in the peritoneal cavities of rats and mice during the rejection of encapsulated allografts and xenografts. 9,[11][12][13] Rejection due to an immune response can be related to direct cytokine-mediated damage, not prevented by the encapsulation material; it could also be related to a significant inflammatory or fibrotic reaction toward the implant, which hampers the transport of nutrients, including oxygen, toward the implanted cells. 7,9,14 The problem of limited construct oxygenation may be exacerbated by the low oxygen at the implantation site, and, in many cases, the absence of vascularization around these implants.…”

Islet transplantation in rodents: do encapsulated islets really work?

“…Such a physical barrier can thus prevent allograft rejection, which depends on recognition of the Major Histocompatibility Complex (MHC) by host lymphocytes. Furthermore it can prevent antibody-mediated cytotoxicity, which plays a role in the autoimmune destruction of beta cells, as well as in allograft and xenograft rejection (31,59) . Immunoprotection by encapsulation can thus enable transplantation of islet tissue in the absence of immunossupression.…”