Development of a Highly Effective Protocol using Local Immune Suppression Strategy in Pancreatic Islet Transplantation. (July 2018)

• Record Type: Journal Article
• Authors: Pathak, Shiva; Regmi, Shobha; Pham, Tung Thanh; Yong, Chul Soon; Kim, Jong Oh; Yook, Simmyung; Park, Min-Hui; Bae, Yong Kyung; Jeong, Jee-Heon
• Is Part Of: Transplantation. Volume 102(2018)Supplement 7S-1
• Publication Date: 2018-07
• Subjects: Transplantation of organs, tissues, etc -- Periodicals; Transplantation immunology -- Periodicals; 617.95
• DOI: 10.1097/01.tp.0000543740.87723.41
• Languages: English
• ISSNs: 0041-1337

Abstract

Abstract : Introduction: Pancreatic islet transplantation is a promising technique to treat type 1 diabetes. Long-term survival of the graft is required for a successful islet transplantation. Repeated use of immunosuppressive drugs after organ/cell transplantation often leads to severe adverse effects including nephrotoxicity, hepatotoxicity, and opportunistic infections. Thus, development of a local immunosuppression protocol is necessary to improve the islet graft survival in clinics. Materials and Methods: Pancreatic islets from Sprague-Dawley rats were transplanted into the subcutaneous space of B6 mice using injectable hydrogel. Briefly, 1000 islet equivalents were suspended in Matrigel premixed with FK506-loaded poly(lactic-co-glycolic acid) microspheres (10 mg/kg) and clodronate liposomes (6.25 mg/kg) and injected into the subcutaneous space over the flanks of streptozocin-induced diabetic mice. Blood glucose level was monitored using a potable glucometer. Results: Islets transplanted without any immunosuppression were rejected within two weeks. In contrast, the islets transplanted with the immunosuppressive regimen of FK506 and clodronate survived indefinitely. Immunological studies revealed that the immunosuppressive cocktail inhibited the proliferation of immune cells residing at the peripheral lymph nodes. Interestingly, the systemic immune system of the transplanted mice remained unaffected. Furthermore, histochemical analysis revealed the intact morphology of the islets at the transplanted site when codelivered with the immunosuppressant. Discussion: Antigen presenting cells and T-cells orchestrate the immune rejection cascade. Macrophage depletion by the liposomal clodronate and the inhibition of T-cell activation by FK506 completely blocked the immune rejection cascade in the immune competent mice. The inhibition of immune stimulation in the peripheral lymph nodes improved the islet grafted into the subcutaneous space. Thus, the use of local immune suppression is an effective approach to enhance the survival of the transplanted islets. Conclusion: We developed a protocol for the local codelivery of pancreatic islets and immune suppressive agents. Indefinite graft survival was obtained with the use of macrophage depleting agent and T-cell inhibitor. The single dose of local immune suppression during transplantation may avoid toxic effects associated with a long-term use of immune suppressive agents in clinics. National Research Foundation of Korea (NRF) Grant nos: 2015R1A5A2009124 and 2017R1D1A1B03027831. Korea Health Industry Development Institute (KHIDI) Grant no: HI16C1767.