Long-Term Survival and Induction of Operational Tolerance to Murine Islet Allografts by Co-Transplanting Cyclosporine A Microparticles and CTLA4-Ig

Abstract

One strategy to prevent islet rejection is to create a favorable immune-protective local environment at the transplant site. Herein, we utilize localized cyclosporine A (CsA) delivery to islet grafts via poly(lactic-co-glycolic acid) (PLGA) microparticles to attenuate allograft rejection. CsA-eluting PLGA microparticles were prepared using a single emulsion (oil-in-water) solvent evaporation technique. CsA microparticles alone significantly delayed islet allograft rejection compared to islets alone (p < 0.05). Over 50% (6/11) of recipients receiving CsA microparticles and short-term cytotoxic T lymphocyte-associated antigen 4-Ig (CTLA4-Ig) therapy displayed prolonged allograft survival for 214 days, compared to 25% (2/8) receiving CTLA4-Ig alone. CsA microparticles alone and CsA microparticles + CTLA4-Ig islet allografts exhibited reduced T-cell (CD4+ and CD8+ cells, p < 0.001) and macrophage (CD68+ cells, p < 0.001) infiltration compared to islets alone. We observed the reduced mRNA expression of proinflammatory cytokines (IL-6, IL-10, INF-γ, and TNF-α; p < 0.05) and chemokines (CCL2, CCL5, CCL22, and CXCL10; p < 0.05) in CsA microparticles + CTLA4-Ig allografts compared to islets alone. Long-term islet allografts contained insulin+ and intra-graft FoxP3+ T regulatory cells. The rapid rejection of third-party skin grafts (C3H) in islet allograft recipients suggests that CsA microparticles + CTLA4-Ig therapy induced operational tolerance. This study demonstrates that localized CsA drug delivery plus short-course systemic immunosuppression promotes an immune protective transplant niche for allogeneic islets.

The Future of Beta Cells Replacement in the Era of Regenerative Medicine and Organ Bioengineering

“…To address these impediments the scientific community has made significant strides in various domains, including stem cell technology, xenotransplantation, encapsulation techniques and immunomodulatory strategies [3][4][5][6][7]. This progress is further amplified by advancements in tissue engineering strategies, including the generation of on-chip technologies and biomimetic scaffolds, the development of organoids containing both therapeutic and support cells, driving the bioengineering of the endocrine pancreas [7][8][9][10][11].…”

“…To address these impediments the scientific community has made significant strides in various domains, including stem cell technology, xenotransplantation, encapsulation techniques and immunomodulatory strategies [3][4][5][6][7]. This progress is further amplified by advancements in tissue engineering strategies, including the generation of on-chip technologies and biomimetic scaffolds, the development of organoids containing both therapeutic and support cells, driving the bioengineering of the endocrine pancreas [7][8][9][10][11]. Concomitantly, the availability of long-term clinical islet transplantation data from different regions allows mapping the activity at the worldwide level to identify regional differences, developing and validating clinical scores to correlate early graft function with long-term transplant outcomes, and the inclusion of patient perspectives and wellbeing in future clinical implementation of current research.…”