Long-term survival and induction of operational tolerance to murine islet allografts through the co-transplantation of cyclosporine A eluting microparticles

Kuppan, P.; Wong, J.; Kelly, S.; Lin, J.; Worton, J.; Castro, C.; Paramor, J.; Seeberger, K.; Anderson, C. C.; Korbutt, G. S.; Pepper, A. R.

doi:10.1101/2023.02.14.528345

bioRxiv · 10.1101/2023.02.14.528345

Long-term survival and induction of operational tolerance to murine islet allografts through the co-transplantation of cyclosporine A eluting microparticles

Kuppan, P.·Wong, J.·Kelly, S.·Lin, J.·Worton, J.·Castro, C.·Paramor, J.·Seeberger, K.·Anderson, C. C.·Korbutt, G. S.·Pepper, A. R.

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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 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 (p>0.05). CsA microparticles + CTLA4-Ig islet allografts exhibited reduced T-cell (CD4+ and CD8+ cells) and macrophage (CD68+ cells) infiltration compared to islets alone. We observed reduced mRNA expression of proinflammatory cytokines (IL-6, IL-10, INF-{gamma} & TNF-; 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. Rapid rejection of third-party skin grafts (C3H) in islet allograft recipients suggested that CsA microparticles + CTLA4-Ig therapy induced donor specific operational tolerance. This study demonstrates that localized CsA drug delivery plus short-course systemic immunosuppression promotes an immune protective transplant niche for allogeneic islets. Article HighlightsO_LISystemic immunosuppression limits patient inclusion for beta cell replacement therapies C_LIO_LILocalized islet graft immunosuppression may reduce drug toxicity and improve graft survival C_LIO_LICyclosporine eluting microparticles + CTLA4-Ig therapy induced donor specific operational tolerance C_LIO_LIGraft localized drug delivery can create an immune protective transplant niche C_LI

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Kuppan, P., Wong, J., Kelly, S., Lin, J., Worton, J., Castro, C., Paramor, J., Seeberger, K., Anderson, C. C., Korbutt, G. S., Pepper, A. R.. 2023-02-15. Long-term survival and induction of operational tolerance to murine islet allografts through the co-transplantation of cyclosporine A eluting microparticles. https://doi.org/10.1101/2023.02.14.528345

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