Search bioRxiv⌕ Search

Biology subjects

Korbutt, G. S.

Publications and source records attributed to Korbutt, G. S..

2 recordsLinked to original sources
bioRxiv2023

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

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

immunology↗
bioRxiv2019

A20 is an immune tolerance factor that can determine islet transplantoutcomes.

Islet transplantation can restore lost glycemic control in type 1 diabetes subjects, but is restricted in its clinical application by limiting supplies of islets and the need for heavy immune suppression to prevent rejection. TNFAIP3, encoding the ubiquitin editing enzyme A20, regulates the activation of immune cells by raising NF-{kappa}B signalling thresholds. Here we show that increasing A20 expression in allogeneic islet grafts resulted in permanent survival for ~45 % of recipients, and >80% survival when combined with subtherapeutic rapamycin. Allograft survival was dependent upon regulatory T cells, was antigen-specific and grafts showed reduced expression of inflammatory factors, but increased TGF{beta} and IL-10. By analysing islets expressing an A20 coding mutation (I325N) that cripples A20s OTU ubiquitin editing domain, we found that A20 regulates intra-graft RIPK1 levels to modulate NF-{kappa}B signalling. Transplantation of I325N islets resulted in increased NF-{kappa}B signalling, graft hyper-inflammation and acute allograft rejection. Neonatal porcine islets (NPI) represent a clinical alternative islet source but are readily rejected. However, forced A20 expression reduced NPI inflammation and increased their function after transplantation. Therapeutic administration of A20 raises NF-{kappa}B signalling thresholds and promotes islet allogeneic survival. Clinically this would allow for reduced immunosuppression supporting the use of alternate islet sources.

immunology↗