@conference{
author = "Koprivica, Ivan and Mićanović, Dragica and Saksida, Tamara and Cavalli, Eugenio and Auci, Dominick and Pejnović, Nada and Stošić-Grujičić, Stanislava and Nicoletti, Ferdinando and Stojanović, Ivana D.",
year = "2019",
abstract = "Background and aims: Type 1 diabetes (T1D) is a multifactorial autoimmune
disease that develops as a consequence of macrophage and T celldependent
pancreatic β cell death. Multiple approaches have been attempted
to induce anti-inflammatory/regulatory immune mechanisms that will attenuate
disease progression, with little or no beneficial effects. To achieve
prolonged stimulation of regulatory immune cells, our aim was to introduce
microparticles (MPs) loaded with all-trans retinoic acid (ATRA) and
transforming growth factor β (TGF-β). Both molecules are well-known synergistic
stimulators of T regulatory cell (Treg) differentiation and stabilization.
Materials and methods: Male C57BL/6 mice were treated with multiple
low doses of streptozotocin (MLDS) for 5 consecutive days to induce
T1D, and with empty MPs or ATRA and TGF-β-loaded MPs (0.1% and
0.03% w/w, respectively) for 10 days (every other day, starting from the
first streptozotocin injection). Blood glucose was monitored on a weekly
basis and ex vivo analyses of immune cells (flow cytometry, qPCR, immunoblot)
were performed and pancreas histology was evaluated 14 days
from the beginning of the T1D induction. ANOVA t test was used for
statistical analysis and significant change was considered at p<0.05.
Results: T1D incidence was significantly lower inATRA/TGF-β MP-treated
mice, as was the degree of immune cell infiltration into the pancreatic islets. In
Peyer’s patches (PP), ATRA/TGF-β MPs up-regulated the tolerogenic population
of dendritic cells (DCs) (CD11c+CD11b-CD103+), while not altering
the proportion of mature DCs (CD11c+CD11b+). Additionally, both IL-1β
expression and production were reduced in PP, as was the ratio of
iNOS/Arginase mRNA expression, reflecting a less inflammatory environment.
This was accompanied by a reduction of the proportion of Th1
(CD4+IFN-γ+) and Th17 (CD4+IL-17+) cells and up-regulation of Treg
(CD4+CD25highFoxP3+). Lower IL-17 expression within CD4+ cells from
PP was in accordance with the observed down-regulation of RORγt
mRNA expression (key transcription factor of IL-17). The situation in the
pancreatic lymph nodes (PLN) was similar to PP regarding the downregulation
of inflammatory Th1 cells. Also, the proportion of
Tbet+CD25med cells (T effector cells) was lower, while the proportion of
Treg expressing T-bet was increased in PLN, suggesting that these cells specifically
mediate the inhibition of Th1 response. Additionally, in response to
ATRA/TGF-β MP treatment, the proliferation (Ki67+) of T effector cells was
reduced in PLN while Treg proliferated more. Furthermore, ATRA/TGF-β
MP treatment favored the presence of CTLA-4+PD1+ and CD39+IL-10+
populations of Treg and thus increased their suppressive activities.
Conclusion: ATRA and TGF-β released from MPs successfully ameliorated
T1D through the potentiation of tolDC and Treg response and inhibition
of Th1 cell differentiation in the draining lymph nodes, thereby
blocking the entrance of immune cells into the pancreatic islets and
protecting β cells from further destruction.",
publisher = "New York: Springer Nature",
journal = "55th EASD Annual Meeting of the European Association for the Study of Diabetes; 2019 Sep 16-20; Barcelona, Spain",
title = "Orally delivered microparticles loaded with all-trans retinoic acid and transforming growth factor β rescue mice from type 1 diabetes development",
doi = "10.1007/s00125-019-4946-6",
pages = "S202"
}
