Date: Sunday, June 2, 2019
Session Name: Concurrent Session: Tissue Engineering & Technology
Session Time: 2:30pm-4:00pm
Presentation Time: 2:54pm-3:06pm
Location: Room 309
*Purpose: Microparticles (MP) loaded with peptide antigen plus other immune signals and delivered directly into lymph nodes (LN) can result in either proinflammatory or antiinflammatory responses. Confining MP delivery to single LN also induces systemic immune deviation. To demonstrate linkage between the modified LN and specificity of systemic tolerance, islet allografted mice received intraLN delivery of MP encapsulating allopeptide plus rapamycin as a suppressive signal. We hypothesized that delivery of alloantigen plus regulatory signals into the LN could prolong allograft survival.
*Methods: MP were composed of poly (lactidecogalactide). Rapamycin (Rapa) and/or class II alloantigen (IEd peptide (Ea)) were incorporated into the MP during assembly. A total of 400 freshly isolated BALB/c (H2d) islets were transplanted beneath the renal capsule of C57BL/6 (H2b) recipients made diabetic by streptozotocin. 2×105 donor alloantigen specific CD4 T cell receptor transgenic TEa T cells were transferred i.v. into recipients. MP (1 μg in 10 μl of empty, Ea, Rapa, or Ea/Rapa loaded) were injected directly into inguinal LN after transplantation.
*Results: Neither empty MP nor EaMP (1.1 μg Ea peptide) prolonged graft survival, with all recipients rejecting between 1015 days after transplant (mean survival time, empty MP 9.2 ± 2 days; EaMP 11 ± 3 days). The RapaMP (5.6 μg Rapa) prolonged graft survival and delayed rejection up to 28 days (23.6 ± 5 days, p<0.01). In contrast, the Ea/RapaMP synergistically prolonged islet graft survival up to 60 days (47.2 ± 6 days, p<0.001). Flow cytometry and histologic analyses showed that intranodal injection of Rapa and Ea/Rapa MPs induced more Treg (16% and 17%, respectively) and fewer activated CD4 T cells (15% and 12%) compared with control MPs (iTreg 12%, activated T cells 20%).
*Conclusions: MP can modify the LN microenvironment to promote regulatory T cell induction, and inhibition of effector cells. The results demonstrate that LN responses are important for systemic suppression, and that altering a single remote LN can prolong allograft survival at a distant site. These findings suggest a new therapeutic strategy to manipulate the LN environment with encapsulated, locally delivered antigen and regulatory signals to promote transplant tolerance.
To cite this abstract in AMA style:Xiong Y, Tostanoski L, Jewell C, Bromberg J. Microparticle Delivery to Lymph Nodes Induces Specific Suppression to Prolong Islet Survival [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/microparticle-delivery-to-lymph-nodes-induces-specific-suppression-to-prolong-islet-survival/. Accessed November 11, 2019.
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