Introduction: Microparticle (MP) loaded with peptide antigen plus other immune signals and delivered directly into lymph nodes (LN) can result in either pro-inflammatory or anti-inflammatory 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 intra-LN 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 (lactide-co-galactide). Rapamycin (rapa) and/or class II alloantigen (I-E^d peptide (Ea)) were incorporated into the MP during assembly. A total of 400 freshly isolated BALB/c (H-2^d) islets were transplanted beneath the renal capsule of C57BL/6 (H-2^b) recipients made diabetic by streptozotocin. MP (1 mg in 10ml; empty, Ea, rapa, or Ea/rapa loaded) were injected directly into inguinal LN after transplantation.

Results: Neither empty MP nor Ea-MP (1.1 mg Ea peptide) prolonged graft survival, with all recipients rejecting between 10-15 days after transplant (mean survival time (MST) empty MP 9.2 ± 2 days; Ea-MP 11 ± 3 days). The rapa-MP (5.6 mg rapa) prolonged graft survival and delayed rejection up to 28 days (MST 23.6 ± 5 days, p<0.01). In contrast, the Ea/rapa-MP synergistically prolonged islet graft survival up to 60 days (MST 47.2 ± 6 days, p<0.001). Flow cytometry and histologic analyses showed that intra-nodal injection of MPs promoted immune suppression and tolerance through changes in the organization and composition of treated LNs. MP injection increased the number of CD11c+ dendritic cells (DC) in the cortex, and increased the numbers of Foxp3+ Treg in the cortical ridge.

Conclusions: A single intra-LN administration of MP containing the combination of specific alloantigen (Ea peptide) plus rapamycin significantly prolonged islet allograft survival. The MP modified the LN microenvironment to promote changes in DC migration and regulatory T cell induction, and inhibition of effector cells. The results demonstrate that LN responses are important for systemic both immunity and 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.

CITATION INFORMATION: Xiong Y., Tostanoski L., Jewell C., Bromberg J. Lymph Node Reprogramming: Microparticle Delivery of Immune Signals to Induce Tolerance and Prolong Allograft Survival Am J Transplant. 2017;17 (suppl 3).

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