Intra-Lymph Node Injection of Microparticles Reprograms the Laminin Stromal Network to Prolong Allograft Survival
1U Maryland, Baltimore, MD, Baltimore, MD, 2U Maryland, College Park, MD, College Park, MD
Meeting: 2020 American Transplant Congress
Abstract number: B-378
Session Information
Session Name: Poster Session B: Tolerance / Immune Deviation
Session Type: Poster Session
Date: Saturday, May 30, 2020
Session Time: 3:15pm-4:00pm
Presentation Time: 3:30pm-4:00pm
Location: Virtual
*Purpose: Microparticles (MPs) carrying peptide antigen with immune signals can be directly delivered to lymph nodes (LNs) to induce pro-inflammatory or anti-inflammatory responses. We hypothesized that delivery of alloantigen plus regulatory signals into the LN can reprogram the local laminin framework resulting in induction of specific suppression to promote transplant tolerance.
*Methods: MPs were composed of poly (lactide co-ga lactide). Rapamycin (Rapa) and/or donor class II alloantigen (IEd peptide (Ea)) were incorporated into MP at the time of assembly. BALB/c (H2d) islets were placed under the renal capsule of diabetic C57BL/6 (H-2b) recipients. Donor alloantigen specific T cell receptor transgenic CD4+ TEa T cells were administered to recipients. At the time of transplantation, mice underwent direct inguinal intra-LN injection of empty, Ea-, Rapa-, or Rapa/Ea-MPs.
*Results: There was no significant prolongation of allograft survival with injection of empty or Ea-MPs, with all animals rejecting between days 10-15 (mean survival time (MST) empty MP 9.2 ± 2 days; EaMP 11 ± 3 days). Rapa-MPs significantly prolonged graft survival up to 28 days (MST 23.6 ± 5 days, p<0.01). Combination Rapa/Ea-MPs further prolonged allograft survival up to 60 days (47.2 ± 6 days, p<0.001). Histologic analysis of inguinal LNs demonstrated that direct injection with Rapa/Ea-MP induced greater expression of laminin α4 around high endothelial venules and cortical ridge, resulting in an increased laminin α4:laminin α5 ratio compared to Ea-MPs and empty MPs, a structure indicative of suppression and tolerance. Flow cytometry and histologic analysis of Rapa/Ea-MP injected LNs demonstrated more alloantigen specific Treg and fewer activated CD4+ T cells in comparison to empty and Ea-MPs.
*Conclusions: Direct intra-LN injection of MPs can modify the local LN laminin stromal network and result in systemic immune changes. Rapa/Ea-MPs induce more laminin α4 and suppress laminin α5 around the HEV and cortical ridge, increasing the laminin α4: α5 ratio, to create a tolerogenic, suppressive microdomain niche. Rapa/Ea-MP treatment significantly increased Treg induction with fewer activated CD4+ T cells. These findings suggest a novel means of manipulating the local immune microenvironment that could promote systemic transplant tolerance.
To cite this abstract in AMA style:
Paluskievicz CM, Xiong Y, Piao W, Willson-Shirkey M, Eppler H, Jewell CM, Bromberg JS. Intra-Lymph Node Injection of Microparticles Reprograms the Laminin Stromal Network to Prolong Allograft Survival [abstract]. Am J Transplant. 2020; 20 (suppl 3). https://atcmeetingabstracts.com/abstract/intra-lymph-node-injection-of-microparticles-reprograms-the-laminin-stromal-network-to-prolong-allograft-survival/. Accessed May 11, 2025.« Back to 2020 American Transplant Congress