Session Time: 7:30pm-8:30pm
Presentation Time: 8:00pm-8:10pm
*Purpose: Lymph node (LN) stromal laminins α4 (Lama4) and α5 (Lama5) are associated with tolerance and immunity, respectively. We hypothesized that stromal Lama4 and Lama5 regulates lymph node (LN) structure to channel T cell distribution and functions.
*Methods: LN stromal cell Lama5 conditional KO (Pdgfrb-Cre+/- x Lama5fl/fl), and Lama4 KO (Pdgfrb-Cre+/- x Lama4fl/fl) mice were created. High endothelial venules (HEV), Treg distribution, chemokines, and cell adhesion molecules in the LNs analyzed by immunohistochemistry and qRT-PCR. Mice received cardiac allografts and monitored for survival.
*Results: Compared to wild type (WT) controls, depleting Lama5 created a tolerogenic niche in LN. The Lama5 KO LNs were characterized by greater HEV size and numbers, increased numbers of Treg and dendritic cells (DC), increased chemokine CCL19, CCL21 and CXCL12, upregulated cytokine IL-33, and more adhesion molecules ICAM-1 and VCAM-1 in CR and around HEVs. In contrast, depletion of Lama4 gave rise to a relatively inflammatory microenvironment. Compared to WT, the Lama4 KO LNs had fewer HEVs, less Treg, DCs, CCL19, CCL21 and CXCL12, downregulated IL-33, and less adhesion molecules in CR and around HEVs. BALB/c hearts were transplanted into Lama5 KO recipients and treated with low dose tacrolimus had significantly longer allograft survival (mean survival time (MST) 89 days versus MST 27.5 days in WT, (p<.002). Lama5 KO recipients receiving a single dose of anti-CD40L displayed a trend for increased survival (MST 155 vs 91 days, p=0.07). Tacrolimus treated Lama4 KO recipients had significantly shorter allograft survival (MST 11.5 days versus MST 18 days in WT (p<.002). Lama4 KO recipients receiving a single dose of anti-CD40L displayed a trend for decreased survival (MST 42.5 vs 60 days, p<0.01).
*Conclusions: Depletion of Lama5 upregulated chemokines, adhesion molecules, DC and Treg in the T cell zones, CR, and around HEV, while depletion of Lama4 down-regulated those same cells and molecules in same areas. Lama5 deficient mice have a tolerant LN niche, while Lama4 deficient mice have a relatively immune LN niche. These results suggest targeting laminins are efficient approaches to modulate immune outcomes in transplantation.
To cite this abstract in AMA style:Li L, Shirkey M, Piao W, Xiong Y, Saxena V, Zhang T, Iyyathurai J, Lakhan R, Abdi R, Bromberg J. Laminin Alpha 4 and Alpha5 Differentially Regulate Lymph Node Tolerogenic Structure [abstract]. Am J Transplant. 2021; 21 (suppl 3). https://atcmeetingabstracts.com/abstract/laminin-alpha-4-and-alpha5-differentially-regulate-lymph-node-tolerogenic-structure/. Accessed June 11, 2021.
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