Background: Fibrillin-1, found in connective tissue, plays a role in the sequestration of TGF-b, and is produced by fibroblastic reticular cells (FRCs). It has been shown that TGF-b, plays a role in inducing regulatory T cells (Tregs) as well as up regulating podoplanin, a molecule that is expressed by lymphatics and FRCs. Furthermore, it has shown that the FRCs produce CCL21, which binds to podoplanin and attracts Tregs. We have shown that spontaneously accepted kidney allografts form structures that we refer to as Treg-rich organized lymphoid structures (TOLS), which we believe are a signature of tolerance. Using immunohistochemistry technique, our lab has shown the expression of podoplanin and latency-associated peptide (LAP) in TOLS. This study compared the frequency and anatomical location of fibrillin-1 and FRC in naïve, accepted, and rejecting murine kidneys We believe that FRCs play a role in the formation and/or maintenance of TOLS, in part by regulating fibrillin-1 expression.

Methods: Fibrillin-1 expression was analyzed in a spontaneously accepted, rejecting kidney, and naïve mice kidneys via immunohistochemistry. Staining for FRCs was performed on frozen sections of spontaneously accepted (6 weeks post transplantation) and naïve kidneys using antibody to ER-TR7 antigen, a protein sectreted by FRCs.

Results: Fibrillin-1 expression increased significantly in the rejecting kidneys when compared to the accepted and naïve kidneys (Figures 1). Rejecting kidneys have more dispersed fibrillin-1 throughout the entire kidney section including greater staining in the interstitium, which was not observed in the accepted kidneys. The accepted kidneys had the highest expression of fibrillin-1 within TOLS.

Conclusions: We have shown that fibrillin-1 is highly expressed TOLS in spontaneously accepted murine kidney allografts. Furthermore, we show that FRCs are also present in TOLS. We hypothesize that fibrillin-1 may be playing a role in renal acceptance, perhaps acting as a sequestering protein that regulates the levels of TGF-b within TOLS and prevents the formation of fibrotic lesions within these structures. Lastly, we believe that fibrillin-1 expression patterns may serve as a predictor of renal allograft rejection and tolerance based on the pattern of expression we observe in accepted verses rejecting kidney allografts.

CITATION INFORMATION: Ayyar A, Yang C, Ndishabandi D, White R, Russell P, Madsen J, Colvin R, Alessandrini A. Increased Expression of Fibrillin-1 and Presence of Fibroblastic Reticular Cells in Treg-Rich Organized Lymphoid Structures (TOLS) of Accepted Kidney Allografts. Am J Transplant. 2017;17 (suppl 3).

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