Background:Contact hypersensitivity (CHS) is a reliable model to assess the immune cell-mediated cutaneous inflammatory response, which includes the three phases of priming/sensitization, elicitation, and resolution, reflecting many aspects of allogeneic responses. Specific modulators of immune cell function at each of these phases are not well defined. Immune cell recruitment to the site of challenge during the individual phases is crucial for CHS reaction, however, the molecular mechanisms that regulate leukocyte trafficking are not fully understood. The lymphotoxin (LT) -LT beta receptor (LTβR) axis regulates lymphatic function and transendothelial migration of leukocytes into lymphatic vessels. We hypothesized that inhibitors of the signaling pathways of the LTβR could regulate CHS.

Methods: Decoy receptor peptides that specifically inhibited the classical pathway of LTβR NFκB signaling were designed and administered in vitro or in vivo. T cell and dendritic cell (DC) migration were assessed with in vivo and in vitro assays. Mice were challenged with the hapten 2, 4-dinitrofluorobenzene (DNFB). The CHS response was measured by ear swelling and immunohistochemistry.

Results:Administration of a decoy peptide which inhibits LTβR-classical NFκB signaling at the time of antigen sensitization augmented the CHS inflammatory response, with increased numbers of T cells and DC infiltrating the DNFB challenged tissues. This result was due to enhanced DC migration to draining lymph nodes, which enhanced T cell priming. Treatment with decoy peptide at the time of antigen challenge and elicitation inhibited CHS with fewer CD3⁺ T cells and CD11c⁺ DC infiltrating the inflamed tissues. This effect was due to enhanced migration of T cells and DC out of the tissues. Administration of the decoy peptide at the time of inflammatory resolution promoted tissue quiescence, with reduced numbers of DC and T cells infiltrating the hapten challenged tissues, again as a result of enhanced migration out of the site of antigen deposition.

Conclusions:LTβR-mediated classical NFκB signaling regulates inflammatory responses through modulation of lymphatic vessel function and transendothelial migration of T cells and DC. Targeting the classical arm of LTβR signaling in lymphatic endothelium facilitates inflammation resolution of CHS. This decoy peptide is a novel intervention to regulate immune cell responses during distinct phases of the inflammatory response, and serves as a proof of concept for developing unique therapeutic molecules to guide immune responses.

CITATION INFORMATION: Piao W., Xiong Y., Li L., Saxena V., Bromberg J. Targeting LTβR Classical NFκB Signaling Facilitates Inflammation Resolution Am J Transplant. 2017;17 (suppl 3).

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