Blocking lymphotoxin signaling abrogates the development of ectopic lymphoid tissue within cardiac allografts and inhibits effector antibody responses

Abstract

Tertiary lymphoid organs (TLOs) may develop within allografts, but their contribution to graft rejection remains unclear. Here, we study a mouse model of autoantibody-mediated cardiac allograft vasculopathy to clarify the alloimmune responses mediated by intragraft TLOs and whether blocking lymphotoxin-β-receptor (LTβR) signaling, a pathway essential for lymphoid organogenesis, abrogates TLO development. TLOs (defined as discrete lymphoid aggregates associated with high endothelial venules) were detectable in 9 of 13 heart allografts studied and were predominantly B cell in composition, harboring germinal-center activity. These are most likely manifestations of the humoral autoimmunity triggered in this model after transplantation; TLOs did not develop if autoantibody production was prevented. Treatment with inhibitory LTβR-Ig fusion protein virtually abolished allograft TLO formation (mean TLOs/heart: 0.2 vs. 2.2 in control recipients; P=0.02), with marked attenuation of the autoantibody response. Recipients primed for autoantibody before transplantation rejected grafts rapidly, but this accelerated rejection was prevented by postoperative administration of LTβR-Ig (median survival time: 18 vs. >50 d, respectively, P=0.003). Our results provide the first demonstration that TLOs develop within chronically rejecting heart allografts, are predominantly B cell in origin, and can be targeted pharmacologically to inhibit effector humoral responses.

Characterization of Resident B Cells of Vascular Walls in Human Atherosclerotic Patients

“…The tertiary lymphoid tissue that develops in chronically rejecting heart allografts are predominantly B cell in origin or have compartmentalized B/T areas (68). AID and switched isotypes are expressed in the lymphoid structures within those grafted hearts.…”

High Endothelial Venule Blood Vessels for Tumor-Infiltrating Lymphocytes Are Associated with Lymphotoxin β–Producing Dendritic Cells in Human Breast Cancer

“…DCs expressed lymphotoxin ligands for LTbR, and DC-derived lymphotoxin was found to be important for HEV-mediated extravasation of lymphocytes in lymph nodes (15). DCs and LTbR signaling have also been implicated in the regulation of HEVs in murine inflamed lymph nodes and chronically inflamed nonlymphoid tissues (16)(17)(18)(19)(20)(21)(22)(23). Despite these important advances in mouse models, little is known yet about the mechanisms governing the development of HEVs in human solid tumors.…”

Cigarette smoke-induced iBALT mediates macrophage activation in a B cell-dependent manner in COPD

“…Highly organized ectopic LFs are referred to as tertiary lymphoid organs (TLOs) because of their structural similarity to secondary lymphoid organs, which include distinct B and T cell areas, germinal centers, and high endothelial venules (1,10,33). TLOs form in various tissues targeted by chronic inflammation and have an important role in maintaining immune responses that can either be harmful or beneficial.…”