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

FASEB J. 2012 Jan;26(1):51-62. doi: 10.1096/fj.11-186973. Epub 2011 Sep 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • Bone Marrow / immunology
  • Bone Marrow / pathology
  • CD4-Positive T-Lymphocytes / immunology
  • Choristoma / immunology
  • Choristoma / pathology
  • Choristoma / prevention & control*
  • Chronic Disease
  • Graft Rejection / immunology
  • Heart Transplantation / immunology*
  • Isoantibodies / immunology
  • Lymphoid Tissue / blood supply
  • Lymphoid Tissue / immunology
  • Lymphoid Tissue / pathology*
  • Lymphotoxin beta Receptor / genetics
  • Lymphotoxin beta Receptor / immunology
  • Lymphotoxin beta Receptor / metabolism*
  • Lymphotoxin-beta / immunology
  • Lymphotoxin-beta / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardium / immunology
  • Myocardium / pathology
  • Neovascularization, Pathologic / immunology
  • Neovascularization, Pathologic / pathology
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction / immunology*
  • Spleen / immunology
  • Spleen / pathology
  • Transplantation, Homologous

Substances

  • Isoantibodies
  • Ltb protein, mouse
  • Lymphotoxin beta Receptor
  • Lymphotoxin-beta
  • Recombinant Fusion Proteins