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(Circulation. 2006;114:I-233 – I-238.)
© 2006 American Heart Association, Inc.

Myocardial Protection and Vascular Biology

Cell–Matrix Contact Prevents Recognition and Damage of Endothelial Cells in States of Heightened Immunity

Heiko Methe, MD; Elazer R. Edelman, MD, PhD

From Harvard-MIT Division of Health Sciences and Technology (H.M., E.R.E.), Massachusetts Institute of Technology, Cambridge, Mass; Cardiovascular Division (E.R.E.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Heiko Methe, Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, 77 Massachusetts Ave, Bldg 56-322; Cambridge, MA 02139. E-mail hmethe{at}mit.edu

Background— Autoimmunity may exacerbate vascular disease, particularly in the form of anti-endothelial cell (EC) antibodies. The increased morbidity of cardiovascular diseases in concert with diabetes mellitus, hypertension, and other systemic illnesses may reflect the increase presence and potency of these antibodies. Matrix-embedded ECs act as powerful regulators of vascular repair accompanied by significant reduction in expected systemic and local inflammation. We compared the immune response against free and matrix-embedded ECs in naïve mice and mice with heightened EC immune reactivity.

Methods and Results— Mice were presensitized to EC with repeated (days 0, 21, 35) subcutaneous injections of saline-suspended porcine EC (PAE) (5x10⁵ cells). Controls received saline injections. On day 42, mice received 5x10⁵ matrix-embedded or free PAEs. Circulating PAE-specific antibodies and effector T-cells were analyzed via flow cytometry, and xenoreactive lymphocytes via ELISPOT, 90 days after implantation. PAE-specific antibody-titers, frequency of CD4⁺-effector cells, and xenoreactive splenocytes were 2- to 4-fold lower (P<0.0001) when naïve mice were injected with matrix-embedded instead of saline-suspended PAEs. Though basal levels of circulating antibodies were significantly elevated after serial PAE injections (2210±341 mean fluorescence intensity, day 42) and almost doubled again 90 days after injection of a fourth set of free PAEs, antibody levels declined by half in recipients of matrix-embedded PAEs at day 42 (P<0.0001). Levels of CD4⁺-effector cells and xenoreactive splenocytes showed similar results.

Conclusions— Implantation of free PAE elicits a significant immune response in naïve mice and even more pronounced in mice with predeveloped anti-endothelial immunity. Matrix-embedding protects xenogeneic ECs against immune reaction in naïve mice and to a similar extent in mice with heightened immune reactivity. Matrix-embedded EC might offer a promising approach for treatment of advanced cardiovascular disease.

Key Words: antibodies • endothelial cell • extracellular matrix • immune system