Matrix embedding alters the immune response against endothelial cells in vitro and in vivo.
BACKGROUND
Endothelial cell (EC) dysfunction represents the first manifestation of atherosclerotic disease. Restoration of endothelium via seeding or transfection is hampered by local alterations in flow, inflammation, and metabolic activation. Perivascular EC matrix implants are shielded from these forces and still control vascular repair. The host immune response to such implants, however, remains largely unknown. We investigated the effect of embedding of ECs within 3-dimensional matrices on host immune responses in vitro and in vivo.


RESULTS
We compared expression of major histocompatibility complex (MHC), costimulatory, and adhesion molecules by free aortic ECs or ECs embedded in Gelfoam matrices by flow-cytometry. T-cell proliferation was assessed by [3H] thymidine incorporation. Humoral immune response (ELISA and FACS analysis) and cellular (histopathology) infiltration were investigated after subcutaneous injection of free porcine aortic ECs (PAEs) or of a Gelfoam/EC block, or after concomitant injection of PAEs adjacent to Gelfoam in rats. Aortic ECs embedded in Gelfoam expressed lower levels of MHC class II, costimulatory, and adhesion molecules compared with free ECs (P<0.001), and induced 3-fold less proliferation of human CD4+ T-cells (P<0.0005). Implantation of a Gelfoam/EC block in rats nearly abrogated the immune response with 1.75- to 9.0-fold downregulation in tumor necrosis factor-alpha, interleukin-6, monocyte chemotactic protein-1, and PAE-specific immunoglobulin G (P<0.005) and 3.3- to 4.5-fold reduction in leukocytic tissue infiltration. Injecting PAEs adjacent to Gelfoam induced a significant response comparable to that of free implanted PAEs.


CONCLUSIONS
Embedding ECs within 3-dimensional matrices alters the host immune response by inhibiting expression of MHC class II, costimulatory, and adhesion molecules, offering the rationale to develop novel therapies for vascular diseases.
Methe
Heiko
H
Massachusetts Institute of Technology, Cambridge, MA 02139, USA. hmethe@mit.edu
Nugent
Helen M
HM
Groothuis
Adam
A
Seifert
Philip
P
Sayegh
Mohamed H
MH
Edelman
Elazer R
ER
D000818:Animals; D001011:Aorta / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics; D018929:Cell Culture Techniques / Q000379:methods*; D015237:Dinoprost / Q000096:biosynthesis / Q000235:genetics; D042783:Endothelial Cells / Q000276:immunology* / Q000637:transplantation; D004730:Endothelium, Vascular / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D005781:Gelatin Sponge, Absorbable; D005786:Gene Expression Regulation; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation; D051381:Rats; D017207:Rats, Sprague-Dawley; D034421:Sus scrofa; D023822:Tissue Engineering / Q000379:methods*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
C078129:6-keto-prostaglandin F2alpha; D015815:Cell Adhesion Molecules; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D015237:Dinoprost