T-helper 2 cells are essential for modulation of vascular repair by allogeneic endothelial cells.
BACKGROUND
Endothelial cells (ECs) embedded within 3-dimensional matrices (MEEC) control lumenal inflammation and intimal hyperplasia when placed in the vascular adventitia. Matrix embedding alters endothelial immunogenicity in vitro. T-helper (Th) cell-driven host immunity is an impediment of allogeneic grafts. We aimed to identify if modulation of Th balance would affect immune compatibility and endothelial regulation of vascular repair in vivo.


METHODS
Pigs (n = 4/group) underwent carotid artery balloon injury and were left untreated (Group 1) or received perivascular porcine MEEC implants (Group 2), 12 days of cyclosporine A (CsA; Group 3), or MEEC and CsA (Group 4). Host immune reactivity was analyzed after 28 and 90 days.


RESULTS
MEEC treatment induced formation of EC-specific immunoglobulin (Ig) G(1) antibodies (41 +/- 6 mean fluorescence intensity [MFI]) and differentiation of host splenocytes into Th2, but not Th1, cytokine-producing cells (interleukin [IL]-4, 242 +/- 102; IL-10, 273 +/- 114 number of spots). Concomitant CsA therapy reduced IgG(1) antibody frequency (25 +/- 2 MFI; p < 0.02) and Th2-cytokine producing splenocytes upon MEEC treatment (IL-4, 157 +/- 19; IL-10, 124 +/- 26 number of spots; p < 0.05). MEECs inhibited luminal occlusion 28 and 90 days after balloon injury (12 +/- 7%) vs untreated controls (68 +/- 14%; p < 0.001) but to a lesser extent with concomitant CsA treatment (34 +/- 13%; p < 0.02 vs Group 2).


CONCLUSIONS
MEECs do not induce a significant Th1-driven immune response but do enhance differentiation of splenocytes into cells producing Th2 cytokine. Reduction in this Th2 response reduces the vasoregulatory effects of allogeneic ECs after injury.
Methe
Heiko
H
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. hmethe@mit.edu
Nanasato
Mamoru
M
Spognardi
Anna-Maria
AM
Groothuis
Adam
A
Edelman
Elazer R
ER
D000818:Animals; D020212:Carotid Artery Injuries / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy*; D017690:Cell Transplantation / Q000379:methods*; D016572:Cyclosporine / Q000627:therapeutic use; D004730:Endothelium, Vascular / Q000166:cytology / Q000637:transplantation*; D007074:Immunoglobulin G / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D015847:Interleukin-4 / Q000378:metabolism; D023421:Models, Animal; D013154:Spleen / Q000166:cytology; D013552:Swine; D018418:Th2 Cells / Q000502:physiology*; D014184:Transplantation, Homologous
D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D015847:Interleukin-4; D016572:Cyclosporine