Relative importance of cytotoxic T lymphocytes and nitric oxide-dependent cytotoxicity in contractile dysfunction of rejecting murine cardiac allografts.
BACKGROUND
Previous in vitro studies have suggested that both cytotoxic T lymphocyte (CTL)-mediated and non-CTL-mediated myocyte lysis occur during murine cardiac heterotopic allograft rejection, but the relative importance of these injury mechanisms on myocardial function is not established. We therefore compared the in vivo effects of depletion of CTL and inhibition of nitric oxide synthase (NOS) on contractility of the rejecting heart.


METHODS
Syngeneic (BALB/c into BALB/c) and allogeneic (BALB/c into C57/B16) heterotopic abdominal cardiac transplants were performed. In some of the allogeneic transplants, CD8+ lymphocytes were depleted by intraperitoneal injection of anti-CD8 monoclonal antibody. NOS inhibition was accomplished by continuous infusion of NG-monomethyl-L-arginine via a subcutaneous osmotic pump. Five days after transplantation, the abdominal cavity was opened and the transplanted heart exposed. Base to apex developed force was measured during spontaneous beating at a diastolic stretch of 4 g by placing a suture through the apex of the heart and attaching it to a strain gauge. Effects of interventions on graft survival were determined by recording the days required for loss of palpable graft contractions.


RESULTS
Allogeneic hearts showed a significant reduction in systolic force compared to non-rejecting syngeneic hearts. Depletion of CD8+ cells improved contractility significantly relative to non-depleted allogeneic hearts, but contractility remained significantly reduced relative to syngeneic hearts. Developed force in allogeneic hearts was also improved by NOS inhibition (P<0.01), and NG-monomethyl-L-arginine infusion slightly prolonged graft survival.


CONCLUSIONS
Both CTL-mediated and NOS-dependent (possibly macrophage-mediated) mechanisms contribute to contractile dysfunction during early cardiac allograft rejection in this model. However, NOS inhibition combined with CTL depletion only slightly prolongs graft survival in this model.
Menon
S G
SG
University of Utah Health Sciences Center, Salt Lake City 84132, USA.
Zhao
L
L
Xu
S
S
Samlowski
W E
WE
Shelby
J
J
McGregor
J
J
Barry
W H
WH
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019001:Nitric Oxide Synthase / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014184:Transplantation, Homologous
D019001:Nitric Oxide Synthase