Rb. Brauer et al., USE OF C6-DEFICIENT RATS TO EVALUATE THE MECHANISM OF HYPERACUTE REJECTION OF DISCORDANT CARDIAC XENOGRAFTS, The Journal of immunology, 151(12), 1993, pp. 7240-7248
C plays a critical role in the hyperacute rejection (HAR) of discordan
t xenografts (Xg), but the relative contribution of early vs late C co
mponents is unknown. In this study, genetic differences in C6 activity
were correlated with HAR of guinea pig cardiac Xg by the rat. Seven r
at strains were tested for C activity. Six strains (PVG.R1 (R1), PVG.1
A (1A), DA, W/F, F344, LEW) had readily detectable C activity in the t
otal and alternative pathways. Some PVG rats also had adequate C activ
ity [PVG (C+)] but others [PBG (C-)] had a profound C6 deficiency. All
rats with adequate C activity (n = 35) rejected cardiac Xg between 15
and 80 min. PVG (C+) (n = 6) rats also rejected cardiac Xg hyperacute
ly (26 +/- 12 min), whereas PVG (C-) (n = 16) rats, which had high pre
formed IgM natural antibody titers, rejected cardiac Xg in 1 to 2 days
(2678 +/- 542 min). Transfer of serum from R1 rats to PVG (C-) recipi
ents with vigorously beating Xg caused HAR of cardiac Xg within 116 +/
- 75 min. Transfer of fresh PVG (C-) serum or heat-inactivated R1 seru
m did not induce HAR. HAR was characterized by intravascular platelet
aggregation and interstitial hemorrhage, whereas Xg transplanted to PV
G (C-) recipients had patent vessels at 30 min but were heavily infilt
rated by granulocytes and monocytes at 2 days. These findings indicate
that a deficiency in C6 prevents HAR but allows an accelerated acute
rejection that may be mediated by the generation of vasoactive and che
motactic C3a and C5a.