The cellular basis of cardiac allograft rejection: VIII. Mechanisms underlying delayed allograft rejection in PVG C6-deficient rats.
BACKGROUND
The delayed allograft rejection in C6-deficient PVG C6- rats compared with normal PVG rats has been attributed to the lack of alloantibody activation of the membrane attack complex of complement. As T cells alone have been shown to effect graft rejection, we examined T-cell responses in PVG C6- rats.


METHODS
The cellular infiltrate and its mRNA for cytokines and effector molecules in DA heart allografts to PVG and PVG C6- rats was compared by immunoperoxidase staining and semiquantitative reverse transcriptase polymerase chain reaction. The ability of pure populations of T cells or alloantibody to mediate DA heart graft rejection in irradiated (750 rads) PVG and PVG C6- rats was also compared.


RESULTS
The median rejection time of DA heart allografts was 8 days in PVG rats and 17.5 days in PVG C6-. PVG C6- rats sensitized to DA by two skin grafts rejected DA heart grafts in 5-6 days. CD3+, CD4+, CD8+, interleukin-2 receptor-positive T cell, macrophage, and natural killer cell infiltration, as well as class II major histocompatibility complex and intercellular adhesion molecule-1 up-regulation, in grafts was similar in naive PVG and PVG C6- rats. mRNA for T helper 1 cytokine interleukin-2, interferon-gamma, tumor necrosis factor-beta, macrophage molecules tumor necrosis factor-alpha, and inducible nitric oxide synthase, as well as cytotoxic T-cell effector molecules perforin and granzyme A and B, were found to be the same in the grafts from both naive PVG and naive PVG C6- rats. Thus, there appeared to be no difference in the T-cell effector response between the PVG and PVG C6- groups. There were higher alloantibody titers in PVG C6- rats than in PVG hosts. Irradiation ablated rejection and alloantibody responses and reconstitution with naive T cells alone restored rejection in both PVG and PVG C6- rats. Irradiated rats given serum from PVG rats that had rejected DA grafts did not effect rejection of DA grafts even if given naive T cells. Sensitized T cells restored second set.


CONCLUSIONS
PVG C6- rats have normal T-cell responses and can mediate allograft rejection in the absence of alloantibody. The failure of PVG C6- to reject allografts rapidly may be a result of the poor clearance of alloantisera leading to enhancement of graft survival rather than a critical role for complement and membrane attack complex in acute rejection.
Merten
S
S
Department of Medicine, University of New South Wales, Liverpool Hospital, Australia.
Chen
J C
JC
Ha
H
H
Plain
K
K
Boyd
R A
RA
Penny
M J
MJ
Leenaerts
P
P
Hall
B M
BM
D000818:Animals; D003183:Complement C6 / Q000172:deficiency; D016207:Cytokines / Q000235:genetics; D006084:Graft Rejection / Q000473:pathology*; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation; D007518:Isoantibodies / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011922:Rats, Mutant Strains / Q000097:blood; D012016:Reference Values; D013601:T-Lymphocytes / Q000502:physiology; D013997:Time Factors; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
D003183:Complement C6; D016207:Cytokines; D007518:Isoantibodies; D012333:RNA, Messenger