Hyperacute rejection in the guinea pig-to-rat model without formation of the membrane attack complex

The guinea pig (GP)-to-rat transplantation model has been widely used to st udy hyperacute rejection (HAR) of xenografts. In this model heart graft sur vival beyond 8 days has never been reported. In contrast, survival times of kidney and heart grafts up to 62 days have been reported in the discordant pig-to-primate model. It is not clear why it is so much more difficult to obtain long-term graft survival in the GP-to-rat model as compared to the pig-to-primate model. We hypothesized that mechanisms other than activation of complement may be in volved in the rejection of guinea pig grafts by rat recipients. Therefore, we have studied in detail the rejection of GP aortic grafts by rat recipien ts, either PVG/c(+) (complement competent, group 1), or PVG/c(-) (complemen t C6 deficient, group 2). PVG/c(-) rats are not able to form the membrane a ttack complex (MAC) of complement. Forty-four GP-to-rat aortic transplantations were performed successfully. R ecipient rats were sacrificed at various intervals after transplantation (4 , 24 and 48 h, and 7 and 28 days, three to six animals per time point per g roup). Twenty-four hours after transplantation the number of cells in the m edia was significantly decreased from 11.1 +/- 0.9 cells/mm(2) to 3.1 +/- 2 .8 cells/mm(2) in group 1, whereas the number of medial cells in group 2 re mained the same. The number of medial cells was significantly decreased in both groups at 48 h post-transplantation (group 1: 1.8 +/- 2.2 cells/mm(2); group 2: 5.5 +/- 3.0 cells/mm(2)). At that time no infiltrating cells were apparent in the grafts of either two groups. Seven days after transplantat ion, the number of medial cells remained low in group 1 (1.8 +/- 2.9 cells/ mm2) but was increased in group 2 (10.7 +/- 2.6 cells/mm(2)) as a consequen ce of infiltrating immune cells. These infiltrating cells consisted mainly of macrophages, but also T cells and NK cells. At 28 days after transplanta tion the grafts in both groups were completely reorganized and no distincti on could be made between media and adventitia. These results show that reje ction of GP grafts by rat recipients can occur in the absence of both MAC o f complement and immune competent cells. This MAC and immune cells independ ent type of rejection has not been described before and may explain the dif ficulty in obtaining long-term graft survival in the GP-to-rat xenotranspla ntation model.