A model for immediate vascularization of skin was devised to examine one of the possible explanations for the differential survival rates of transplants of freely grafted skin and organs, i.e., the increased vulnerability of skin to early ischemic necrosis prior to revascularization. Female Fischer (F) rat skin was transplanted beneath the kidney capsule of tolerant female Lewis (LEW) recipients. This skin healed in and initially appeared to be normal grossly and microscopically. In 27 rats, after 30 days, the composite grafts were excised, and immediately transplanted by means of vascular anastomosis into normal LEW recipients (syngeneic to the kidney portion of the graft and allogeneic to the skin). For 5 days after transplantation of the composite graft, the skin appeared to be normal with minimal or no inflammation in a panel of 11 recipients. From the 6th to 11th day, an active rejection reaction developed at the skin-kidney interface in a panel of six rats. In 10 rats, in which the composite grafts remained in their secondary hosts for 12 to 21 days, rejection of the skin was complete. The renal portion of all composite grafts appeared to be normal histologically. All recipients of composite grafts rejected subsequent orthotopic F skin grafts in an accelerated manner, with median survival times of 8.2 ± 0.3 days compared to 11.5 ± 0.7 days in untreated F LEW controls, demonstrating that the skin on the composite graft was fully immunogenic. These results demonstrate that immediately vascularized skin allografts between rats compatible at the major Ag-B1 locus will still be rejected within 2 weeks compared to survivals of up to 48 weeks in renal allografts in the same histocompatibility combination, suggesting that anatomical factors are not sufficient to account for the differences in survival times between skin and solid organs.
It has been demonstrated by a number of workers (1–5) that tissues from the same donor may behave differently in their susceptibility to rejection when transplanted as allografts to a given recipient strain, i.e., it appears that tissues and organs are not equally vulnerable to transplantation immunity. This is clearly evident from the work of White et al. (6), who showed significantly prolonged survival of F rat kidney allografts in LEW recipients (>48 weeks) compared to the survival rates of skin grafts in the same strain combination (10.3 days). Pettirossi et al. (7) have determined similar differential survivals of various organ allografts across the same histocompatibility barrier, noting that one-third of the kidneys grafted from (BN X LEW) F! hybrid rats survived from 32 to 71 days in parental strain (LEW) recipients compared to skin graft survivals of 9.1 days. Longer survival times, but not as dramatically prolonged as renal allograft survival times, were seen for heart and pancreas grafts by the same workers. Furthermore, Barker and Bil-lingham (1) using Ag-B-compatible donors and recipients noted survival times as long as 100 days for cardiac allografts compared to skin survivals of 13.8 days. Using backcross animals, they also noted prolonged survival of cardiac allografts as compared with skin from (F X LEW)F1 X LEW R2 in LEW recipients, suggesting that heart transplants across a spectrum of histocompatibility barriers other than Ag-B are less vulnerable to rejection than skin grafts but apparently more susceptible than kidney allografts.
These reports and others (8–10) demonstrate that skin allograft survival does not necessarily dictate the duration of survival of allografts of other tissues. Various explanations for these observations include qualitative and/or quantitative differences in the antigenicity of skin and other organs (11–14), a different intrinsic vulnerability to the immune attack (I, 15), differences in the routes by which antigenic material first “informs” the host of its presence (16, 17), and the difference in lymphatic vascular supply of the allograft (18), the lymphatics being a primary pathway for sensitization by skin but not solid organ grafts (19). Finally, the capacity of the grafted tissue to withstand ischemia may be influential, since areas of necrosis and inflammation may facilitate the release of antigenic material and the accumulation of acute inflammatory cells, possibly potentiating the immune reflex (20, 21). The following experiment was undertaken to evaluate the contribution of the route of sensitization, and the nature of the revascularization to the differential survival rates of skin and renal grafts. A model was devised for the immediate revascularization of skin, thus avoiding the 2− to 4-day period of relative ischemia required for the healing via neovascularization of conventional grafts (22).