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Quantity of donor tissue and rat allograft survival
ELSEVIER
Quantity of Donor Tissue and Rat Allograft Survival J. Sun, G. Bishop,
C. Wang, L. Wang, G. McCaughan,
L
IVER allografts in some rat strain combinations are spontaneously accepted across a complete MHC barrier while other organs such as heart or kidney are rejected.’ In order to determine if the different fate of the allografts is associated with the size of the organs, we have investigated the dose effect on rat renal and cardiac allograft survival. MATERIALS AND METHODS Male PVG(RT1’) and DA(RTla) rats weighing 200 to 300 g were used as donors and recipients, respectively. There were 5 experimental groups: group 1, single kidney transplantation; group 2, double kidney transplantation; group 3, single heart transplantation; group 4, double heart transplantation; group 5 double heart plus single kidney transplantation. For single kidney transplantation, the graft was implanted orthotopically as described by French and Batchelo? with end-to-end anastomoses of the renal arteries, veins, and ureters of graft and recipient after left nephrectomy. The recipient’s remaining right kidney was removed on day 2 in group 1. For double kidney transplantation, orthotopic right renal allografting with end-to-end anastomoses of the renal arteries and ureters and end-to-side anastomosis of the renal veins of graft and recipient and right nephrectomy followed on day 2 by left renal allografting as described above. Graft rejection was considered complete at the time of animal death. For single heart transplantation, the graft was implanted heterotopically using a modified technique of Ono and Lindsey3 with the donor aorta and pulmonary artery anastomosed end-to-side to the recipient’s abdominal aorta and inferior vena cava, respectively. For double heart transplantation, the second graft was implanted distally beside the first graft. Graft survival was determined by daily palpation. Rejection was considered complete at the time of cessation of a palpable heart beat and confirmed by histological examination. For double heart plus single kidney transplantation, cardiac grafting was followed on day 2 by renal grafting with the techniques described above. Graft survival time in multiorgan transplantation was counted from the date when the first organ was implanted to the date when every organ was rejected.
RESULTS
Median survival time (MST) of grafts in single kidney transplantation was 8.5 days (8,8,9,9, n = 4) and in double kidney transplantation more than 60 days (12, 13, >60 X 3, n = 5) (P = .016). MST of grafts in single heart transplan0 1997 by Elsevier Science Inc. 655 Avenue of the Americas,
New York, NY 10010
and R. Sheil
tation was 9 days (7,8,8, 9, 10, 10, 11, n = 7) and in double heart transplantation 15.5 days (12, 15, 16, 18, n = 4) (P = .019). Double heart plus single kidney transplantation resulted in prolonged survival of more than 100 days in 3 of 4 animals in group 5. Another animal in this group was sacrificed on day 55 because of paralysis of the rear limbs. Laparotomy showed induration of the heart and kidney grafts and diminution in the strength of pulsation. Histologic examination revealed extensive fibrosis, mononuclear infiltrates, and vascular lesions in all the grafts indicative of chronic rejection.
DISCUSSION
Early studies which examined the quantity of tissue transplanted suggested that rejection was accelerated with increased amounts of transplanted skin4 Quantitative studies of donor tissue in organ transplantation have not been reported before. Findings in this study demonstrate that the survival of allografts is associated with the quantity of donor tissue. Double renal or cardiac grafts survived significantly longer than single grafts. Triple grafts (2 hearts + 1 kidney) survived beyond 100 days. However, these grafts developed features of chronic rejection in both hearts and kidneys. There is thus a spectrum of response to transplanted organs ranging from rapid rejection of a single organ to prolonged survival of triple grafts albeit with chronic rejection. Recently we have induced renal and cardiac allograft acceptance by quadruple transplants (2 hearts + 2 kidneys) and simultaneous leukocyte inoculation? In this case, 4 organs plus large numbers of donor leukocytes were accepted without evidence of chronic rejection 200 days after transplantation. It
From the Department of Surgery, University of Sydney (J.S., C.W., L.W., R.S.) and A.W. Morrow Gastroenterology and Liver Laboratory, Centenary Institute, Royal Prince Alfred Hospital (G.B., G.M.), Sydney, Australia. Supported by Grant 940430 from the National Health and Medical Research Council of Australia and by the Bushell Foundation. Address reprint requests to J. Sun, MD, Department of Surgery, University of Sydney, Sydney 2006, Australia.
0041-1345/97/$17.00 PII SO041 -1345(96)00494-O
1143
Transplantation
Proceedings,
29, 1143-l 144 (1997)
1144
thus appears that acceptance of organ transplants in this model requires a large amount of donor tissue consisting of both parenchymal tissue and passenger leukocytes. We conclude that the quantity of donor tissue is an important factor in allograft rejection and tolerance. In this study, increased amounts of donor tissue led to prolongation of rat renal and cardiac allograft survival.
SUN, BISHOP, WANG ET AL
REFERENCES
1. Kamada N, Davies H, Roser B: Nature 292:840, 1981 2. French ME, Batchelor JR: Lancet 2:1103, 1969 3. Ono K, Lindsey ES: J Thorac Cardiovasc Surg 57~225, 1969 4. Medawar PB: J Anatomy 78:176, 1944 5. Sun J, Sheil AGR, Wang C, et al: Transplantation
(in press)
Quantity of Donor Tissue and Rat Allograft Survival J. Sun, G. Bishop,
C. Wang, L. Wang, G. McCaughan,
L
IVER allografts in some rat strain combinations are spontaneously accepted across a complete MHC barrier while other organs such as heart or kidney are rejected.’ In order to determine if the different fate of the allografts is associated with the size of the organs, we have investigated the dose effect on rat renal and cardiac allograft survival. MATERIALS AND METHODS Male PVG(RT1’) and DA(RTla) rats weighing 200 to 300 g were used as donors and recipients, respectively. There were 5 experimental groups: group 1, single kidney transplantation; group 2, double kidney transplantation; group 3, single heart transplantation; group 4, double heart transplantation; group 5 double heart plus single kidney transplantation. For single kidney transplantation, the graft was implanted orthotopically as described by French and Batchelo? with end-to-end anastomoses of the renal arteries, veins, and ureters of graft and recipient after left nephrectomy. The recipient’s remaining right kidney was removed on day 2 in group 1. For double kidney transplantation, orthotopic right renal allografting with end-to-end anastomoses of the renal arteries and ureters and end-to-side anastomosis of the renal veins of graft and recipient and right nephrectomy followed on day 2 by left renal allografting as described above. Graft rejection was considered complete at the time of animal death. For single heart transplantation, the graft was implanted heterotopically using a modified technique of Ono and Lindsey3 with the donor aorta and pulmonary artery anastomosed end-to-side to the recipient’s abdominal aorta and inferior vena cava, respectively. For double heart transplantation, the second graft was implanted distally beside the first graft. Graft survival was determined by daily palpation. Rejection was considered complete at the time of cessation of a palpable heart beat and confirmed by histological examination. For double heart plus single kidney transplantation, cardiac grafting was followed on day 2 by renal grafting with the techniques described above. Graft survival time in multiorgan transplantation was counted from the date when the first organ was implanted to the date when every organ was rejected.
RESULTS
Median survival time (MST) of grafts in single kidney transplantation was 8.5 days (8,8,9,9, n = 4) and in double kidney transplantation more than 60 days (12, 13, >60 X 3, n = 5) (P = .016). MST of grafts in single heart transplan0 1997 by Elsevier Science Inc. 655 Avenue of the Americas,
New York, NY 10010
and R. Sheil
tation was 9 days (7,8,8, 9, 10, 10, 11, n = 7) and in double heart transplantation 15.5 days (12, 15, 16, 18, n = 4) (P = .019). Double heart plus single kidney transplantation resulted in prolonged survival of more than 100 days in 3 of 4 animals in group 5. Another animal in this group was sacrificed on day 55 because of paralysis of the rear limbs. Laparotomy showed induration of the heart and kidney grafts and diminution in the strength of pulsation. Histologic examination revealed extensive fibrosis, mononuclear infiltrates, and vascular lesions in all the grafts indicative of chronic rejection.
DISCUSSION
Early studies which examined the quantity of tissue transplanted suggested that rejection was accelerated with increased amounts of transplanted skin4 Quantitative studies of donor tissue in organ transplantation have not been reported before. Findings in this study demonstrate that the survival of allografts is associated with the quantity of donor tissue. Double renal or cardiac grafts survived significantly longer than single grafts. Triple grafts (2 hearts + 1 kidney) survived beyond 100 days. However, these grafts developed features of chronic rejection in both hearts and kidneys. There is thus a spectrum of response to transplanted organs ranging from rapid rejection of a single organ to prolonged survival of triple grafts albeit with chronic rejection. Recently we have induced renal and cardiac allograft acceptance by quadruple transplants (2 hearts + 2 kidneys) and simultaneous leukocyte inoculation? In this case, 4 organs plus large numbers of donor leukocytes were accepted without evidence of chronic rejection 200 days after transplantation. It
From the Department of Surgery, University of Sydney (J.S., C.W., L.W., R.S.) and A.W. Morrow Gastroenterology and Liver Laboratory, Centenary Institute, Royal Prince Alfred Hospital (G.B., G.M.), Sydney, Australia. Supported by Grant 940430 from the National Health and Medical Research Council of Australia and by the Bushell Foundation. Address reprint requests to J. Sun, MD, Department of Surgery, University of Sydney, Sydney 2006, Australia.
0041-1345/97/$17.00 PII SO041 -1345(96)00494-O
1143
Transplantation
Proceedings,
29, 1143-l 144 (1997)
1144
thus appears that acceptance of organ transplants in this model requires a large amount of donor tissue consisting of both parenchymal tissue and passenger leukocytes. We conclude that the quantity of donor tissue is an important factor in allograft rejection and tolerance. In this study, increased amounts of donor tissue led to prolongation of rat renal and cardiac allograft survival.
SUN, BISHOP, WANG ET AL
REFERENCES
1. Kamada N, Davies H, Roser B: Nature 292:840, 1981 2. French ME, Batchelor JR: Lancet 2:1103, 1969 3. Ono K, Lindsey ES: J Thorac Cardiovasc Surg 57~225, 1969 4. Medawar PB: J Anatomy 78:176, 1944 5. Sun J, Sheil AGR, Wang C, et al: Transplantation
(in press)