Induction of Unresponsiveness to Major Transplantable Organs in Adult Mammals A Recapitulation of Ontogeny by Irradiation and Bone Marrow Replacement

Abstract

Transplantation of renal allografts obtained from prospectively selected genotypically DLA-identical donors into supralethally irradiated dogs reconstituted with their own stored bone marrow has produced a state of unresponsiveness to these kidneys in the recipients. Eleven of 18 kidneys transplanted at 12 hours after marrow replacement currently survive with normal function and maintain life in the recipients for 757, 800, 825, 978, 1062, 1092, 1136, 1282, 1373, 1380, and 1381 days, respectively. Similar results occurred in eight of 13 allografts transplanted at 28 hours after marrow replacement, which currently survive for 349, 363, 377, 407,436,470, 485, and 513 days, respectively, and in eight of 13 kidneys grafted at 36 hours after marrow replacement, which are surviving for 197, 247, 298, 324, 337, 396, 443, and 472 days, respectively. Achievement of optimal results is dependent on the specific timing and sequence of each procedure. Only four of 16 recipients of kidneys transplanted at the time of marrow replacement were unresponsive to their allografts. Similarly, only five of 19 recipients of kidneys placed in irradiated dogs at 40 hours before marrow replacement accepted such allografts. When kidney transplants were placed into the recipients 20 hours before removal of marrow, irradiation, and reconstitution with stored marrow, only three of 21 dogs became unresponsive to such ailografts. In five of 12 instances, the recipients were also unresponsive to skin allografts obtained from their respective kidney donors. Such skin grafts currently survive for 606, 673, 687, 701, and 708 days, respectively. The remaining seven skin grafts were rejected at 28, 39,42, 84, 90, 92, and 115 days, respectively. Second- and third-set skin grafts from the same kidney donor were rejected by six of these dogs at 19, 20, 21, 29, 29, and 30 days, and at 21, 22, 23, 24, 27, and 27 days, respectively. Rejection of these skin grafts had no detectable effect on the function and survival of kidney allografts from the same source. Seven of eight skin grafts obtained from other DLA-identical donors were rejected at 13,14,16,25,28,38, and 84 days, respectively; one allograft continues to survive for 708 days. Eleven DLA-incompatible skin allografts placed on the recipients at the same time were rejected within 11-20 days. Supralethal total body irradiation and bone marrow replacement can establish in the adult canine host a privileged phase of immunological reactivity during which exposure to alloantigens produces specific long-term unresponsiveness rather than sensitization. The use of stored autologous rather than allogeneic bone marrow for reconstitution of the irradiated recipient eliminates the hazards of GVH complication usually associated with this procedure. This consideration and the apparent capacity of the tolerant host to maintain a long-term state of unresponsiveness without any further immunosuppressive therapy point to the potential relevance of the results to human transplantation.