just some background for the allomune (no partner, now in phase I) and xenomune (Sandoz/Novartis) programs, or whatever they're called.... key words.... "remains speculative".....
Am J Kidney Dis 1998 Feb;31(2):197-212
Cellular basis of long-term organ transplant acceptance: pivotal role of
intrathymic clonal deletion and thymic dependence of bone marrow
microchimerism-associated tolerance.
Remuzzi G
Department of Transplant Immunology and Innovative Antirejection Therapies, Ospedali Riunit, Bergamo, Mario Negri
Institute for Pharmacological Research, Italy.
Long-term acceptance of MHC-incompatible organ allografts without chronic immunosuppressive therapy has been achieved in
experimental animals. There are also reports, mainly in liver transplant, of patients who after complete withdrawal of
immunosuppressants still have a functioning graft. It has been proposed that organ transplant implies a migratory flux of donor
"passenger" leukocytes out of the graft into the recipient tissues or organs, serving to establish a persistent condition of
"microchimerism," and being a tolerogenic precursor of chimeric cells. Although there is evidence that the same migratory
mechanisms apply to all organ grafts, migration of passenger leukocytes is less in organs other than the liver, such as the kidney
and heart. To enhance the acceptance of organs less tolerogenic than the liver, perioperative infusion of donor bone marrow
has been attempted to increase the migration of donor leukocytes of bone marrow origin. It has been suggested that such
peripheral donor microchimerism is not only associated with long-term acceptance of the organ graft but that it plays an active
role in induction and maintenance of unresponsiveness. However, the intimate mechanisms(s) responsible for prolonged organ
survival in this setting remains speculative. Experimental evidence that the thymus plays the major role in the development of
self-tolerance and is also critical in the induction of acquired tolerance to exogenous antigens has focussed the attention on the
intrathymic events that lead to donor-specific unresponsiveness to allograft. Data are available showing that after direct
intrathymic injection of donor cells, clonal deletion of maturing host thymocytes occurs and is the major mechanism in the
induction of donor-specific tolerance. The central role of the thymus in transplant tolerance is also supported by more recent
findings that in mixed allogeneic bone marrow chimeras in mice with a nonmyeloablative conditioning regimen, migration of
donor bone marrow-derived dendritic cells to the thymus serves to negatively select newly developing host T cells. Therefore,
the peripheral T-cell component would be devoid of alloreactive population. Thus, lifelong intrathymic clonal deletion is the only
significant mechanism involved in the maintenance of donor-specific T-cell tolerance that would allow the subsequent
vascularized organ from the same donor to survive indefinitely. |
