Mechanisms of tolerance induction after intrathymic islet injection: determination of the fate of alloreactive thymocytes.
BACKGROUND
Intrathymic (IT) administration of antigen when combined with peripheral T-cell depletion has been shown to induce operational tolerance in a wide range of experimental protocols. IT injection of pancreatic islets has been demonstrated not only to induce tolerance to alloantigen but also to prevent the development of autoimmune beta-cell destruction in models of type I diabetes. However, little is known about the mechanisms involved in tolerance induction after IT islet injection.


RESULTS
A protocol for the induction of tolerance to fully allogeneic (C57BL/10; H2b) peripheral islet allografts was developed in CBA/Ca (H2k) recipients by the IT injection of allogeneic islets combined with depletion of peripheral CD4+ T cells. This protocol was based upon our own data and those of others showing that CD4+ T cells play a critical role in islet allograft rejection. Using this regimen, donor-type peripheral islet allografts survived indefinitely whereas third-party grafts were rejected. To determine the fate of alloreactive thymocytes that recognize donor major histocompatibility complex antigens via the direct pathway, T-cell receptor transgenic mice specific for the major histocompatibility complex class I molecule Kb (BM3 and DES) were used as recipients. IT injection of islets expressing the specific alloantigen Kb resulted in clonal deletion of alloreactive thymocytes in T-cell receptor transgenic recipients. No evidence of clonal inactivation in the residual peripheral alloreactive population was observed in this system.


CONCLUSIONS
IT injection of allogeneic islets and concomitant CD4+ T-cell depletion is able to induce donor-specific unresponsiveness. One mechanism responsible for this unresponsiveness is the clonal deletion of thymocytes that recognize alloantigen via the direct pathway.
Turvey
S E
SE
Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, United Kingdom.
Hara
M
M
Morris
P J
PJ
Wood
K J
KJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D005260:Female; D006084:Graft Rejection / Q000276:immunology; D007108:Immune Tolerance; D007150:Immunohistochemistry; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000379:methods; D007519:Isoantigens / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology; D016042:Transplantation, Heterotopic / Q000379:methods
D000911:Antibodies, Monoclonal; D007519:Isoantigens