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BACKGROUND: This study addresses the question of the mechanism for maintaining tolerance to donor alloantigen in the absence of antigen and the role of secondary lymphoid tissues. METHODS: Depleting anti-CD4 antibody administration in conjunction with allogeneic heart transplantation generates donor-specific operational tolerance. Primary C57BL/6 heart grafts were transplanted into the neck cavity of the anti-CD4 antibody pretreated C3H/He mice. At day 50, functioning heart grafts were removed from tolerant mice. At day 100, a secondary C57BL/6 or a third-party heart was transplanted into the abdomen. RESULTS: Anti-CD4 antibody therapy induced CD4CD25 regulatory T cells by 50 days after transplantation, as depleting anti-CD25 treatment in tolerant mice abrogated graft prolongation when spleen leukocytes were adoptively transferred to syngeneic mice. Tolerance was maintained by CD4CD25 regulatory T cells via a CTLA-4 signal at 100 days, even after removal of the primary graft at day 50. Administration of anti-CD25 antibody immediately after removal of the primary graft did not break tolerance, as five out of six second allografts transplanted at day 100 were accepted. Anti-CD25 antibody therapy in conjunction with splenectomy, but not thymectomy, immediately after removal of primary heart grafts at day 50 broke tolerance at day 100; all allografts were rejected. CONCLUSION: The spleen is important in maintaining CD4CD25 regulatory T cells after primary allograft removal.

Original publication




Journal article



Publication Date





1226 - 1233


Adoptive Transfer, Animals, Antibodies, Monoclonal, Antigens, CD, Antigens, Differentiation, CTLA-4 Antigen, Cardiac Surgical Procedures, Drug Administration Schedule, Heart Transplantation, Immune Tolerance, Interleukin-2 Receptor alpha Subunit, Isoantigens, Mice, Mice, Inbred Strains, Postoperative Period, Spleen, Splenectomy, T-Lymphocytes, Regulatory, Tissue Donors, Transplantation, Heterotopic, Transplantation, Homologous