Spleen plays an important role in maintaining tolerance after removal of the vascularized heart graft.
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.


CONCLUSIONS
The spleen is important in maintaining CD4CD25 regulatory T cells after primary allograft removal.
Chosa
Eiichi
E
Department of Surgery II, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
Hara
Masaki
M
Watanabe
Akira
A
Matsuzaki
Yasunori
Y
Nakamura
Kunihide
K
Hamano
Kimikazu
K
Wood
Kathryn J
KJ
Onitsuka
Toshio
T
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology; D000943:Antigens, Differentiation / Q000276:immunology; D060908:CTLA-4 Antigen; D006348:Cardiac Surgical Procedures; D004334:Drug Administration Schedule; D016027:Heart Transplantation / Q000276:immunology*; D007108:Immune Tolerance / Q000187:drug effects; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis / Q000276:immunology; D007519:Isoantigens / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D011184:Postoperative Period; D013154:Spleen / Q000276:immunology*; D013156:Splenectomy; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D014019:Tissue Donors; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D007519:Isoantigens