Prevention of chronic rejection in murine cardiac allografts: a comparison of chimerism- and nonchimerism-inducing costimulation blockade-based tolerance induction regimens.
We have previously described a nonirradiation-based regimen combining costimulation blockade, busulfan, and donor bone marrow cells that promotes stable, high level chimerism, deletion of donor-reactive T cells, and indefinite survival of skin allografts in mice. The purpose of the current study is to determine the efficacy of this tolerance regimen in preventing acute and chronic rejection in a vascularized heart graft model and to compare this regimen with other putative tolerance protocols. Mice receiving costimulation blockade (CTLA4-Ig and anti-CD40 ligand) alone or in combination with donor cells enjoyed markedly prolonged heart graft survival and initially preserved histological structure. However, tolerance was not achieved, as evidenced by the eventual onset of chronic rejection characterized by obliterative vasculopathy and the rejection of secondary skin grafts. In contrast, following treatment with costimulation blockade, busulfan, and bone marrow, heart grafts survived indefinitely without detectable signs of chronic rejection or structural damage, even 100 days after placement of a secondary donor skin graft. We detected multilineage chimerism in peripheral blood, spleen, lymph nodes, and thymus, and peripheral deletion of donor-reactive cells was complete by day 90. These findings indicate that only the CD40/CD28 blockade chimerism induction regimen prevents both acute and chronic rejection of vascularized organ transplants. Further testing of these strategies in a preclinical large animal model is warranted.
The Carlos and Marguerite Mason Transplantation Biology Research Center, Departments of Surgery, Emory University School of Medicine, Atlanta, GA 30322, USA.
Nozomu
N
Shirasugi
Andrew B
AB
Adams
Megan M
MM
Durham
Aron E
AE
Lukacher
Huaying
H
Xu
Phyllis
P
Rees
Shannon R
SR
Cowan
Matthew A
MA
Williams
Thomas C
TC
Pearson
Christian P
CP
Larsen
D000208:Acute Disease; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D016026:Bone Marrow Transplantation / Q000276:immunology; D002066:Busulfan / Q000627:therapeutic use; D002908:Chronic Disease; D017637:Clonal Deletion / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival / Q000235:genetics / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology* / Q000379:methods / Q000473:pathology; D006410:Hematopoiesis / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance / Q000235:genetics; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D018183:Transplantation Chimera / Q000276:immunology*; D019172:Transplantation Conditioning / Q000379:methods*
D007166:Immunosuppressive Agents; D016693:Receptors, Antigen, T-Cell, alpha-beta; D002066:Busulfan