Progression of alloresponse and tissue-specific immunity during graft coronary artery disease.
Chronic rejection remains the major obstacle for long-term transplant survival. Both indirect alloresponse and tissue-specific autoimmunity have been implicated in its pathogenesis. The interrelationship between these two types of host anti-graft response remains poorly understood. We have developed an immunosuppression-free mouse model of graft coronary artery disease (GCAD), in which all FVB (H-2(q)) cardiac allografts placed into minor Ag (mHC)-mismatched DBA/1 (H-2(q)) hosts survived more than 112 days, and developed GCAD. We then examined the kinetics of both anti-mHC alloresponse and host autoimmunity against heart-specific antigen, cardiac myosin (CM). At 8 days post-transplantation, recipient mice showed minimal intragraft inflammation and apoptosis, and limited expansion of allo-specific T cells. In addition, we observed early production of anti-myosin IgG1 autoantibodies, which occurred in the absence of activated CM-specific T lymphocytes. By day 56, GCAD indices, the numbers of mHC- and CM-reactive T cells, and the levels of circulating allo- and CM-specific antibodies were all significantly increased. While host alloresponse was exhausted at 112 days post-transplant, T-cell reactivity against CM persisted. Our data suggest that both allo- and tissue-specific immunity might contribute to the induction of GCAD. They indicate that continual autoimmune response against graft tissue antigens may provide for GCAD sustenance.
Tanaka
Masashi
M
Department of Cardiothoracic Surgery, Stanford University School of Medicine, Stanford, CA 94305-5407, USA. masashi@omiya.jichi.ac.ap
Zwierzchoniewska
Monika
M
Mokhtari
Golnaz K
GK
Terry
Raya D
RD
Balsam
Leora B
LB
Robbins
Robert C
RC
Fedoseyeva
Eugenia V
EV
D000818:Animals; D000917:Antibody Formation; D015551:Autoimmunity / Q000276:immunology*; D024722:Cardiac Myosins / Q000276:immunology* / Q000378:metabolism; D003324:Coronary Artery Disease / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D006084:Graft Rejection / Q000276:immunology*; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007108:Immune Tolerance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014184:Transplantation, Homologous
D015395:Histocompatibility Antigens Class I; D024722:Cardiac Myosins