T-cell response to cardiac myosin persists in the absence of an alloimmune response in recipients with chronic cardiac allograft rejection.
BACKGROUND
Immune-mediated injury to the graft has been implicated in the pathogenesis of chronic rejection. However, little is known regarding the nature of the antigen(s) involved in this immune process. We demonstrated that cardiac transplantation in mice induces an autoimmune T-cell response to a heart tissue-specific protein, cardiac myosin (CM). This response contributes to transplant rejection in that its modulation affects cardiac graft survival. This study investigates whether anti-CM T cells undergo activation and expansion in mice with chronic cardiac allograft rejection.


METHODS
The frequency of CM- and donor major histocompatibility complex (MHC)-specific interferon (IFN)-gamma-producing T cells were assessed by ELISPOT in BALB/c mice, which were injected with anti-CD40L (MR1) mAb (chronic rejection group) or CTLA4Ig fusion protein (tolerant group) and transplanted with C57BL/6 cardiac allografts.


CONCLUSIONS
MR1-treated BALB/c recipients of C57BL/6 hearts with chronic rejection displayed a high frequency of activated CM-specific T cells, whereas the frequency of activated alloreactive T cells were similar to naïve, nontransplanted mice. In contrast, no activation of CM-reactive T cells was detected in tolerant recipients after CTLA4Ig treatment. Therefore, in the absence of alloimmunity, chronic rejection is associated with persistence of a T-cell response against CM. Our data indicate that anti-CM autoimmunity may be involved in the immune mechanisms of chronic rejection and suggest that tolerance strategies should target both allo- and autoimmune responses to prevent this process.
Rolls
Hillary K
HK
Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, MA 02114-2500, USA.
Kishimoto
Koji
K
Dong
Victor M
VM
Illigens
Ben M-W
BM
Sho
Masayuki
M
Sayegh
Mohamed H
MH
Benichou
Gilles
G
Fedoseyeva
Eugenia V
EV
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000917:Antibody Formation; D023201:CD40 Ligand / Q000276:immunology; D024722:Cardiac Myosins / Q000276:immunology*; D002455:Cell Division; D002908:Chronic Disease; D000939:Epitopes; D006084:Graft Rejection / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D014184:Transplantation, Homologous / Q000276:immunology
D000911:Antibodies, Monoclonal; D000939:Epitopes; D023201:CD40 Ligand; D024722:Cardiac Myosins