Effects of preexisting autoimmunity on heart graft prolongation after donor-specific transfusion and anti-CD154.
BACKGROUND
Alloreactive memory T cells prevent costimulatory blockade-induced heart graft survival in mice, but whether and how preexisting autoreactive T cells affect solid-organ transplants under these conditions is unknown.


METHODS
We tested the impact of preexisting cardiac myosin (CM)-specific immunity on murine heart transplant recipients treated with donor-specific transfusion (DST) plus anti-CD154 monoclonal antibody MR1.


RESULTS
Preimmunization with CM but not control ovalbumin abrogated the graft prolonging effects of DST/MR1, whether administered 2 weeks or more than 6 weeks before transplantation. Adoptive transfer of spleen cells from CM-immunized mice into naïve recipients had similar effects. CM-specific immunity did not cross-react with donor antigens and preimmunization with CM had no impact on the survival or histology of DST/MR1-treated syngeneic heart grafts, the latter indicating that persistent autoimmunity is insufficient to cause rejection in the context of costimulatory blockade. We observed that the CM preimmunized mice produced higher frequencies of donor-reactive T cells with higher ratios of CD8/CD4Foxp3 cells, suggesting that the autoreactive memory T cells provide help for activation of alloreactive T cells despite the costimulatory blockade.


CONCLUSIONS
These mechanistic insights linking autoimmunity and alloimmunity in a model of murine heart transplantation have clinical relevance to the known association between autoimmunity and an elevated risk of acute and chronic heart transplant injury in humans.
1 Division of Nephrology, Department of Medicine, The Immunology Institute, The Recanati-Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, New York, NY. 2 Address correspondence to: Peter S. Heeger, M.D., Division of Nephrology, Department of Medicine, The Immunology Institute, The Recanati-Miller Transplant Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1243, New York, NY 10029.
Safa
S
Kalache
Parth
P
Lakhani
Peter S
PS
Heeger
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001324:Autoantigens / Q000008:administration & dosage / Q000276:immunology*; D015551:Autoimmunity / Q000187:drug effects*; D023201:CD40 Ligand / Q000276:immunology*; D024722:Cardiac Myosins / Q000008:administration & dosage / Q000276:immunology*; D002478:Cells, Cultured; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000009:adverse effects; D007114:Immunization / Q000379:methods*; D007156:Immunologic Memory / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D013997:Time Factors
D000911:Antibodies, Monoclonal; D001324:Autoantigens; D007166:Immunosuppressive Agents; D023201:CD40 Ligand; D024722:Cardiac Myosins