Central tolerance to myogenic cell transplants does not include muscle neoantigens.
BACKGROUND
Duchenne muscular dystrophy is a fatal genetic disease caused by lack of dystrophin. Myogenic cell transplantation (MT), a potential therapy for Duchenne muscular dystrophy, can restore dystrophin expression in muscles. Because allogeneic MT is highly resistant to peripheral tolerance, we proposed to induce central tolerance. However, given its immunogenicity, we asked whether central tolerance to donor major histocompatibility complex would allow long-term expression of dystrophin, a tissue-specific neoantigen in dystrophic recipients.


METHODS
Central tolerance was induced in C57BL/10J mdx (dystrophic) mice by allogeneic bone marrow transplantation (BMT) after conditioning with either lethal total body irradiation (TBI) or an established nonmyeloablative protocol (anti-CD154, anti-CD8 mAbs, and low-dose TBI). Recipients subsequently received donor-strain MT or skin grafts.


RESULTS
Long-term hematopoietic chimeras generated using either lethal TBI or the nonmyeloablative regimen were tolerant to donor skin grafts and both primary and secondary donor MT (>90 days). Myogenic cell transplantation survival was decreased when chimerism was transient, which was most common with nonmyeloablative conditioning and fully rather than haplo-mismatched donors. Interestingly, regardless of conditioning, MT was associated with localized muscle infiltration with Foxp3CD4, CD25CD4, and PerforinCD8 cells, whereas skin grafts lacked infiltration.


CONCLUSIONS
Central tolerance achieved using regimens that eliminate nearly all endogenous peripheral lymphocytes (i.e., lethal irradiation) or a nonmyeloablative protocol that depleted peripheral CD8 cells, results in lymphocytic infiltration in muscles that received MT but not in skin allografts. This suggests that muscle-specific infiltration may result from lack of negative selection for peripheral neoantigens in the thymus after BMT and that tolerance after MT may rely on peripheral regulatory mechanisms.
Camirand
Geoffrey
G
Internal Medicine, Yale University School of Medicine, New Haven, CT, USA.
Stéphan
Lionel
L
Rousseau
Joël
J
Sackett
Mélanie K
MK
Caron
Nicolas J
NJ
Mills
Philippe
P
Kurtz
Josef
J
Sykes
Megan
M
Rothstein
David M
DM
Tremblay
Jacques P
JP
D000818:Animals; D000941:Antigens / Q000276:immunology*; D016026:Bone Marrow Transplantation / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D023201:CD40 Ligand / Q000276:immunology; D016827:CD8 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D017690:Cell Transplantation; D002678:Chimera / Q000276:immunology; D004195:Disease Models, Animal; D016189:Dystrophin / Q000276:immunology* / Q000378:metabolism; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology* / Q000528:radiation effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D009137:Muscular Dystrophy, Animal / Q000276:immunology / Q000473:pathology / Q000601:surgery; D016038:Skin Transplantation / Q000276:immunology; D014916:Whole-Body Irradiation
D000941:Antigens; D016827:CD8 Antigens; D016189:Dystrophin; D023201:CD40 Ligand