The mechanism of specific prolongation of class I-mismatched skin grafts induced by retroviral gene therapy.
In the present study, we examine the mechanism of specific hyporesponsiveness to major histocompatibility complex (MHC) class I-mismatched skin allografts induced by retrovirus-mediated gene transfer of an allogeneic class I gene into syngeneic bone marrow (BM). Using appropriate congenic recombinant mouse strains, we have mapped MHC determinants that are capable of restoring rapid rejection of Kb-bearing skin grafts. Our results indicate that either a single class I or a single class II alloantigen expressed on skin in association with Kb is able to restore the rapid rejection of Kb-mismatched skin grafts. These data suggest that third-party alloantigens expressed on skin in association with Kb abrogate hyporesponsiveness by providing T cell help. Consistent with this interpretation, spleen cells from mice reconstituted with Kb-transduced BM were unable to elicit a significant anti-Kb cytotoxic T lymphocyte response in vitro unless interleukin-2 was added to the culture medium. Skin graft survival was also analyzed on B10. AKM mice thymectomized 3-4 weeks post-reconstitution with Kb-transduced BM. Thymectomy did not result in significantly prolonged survival of B10. MBR skin grafts compared to euthymic controls, suggesting that even early after reconstitution, intrathymic deletion of Kb-reactive T cells must have been incomplete. Taken together, these data suggest that prolongation of skin allograft survival in this model is controlled at the level of T cell help.
Mayfield
R S
RS
Transplantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, Boston 02129, USA.
Hayashi
H
H
Sawada
T
T
Bergen
K
K
LeGuern
C
C
Sykes
M
M
Sachs
D H
DH
Iacomini
J
J
D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology; D005260:Female; D015316:Genetic Therapy; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology; D006085:Graft Survival / Q000276:immunology*; D006183:H-2 Antigens / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D006650:Histocompatibility Testing; D007108:Immune Tolerance / Q000235:genetics; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D012190:Retroviridae / Q000235:genetics*; D016038:Skin Transplantation / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology
D006183:H-2 Antigens; C032876:H-2Kb protein, mouse