Syngeneic bone marrow transduced with a recombinant retroviral vector to express endoplasmic reticulum signal-sequence-deleted major histocompatibility complex class-I alloantigen can induce specific immunologic unresponsiveness in vivo.
Spriewald BM., Billing JS., Jenkins S., Wheeler P., Steger U., Bushell A., Hyde K., Morris PJ., Wood KJ.
BACKGROUND: Long-term survival of fully allogeneic cardiac grafts can be induced in mice through transduction of recipient bone marrow cells (BMCs) with a recombinant retroviral vector encoding a single full-length major histocompatibility complex (MHC) class I alloantigen. This study investigated whether cell surface expression of the transduced MHC antigen was necessary for the induction of specific unresponsiveness. METHOD The signal sequence for translocation into the endoplasmic reticulum was deleted from H-2K (SDELKb). Syngeneic BMCs from CBA.Ca (H2k) recipients were transduced with an MFG retroviral vector encoding either wild-type Kb or the mutant SDELKb and reinfused in conjunction with an anti-CD4 therapy. Four weeks later, the recipients underwent transplantation with a fully allogeneic C57BL/10 cardiac graft. Graft survival and the development of transplant arteriosclerosis were assessed. RESULTS: Expression of both the wild-type Kb or SDELK in recipient CBA mice before transplantation resulted in prolonged survival of C57BL/10 grafts. Grafts from recipients pretreated with SDELKb developed 48%+/-22% intimal proliferation compared with 61%+/-21% in grafts from recipients pretreated with wild-type Kb. However, this difference did not reach statistical significance. CONCLUSION Cell surface expression, and therefore direct recognition, of an MHC class I alloantigen is not required to induce long-term survival of fully allogeneic cardiac grafts after retroviral transduction of recipient BMCs.