Donor-derived soluble MHC antigens plus low-dose cyclosporine induce transplantation unresponsiveness independent of the thymus by down-regulating T cell-mediated alloresponses in a rat transplantation model.
BACKGROUND
In vitro, soluble MHC (sMHC) antigens modulate and induce apoptosis in alloreactive and antigen-specific T cells, demonstrating their potency to regulate T cell-mediated immune responses. However, their efficacy to regulate immunological responses in vivo remains unclear. Here, we report that repetitive intraperitoneal injection of recombinant Lewis rat-derived MHC class I antigens in Dark Agouti (DA) rats modulates alloreactivity.


METHODS
RT1.A1 (Lewis derived) genes were cloned into mammalian expression vectors, and RT1.Aa (DA derived) genes were used to transfect a rat myeloma cell line. RT1.A1 molecules were injected intraperitoneally in DA recipients that subsequently underwent transplantation with Lewis-derived cardiac allografts.


RESULTS
Soluble class I antigens were secreted by the transfected cells and were shown to be heterodimeric, peptide-loaded, and conformationally folded. Injection of donor-derived soluble MHC significantly reduced the ability of recipient animals to mount a cytotoxic T-cell response to donor-derived tissue. More interestingly, this treatment significantly prolonged donor-graft survival and allowed 60% of treated animals to develop graft tolerance (>120 days), when donor sMHC were combined with a single subtherapeutic dosage of cyclosporine. Thymectomy of recipient animals before transplantation did not interfere with induction of peripheral tolerance.


CONCLUSIONS
Donor-derived sMHC are potential tolerogens for down-regulating the cytotoxic T-cell response of animals that undergo transplantation. Thus, these data provide for the first time a rationale for the application of directly injected sMHC in vivo to down-regulate immunological responses and aid the induction of graft tolerance.
Behrens
D
D
Corixa Corporation, Redwood City, California, USA.
Lange
K
K
Fried
A
A
Yoo-Ott
K A
KA
Richter
K
K
Fändrich
F
F
Krönke
M
M
Zavazava
N
N
D000818:Animals; D000917:Antibody Formation; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D016572:Cyclosporine / Q000008:administration & dosage* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation / Q000276:immunology*; D006649:Histocompatibility Antigens / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000494:pharmacology; D007518:Isoantibodies / Q000096:biosynthesis; D009206:Myocardium / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000502:physiology; D013950:Thymus Gland / Q000502:physiology; D014019:Tissue Donors; D014162:Transfection; D023001:Transplantation Tolerance; D014407:Tumor Cells, Cultured
D006649:Histocompatibility Antigens; D015395:Histocompatibility Antigens Class I; D007166:Immunosuppressive Agents; D007518:Isoantibodies; C038353:histocompatibility antigens RT, rat; D016572:Cyclosporine