Induction of operational tolerance to discordant dopaminergic porcine xenografts.
BACKGROUND
Porcine embryonic neural tissue transplanted intracerebrally could potentially relieve the symptoms of Parkinson's disease if the immune response toward the graft could be overcome. However, conventional immunosuppressive treatments have proven inefficient in preventing rejection. An alternative is blocking the costimulatory signals for lymphocyte activation. Treatment with cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA4Ig) and anti-CD40L has been successful in preventing rejection of xenografts in some experimental studies, but not all. Lymphocyte function antigen (LFA)-1 is an important costimulatory molecule for CD8+ T cells, and we hypothesize that blockade with anti-LFA-1 may enhance the efficacy of CTLA4Ig and anti-CD40L therapy.


METHODS
C57BL/6 mice received intracerebral transplants of ventral mesencephalic tissue from embryonic porcine donors. CTLA4Ig, anti-CD40L, and anti-LFA-1 were administered every other day on days 0 to 8, and the transplants were studied after 4 to 6 weeks. Grafts were histologically analyzed for size, survival of dopaminergic nerve cells, and immune responses. Recipients were challenged with cultured glia cells of donor origin or an allogeneic skin graft to evaluate tolerance induction.


RESULTS
Mice treated with all three substances had large grafts containing high amounts of dopamine cells but a low degree of immune response. Grafts in recipients challenged with glial cells showed an increased immunologic activity but were not rejected. Triple-treated mice showed a normal rejection process of the allogeneic skin grafts.


CONCLUSIONS
After a short course of costimulation blocking therapy, discordant neural xenografts demonstrate long-term survival, withstand immunologic challenge, yet maintain host-versus-graft reactivity. Anti-LFA-1 complements CTLA4Ig and anti-CD40L in the induction of operational tolerance to these xenografts.
Larsson
Lena C
LC
Section for Neuronal Survival, Wallenberg Neuroscience Center, Lund University, Sweden.
Corbascio
Matthias
M
Pearson
Thomas C
TC
Larsen
Christian P
CP
Ekberg
Henrik
H
Widner
Håkan
H
D000069594:Abatacept; D000818:Animals; D016380:Brain Tissue Transplantation; D023201:CD40 Ligand / Q000276:immunology; D004298:Dopamine / Q000032:analysis*; D016332:Fetal Tissue Transplantation; D006085:Graft Survival; D018796:Immunoconjugates / Q000627:therapeutic use; D007165:Immunosuppression Therapy / Q000379:methods*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D008636:Mesencephalon / Q000637:transplantation*; D051379:Mice; D008810:Mice, Inbred C57BL; D016038:Skin Transplantation; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*
D018796:Immunoconjugates; D016169:Lymphocyte Function-Associated Antigen-1; D023201:CD40 Ligand; D000069594:Abatacept; D004298:Dopamine