Simultaneous inhibition of B7 and LFA-1 signaling prevents rejection of discordant neural xenografts in mice lacking CD40L.
Transplantation of embryonic human neural tissue can restore dopamine neurotransmission and improve neurological function in patients with Parkinson's disease. Logistical and ethical factors limit the availability of human embryonic allogeneic tissue. Embryonic xenogeneic neural tissue from porcine donors is an alternative form of donor tissue, but effective immunomodulatory techniques are warranted for neural xenotransplantation to become clinically feasible. We transplanted embryonic porcine ventral mesencephalic tissue into the brains of adult untreated C57BL/6 mice, untreated CD40L-/-mice and CD40L-/-mice that received injections of anti-LFA-1, CTLA41g or both compounds. Double-treated CD40L-/-mice had large grafts with high numbers of dopaminergic neurons 4 wk after transplantation. The grafts were completely devoid of lymphocytes, macrophages and activated microglia. Untreated C57BL/6 mice had rejected their grafts. Untreated CD40L-/-mice and CD40L-/-mice treated with monotherapy of anti-LFA-1 or CTLA41g had smaller grafts and more microglial and lymphocytic infiltration than double-treated CD40L-/-mice. We conclude that immunomodulation with concomitant inhibition of LFA-1 and B7 signaling in the perioperative period in CD40L-/-mice prevented the rejection of discordant neural xenografts. The treatment most likely reduced antigen presenting capacity and interfered with the costimulatory signaling needed for T cell activation to occur.
Larsson
Lena C
LC
Section for Neuronal Survival, Wallenberg Neuroscience Center, Lund University, Sweden. Lena.Larsson@mphy.lu.se
Corbascio
Matthias
M
Widner
Håkan
H
Pearson
Thomas C
TC
Larsen
Christian P
CP
Ekberg
Henrik
H
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D018122:B7-1 Antigen / Q000235:genetics / Q000502:physiology*; D051940:B7-2 Antigen; D016380:Brain Tissue Transplantation / Q000276:immunology* / Q000379:methods / Q000473:pathology; D015704:CD4 Antigens / Q000032:analysis; D023201:CD40 Ligand / Q000235:genetics / Q000502:physiology*; D016827:CD8 Antigens / Q000032:analysis; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D015398:Signal Transduction / Q000276:immunology*; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*
D015703:Antigens, CD; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D015704:CD4 Antigens; D016827:CD8 Antigens; C497964:CD86 protein, human; C497965:Cd86 protein, mouse; D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; D023201:CD40 Ligand