Xenografts of MHC-deficient mouse embryonic mesencephalon improve behavioral recovery in hemiparkinsonian rats.
The limited availability of human embryonic tissue for dopamine cell transplants in Parkinson's patients has led to an increased interest in using xenogeneic donor tissue. Unfortunately, without aggressive immunosuppression, such brain xenografts are rejected by the host immune system. Chronic brain xenograft rejection is largely mediated by helper T cells, which require presentation of xenoantigens by major histocompatability complex (MHC) class II for their activation. We examined survival and function of xenografts of E13 mouse mesencephalon deficient in either MHC class I, class II, or both after transplantation into adult hemiparkinsonian rats without immunosuppression. Recipients received grafts from C57BL/6 mice that were either: 1) wild-type (wt), 2) MHC class I knockout (KO), 3) MHC class II KO, 4) MHC class I and II double KO, or 5) saline sham transplants. At 6 weeks after transplantation, recipients of MHC class I KO, class II KO, and double KO xenografts significantly reduced methamphetamine-induced circling rate while rats with wt xenografts and sham-operated rats showed no improvement. MHC class II KO grafts had the greatest number of surviving dopamine neurons. All transplants, including saline sham controls, contained infiltrating host MHC class II-positive cells. Saline sham grafts and MHC class II KO xenografts contained significantly fewer infiltrating host MHC class II-positive cells than did wt grafts. Our results show that MHC class II-deficient xenografts survive transplantation for at least 6 weeks in the absence of immunosuppression, reduce rotational asymmetry, and provoke lesser immune reaction than wt grafts.
Veng
Lone M
LM
Department of Medicine, University of Colorado School of Medicine, Denver 80262, USA.
Bjugstad
Kimberly B
KB
Freed
Curt R
CR
Marrack
Philippa
P
Clarkson
Edward D
ED
Bell
K Patricia
KP
Hutt
Cindy
C
Zawada
W Michael
WM
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism / Q000601:surgery; D004298:Dopamine / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007150:Immunohistochemistry; D008285:Major Histocompatibility Complex / Q000235:genetics* / Q000276:immunology; D008297:Male; D008636:Mesencephalon / Q000166:cytology / Q000196:embryology / Q000637:transplantation*; D008694:Methamphetamine / Q000633:toxicity; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000737:chemistry / Q000378:metabolism; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease / Q000276:immunology / Q000628:therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D013565:Sympatholytics / Q000494:pharmacology; D013997:Time Factors; D014183:Transplantation, Heterologous / Q000276:immunology*; D016042:Transplantation, Heterotopic / Q000276:immunology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000949:Histocompatibility Antigens Class II; D013565:Sympatholytics; D008694:Methamphetamine; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine