Increased host neuronal survival and motor function in BMT Parkinsonian mice: involvement of immunosuppression.
We examined the potential of bone marrow transplantation (BMT) to rescue dopaminergic neurons in a mouse model of Parkinson's disease (PD). A BMT from mice transgenic for green fluorescent protein (GFP(+)) given either before or after administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) led to the accumulation of transplanted adult GFP(+) bone-marrow-derived cells (BMDC) in the substantia nigra, where dopaminergic neurodegeneration occurs in PD. Post-BMT, mice exposed to MPTP had substantially greater numbers of endogenous tyrosine hydroxylase-positive neuronal cell bodies in the substantia nigra and increased dopamine transporter-positive projections into the striatum compared to controls. Moreover, motor function was restored to normal within 1 month post-MPTP in BMT-treated mice assayed by a rotarod behavioral test. The effect of BMT on PD was indirect, as no evidence of BMDC fusion with or transdifferentiation into dopaminergic neurons was observed. BMDC activated by BMT or associated factors could play a trophic role in rescuing damaged cells. Alternatively, the beneficial effects of BMT are due to immunosuppression reflected by a reduction in the proportion of T-cells and a reduction of T-cell proliferation in BMT mice. These findings highlight that when immunosuppression is required for transplantation studies, the amelioration of symptoms may not be due to the transplant itself. Further, they suggest that the immune system plays a role in the development of characteristics typical of PD.
Keshet
Gilmor I
GI
Baxter Laboratory for Genetic Pharmacology, Stanford University School of Medicine, Department of Microbiology and Immunology, Stanford University, Stanford, California 94305, USA.
Tolwani
Ravi J
RJ
Trejo
Angelica
A
Kraft
Peggy
P
Doyonnas
Regis
R
Clayberger
Carol
C
Weimann
James M
JM
Blau
Helen M
HM
D000704:Analysis of Variance; D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000502:physiology; D003208:Concanavalin A / Q000494:pharmacology; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000378:metabolism; D007108:Immune Tolerance / Q000502:physiology*; D020267:MPTP Poisoning / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D051379:Mice; D008934:Mitogens / Q000494:pharmacology; D009043:Motor Activity / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D013378:Substantia Nigra / Q000378:metabolism / Q000503:physiopathology; D013601:T-Lymphocytes / Q000502:physiology; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D008934:Mitogens; D003208:Concanavalin A; D049452:Green Fluorescent Proteins; D014446:Tyrosine 3-Monooxygenase