Cellular immune response to intrastriatally implanted allogeneic bone marrow stromal cells in a rat model of Parkinson's disease.
BACKGROUND
Marrow stromal cells (MSC), the non-hematopoietic precursor cells in bone marrow, are being investigated for therapeutic potential in CNS disorders. Although in vitro studies have suggested that MSC may be immunologically inert, their immunogenicity following transplantation into allogeneic recipients is unclear. The primary objective of this study was to investigate the cellular immune response to MSC injected into the striatum of allogeneic recipients (6-hydroxydopamine [6-OHDA]-hemilesioned rats, an animal model of Parkinson's disease [PD]), and the secondary objective was to determine the ability of these cells to prevent nigrostriatal dopamine depletion and associated motor deficits in these animals.


METHODS
5-Bromo-2-deoxyuridine (BrdU) - labeled MSC from two allogeneic sources (Wistar and ACI rats) were implanted into the striatum of adult Wistar rats at the same time as 6-OHDA was administered into the substantia nigra. Behavioral tests were administered one to two weeks before and 16-20 days after 6-OHDA lesioning and MSC transplantation. Immunocytochemical staining for T helper and T cytotoxic lymphocytes, microglia/macrophages, and major histocompatibility class I and II antigens was performed on post-transplantation days 22-24. MSC were detected with an anti-BrdU antibody.


RESULTS
Tissue injury due to the transplantation procedure produced a localized cellular immune response. Unexpectedly, both sources of allogeneic MSC generated robust cellular immune responses in the host striatum; the extent of this response was similar in the two allograft systems. Despite these immune responses, BrdU+ cells (presumptive MSC) remained in the striatum of all animals that received MSC. The numbers of remaining MSC tended to be increased (p = 0.055) in rats receiving Wistar MSC versus those receiving ACI MSC. MSC administration did not prevent behavioral deficits or dopamine depletion in the 6-OHDA-lesioned animals.


CONCLUSIONS
MSC, when implanted into the striatum of allogeneic animals, provoke a marked immune response which is not sufficient to clear these cells by 22-24 days post-transplantation. In the experimental paradigm in this study, MSC did not prevent nigrostriatal dopamine depletion and its associated behavioral deficits. Additional studies are indicated to clarify the effects of this immune response on MSC survival and function before initiating trials with these cells in patients with PD or other neurodegenerative disorders.
Camp
Dianne M
DM
Division of Neurology, William Beaumont Hospital Research Institute, Royal Oak, Michigan 48073, USA. campdm@yahoo.com
Loeffler
David A
DA
Farrah
Diane M
DM
Borneman
Jade N
JN
LeWitt
Peter A
PA
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation; D003342:Corpus Striatum / Q000187:drug effects / Q000276:immunology* / Q000503:physiopathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005260:Female; D008297:Male; D009043:Motor Activity; D016627:Oxidopamine; D010300:Parkinson Disease / Q000276:immunology* / Q000628:therapy*; D051381:Rats; D011912:Rats, Inbred ACI; D017208:Rats, Wistar; D017154:Stromal Cells / Q000166:cytology / Q000637:transplantation*; D014184:Transplantation, Homologous; D016896:Treatment Outcome
D016627:Oxidopamine; D004298:Dopamine