Non-HLA angiotensin-type-1 receptor autoantibodies mediate the long-term loss of grafted neurons in Parkinson’s disease models
Rodríguez-Pérez, Ana I. ; Garrido-Gil, Pablo ; García-Garrote, Maria LU
; Muñoz, Ana
LU
; Parga, Juan A.
; Labandeira-García, Jose Luis
and Rodríguez-Pallares, Jannette
(2024)
In Stem Cell Research and Therapy
15(1).
- Abstract
Background: Clinical trials have provided evidence that transplants of dopaminergic precursors, which may be replaced by new in vitro stem cell sources, can integrate into the host tissue, and alleviate motor symptoms in Parkinson´s disease (PD). In some patients, deterioration of graft function occurred several months after observing a graft-derived functional improvement. Rejection of peripheral organs was initially related to HLA-specific antibodies. However, the role of non-HLA antibodies is now considered also relevant for rejection. Angiotensin-II type-1 receptor autoantibodies (AT1-AA) act as agonists of the AT1 receptors. AT1-AA are the non-HLA antibodies most widely associated with graft dysfunction or rejection after... (More)
Background: Clinical trials have provided evidence that transplants of dopaminergic precursors, which may be replaced by new in vitro stem cell sources, can integrate into the host tissue, and alleviate motor symptoms in Parkinson´s disease (PD). In some patients, deterioration of graft function occurred several months after observing a graft-derived functional improvement. Rejection of peripheral organs was initially related to HLA-specific antibodies. However, the role of non-HLA antibodies is now considered also relevant for rejection. Angiotensin-II type-1 receptor autoantibodies (AT1-AA) act as agonists of the AT1 receptors. AT1-AA are the non-HLA antibodies most widely associated with graft dysfunction or rejection after transplantation of different solid organs and hematopoietic stem cells. However, it is not known about the presence and possible functional effects of AT1-AA in dopaminergic grafts, and the effects of treatment with AT1 receptor blockers (ARBs) such as candesartan on graft survival. Methods: In a 6-hydroxydopamine PD rat model, we studied the short-term (10 days)- and long-term (3 months) effects of chronic treatment with the ARB candesartan on survival of grafted dopaminergic neurons and microglial graft infiltration, as well as the effects of dopaminergic denervation and grafting on serum and CSF AT1-AA levels. The expression of AT1 receptors in grafted neurons was determined by laser capture microdissection. Results: At the early period post-grafting, the number of grafted dopaminergic neurons that survived was not significantly different between treated and untreated hosts (i.e., control rats and rats treated with candesartan), probably because, just after grafting, other deleterious factors are predominant for dopaminergic cell death, such as mechanical trauma, lack of growth factors/nutrients and ischemia. However, several months post-grafting, we observed a significantly higher number of surviving dopaminergic neurons and a higher density of striatal dopaminergic terminals in the candesartan-treated group. For several months, grafted rats showed blood and cerebrospinal fluid levels of AT1-AA higher than normal controls, and also higher AT1-AA levels than non-grafted parkinsonian rats. Conclusions: The results suggest the use of ARBs such as candesartan in PD patients, particularly before and after dopaminergic grafts, and the need to monitor AT1-AA levels in PD patients, particularly in those candidates for dopaminergic grafting.
(Less)
- author
- Rodríguez-Pérez, Ana I.
; Garrido-Gil, Pablo
; García-Garrote, Maria
LU
; Muñoz, Ana
LU
; Parga, Juan A.
; Labandeira-García, Jose Luis
and Rodríguez-Pallares, Jannette
- publishing date
- 2024-12
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Angiotensin, AT1, Autoimmunity, Cell grafts, Cell transplantation, Microglia, Neurodegeneration, Parkinson, Rejection, Renin-angiotensin system
- in
- Stem Cell Research and Therapy
- volume
- 15
- issue
- 1
- article number
- 138
- publisher
- BioMed Central (BMC)
- external identifiers
-
- pmid:38735991
- scopus:85192894160
- ISSN
- 1757-6512
- DOI
- 10.1186/s13287-024-03751-y
- language
- English
- LU publication?
- no
- additional info
- Publisher Copyright: © The Author(s) 2024.
- id
- b581546b-6bb4-4ef9-beba-bef6deadb4de
- date added to LUP
- 2025-01-24 11:47:43
- date last changed
- 2025-07-12 12:45:41
@article{b581546b-6bb4-4ef9-beba-bef6deadb4de,
abstract = {{<p>Background: Clinical trials have provided evidence that transplants of dopaminergic precursors, which may be replaced by new in vitro stem cell sources, can integrate into the host tissue, and alleviate motor symptoms in Parkinson´s disease (PD). In some patients, deterioration of graft function occurred several months after observing a graft-derived functional improvement. Rejection of peripheral organs was initially related to HLA-specific antibodies. However, the role of non-HLA antibodies is now considered also relevant for rejection. Angiotensin-II type-1 receptor autoantibodies (AT1-AA) act as agonists of the AT1 receptors. AT1-AA are the non-HLA antibodies most widely associated with graft dysfunction or rejection after transplantation of different solid organs and hematopoietic stem cells. However, it is not known about the presence and possible functional effects of AT1-AA in dopaminergic grafts, and the effects of treatment with AT1 receptor blockers (ARBs) such as candesartan on graft survival. Methods: In a 6-hydroxydopamine PD rat model, we studied the short-term (10 days)- and long-term (3 months) effects of chronic treatment with the ARB candesartan on survival of grafted dopaminergic neurons and microglial graft infiltration, as well as the effects of dopaminergic denervation and grafting on serum and CSF AT1-AA levels. The expression of AT1 receptors in grafted neurons was determined by laser capture microdissection. Results: At the early period post-grafting, the number of grafted dopaminergic neurons that survived was not significantly different between treated and untreated hosts (i.e., control rats and rats treated with candesartan), probably because, just after grafting, other deleterious factors are predominant for dopaminergic cell death, such as mechanical trauma, lack of growth factors/nutrients and ischemia. However, several months post-grafting, we observed a significantly higher number of surviving dopaminergic neurons and a higher density of striatal dopaminergic terminals in the candesartan-treated group. For several months, grafted rats showed blood and cerebrospinal fluid levels of AT1-AA higher than normal controls, and also higher AT1-AA levels than non-grafted parkinsonian rats. Conclusions: The results suggest the use of ARBs such as candesartan in PD patients, particularly before and after dopaminergic grafts, and the need to monitor AT1-AA levels in PD patients, particularly in those candidates for dopaminergic grafting.</p>}},
author = {{Rodríguez-Pérez, Ana I. and Garrido-Gil, Pablo and García-Garrote, Maria and Muñoz, Ana and Parga, Juan A. and Labandeira-García, Jose Luis and Rodríguez-Pallares, Jannette}},
issn = {{1757-6512}},
keywords = {{Angiotensin; AT1; Autoimmunity; Cell grafts; Cell transplantation; Microglia; Neurodegeneration; Parkinson; Rejection; Renin-angiotensin system}},
language = {{eng}},
number = {{1}},
publisher = {{BioMed Central (BMC)}},
series = {{Stem Cell Research and Therapy}},
title = {{Non-HLA angiotensin-type-1 receptor autoantibodies mediate the long-term loss of grafted neurons in Parkinson’s disease models}},
url = {{http://dx.doi.org/10.1186/s13287-024-03751-y}},
doi = {{10.1186/s13287-024-03751-y}},
volume = {{15}},
year = {{2024}},
}