Cell Therapy for Parkinson's Disease: A Translational Approach to Assess the Role of Local and Systemic Immunosuppression

被引：23

作者：

Badin, R. Aron ^{[1
]}

Vadori, M. ^{[3
]}

Vanhove, B. ^{[4
,5
]}

Nerriere-Daguin, V. ^{[4
]}

Naveilhan, P. ^{[6
]}

Neveu, I. ^{[6
]}

Jan, C. ^{[1
]}

Leveque, X. ^{[4
]}

Venturi, E. ^{[7
]}

Mermillod, P. ^{[7
]}

Van Camp, N. ^{[1
]}

Dolle, F. ^{[2
]}

Guillermier, M. ^{[1
]}

Denaro, L. ^{[8
]}

Manara, R. ^{[8
]}

Citton, V. ^{[8
]}

Simioni, P. ^{[8
]}

Zampieri, P. ^{[8
]}

D'avella, D. ^{[8
]}

Rubello, D. ^{[9
]}

Fante, F. ^{[3
]}

Boldrin, M. ^{[3
]}

De Benedictis, G. M. ^{[10
]}

Cavicchioli, L. ^{[11
]}

Sgarabotto, D. ^{[12
]}

Plebani, M. ^{[13
]}

Stefani, A. L. ^{[14
]}

Brachet, P. ^{[4
]}

Blancho, G. ^{[4
,5
]}

Soulillou, J. P. ^{[4
]}

Hantraye, P. ^{[1
]}

Cozzi, E. ^{[3
,15
]}

机构：

[1] CEA, UMR 9199, MIRCen, Fontenay Aux Roses, France

[2] CEA, I2BM, Serv Hosp Frederic Joliot, Orsay, France

[3] CORIT Consortium Res Organ Transplantat, Padua, Italy

[4] INSERM, UMR1064, Nantes, France

[5] Univ Nantes, CHU Nantes, Inst Transplantat Urol Nephrol, Nantes, France

[6] INSERM, UMR913, Nantes, France

[7] INRA Physio Reprod Femelle CR Tours, Nouzilly, France

[8] Univ Padua, Neurosci, Padua, Italy

[9] S Maria della Misericordia Hosp, Nucl Med, Rovigo, Italy

[10] Univ Padua, Dept Anim Med Prod & Hlth, Legnaro, Italy

[11] Univ Padua, Dept Comparat Biomed & Food Sci, Legnaro, Italy

[12] Padua Univ Hosp, Transplant Infect Dis Unit, Padua, Italy

[13] Padua Univ Hosp, Dept Lab Med, Padua, Italy

[14] Ist Zooprofilatt Sperimentale Venezie, Legnaro, Italy

[15] Padua Univ Hosp, Transplant Immunol Unit, Padua, Italy

来源：

AMERICAN JOURNAL OF TRANSPLANTATION | 2016年 / 16卷 / 07期

关键词：

translational research; science; xenotransplantation; immunosuppression; immune modulation; immunosuppressant; other; rejection; FETAL NIGRAL TRANSPLANTATION; LONG-TERM SURVIVAL; NONHUMAN PRIMATE; STEM-CELLS; NEURAL TRANSPLANTATION; TRANSGENE EXPRESSION; MESENCEPHALIC TISSUE; IMMUNE-RESPONSES; NERVOUS-SYSTEM; RAT MODEL;

D O I：

10.1111/ajt.13704

中图分类号：

R61 [外科手术学];

学科分类号：

摘要：

Neural transplantation is a promising therapeutic approach for neurodegenerative diseases; however, many patients receiving intracerebral fetal allografts exhibit signs of immunization to donor antigens that could compromise the graft. In this context, we intracerebrally transplanted mesencephalic pig xenografts into primates to identify a suitable strategy to enable long-term cell survival, maturation, and differentiation. Parkinsonian primates received WT or CTLA4-Ig transgenic porcine xenografts and different durations of peripheral immunosuppression to test whether systemic plus graft-mediated local immunosuppression might avoid rejection. A striking recovery of spontaneous locomotion was observed in primates receiving systemic plus local immunosuppression for 6 mo. Recovery was associated with restoration of dopaminergic activity detected both by positron emission tomography imaging and histological examination. Local infiltration by T cells and CD80/86+ microglial cells expressing indoleamine 2,3-dioxigenase were observed only in CTLA4-Ig recipients. Results suggest that in this primate neurotransplantation model, peripheral immunosuppression is indispensable to achieve the long-term survival of porcine neuronal xenografts that is required to study the beneficial immunomodulatory effect of local blockade of T cell costimulation. The intragraft expression of CTLA4-Ig, a costimulation blocker, and the duration of the peripheral immunosuppressive treatment can improve cell survival and delay local xenogeneic T cell activation following intracerebral transplantation of transgenic CTLA4-Ig+/+ pig xenografts in parkinsonian nonhuman primates.

引用

页码：2016 / 2029

页数：14

共 62 条

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