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Induction of operational tolerance to discordant dopaminergic porcine xenografts.

Larsson, Lena C; Corbascio, Matthias; Pearson, Thomas C; Larsen, Christian P; Ekberg, Henrik LU and Widner, Håkan LU (2003) In Transplantation 75(9). p.1448-1454
Abstract
BACKGROUND: Porcine embryonic neural tissue transplanted intracerebrally could potentially relieve the symptoms of Parkinson's disease if the immune response toward the graft could be overcome. However, conventional immunosuppressive treatments have proven inefficient in preventing rejection. An alternative is blocking the costimulatory signals for lymphocyte activation. Treatment with cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA4Ig) and anti-CD40L has been successful in preventing rejection of xenografts in some experimental studies, but not all. Lymphocyte function antigen (LFA)-1 is an important costimulatory molecule for CD8+ T cells, and we hypothesize that blockade with anti-LFA-1 may enhance the efficacy of CTLA4Ig and... (More)
BACKGROUND: Porcine embryonic neural tissue transplanted intracerebrally could potentially relieve the symptoms of Parkinson's disease if the immune response toward the graft could be overcome. However, conventional immunosuppressive treatments have proven inefficient in preventing rejection. An alternative is blocking the costimulatory signals for lymphocyte activation. Treatment with cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA4Ig) and anti-CD40L has been successful in preventing rejection of xenografts in some experimental studies, but not all. Lymphocyte function antigen (LFA)-1 is an important costimulatory molecule for CD8+ T cells, and we hypothesize that blockade with anti-LFA-1 may enhance the efficacy of CTLA4Ig and anti-CD40L therapy. METHODS: C57BL/6 mice received intracerebral transplants of ventral mesencephalic tissue from embryonic porcine donors. CTLA4Ig, anti-CD40L, and anti-LFA-1 were administered every other day on days 0 to 8, and the transplants were studied after 4 to 6 weeks. Grafts were histologically analyzed for size, survival of dopaminergic nerve cells, and immune responses. Recipients were challenged with cultured glia cells of donor origin or an allogeneic skin graft to evaluate tolerance induction. RESULTS: Mice treated with all three substances had large grafts containing high amounts of dopamine cells but a low degree of immune response. Grafts in recipients challenged with glial cells showed an increased immunologic activity but were not rejected. Triple-treated mice showed a normal rejection process of the allogeneic skin grafts. CONCLUSION: After a short course of costimulation blocking therapy, discordant neural xenografts demonstrate long-term survival, withstand immunologic challenge, yet maintain host-versus-graft reactivity. Anti-LFA-1 complements CTLA4Ig and anti-CD40L in the induction of operational tolerance to these xenografts. (Less)
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keywords
CD40 Ligand: immunology, Brain Tissue Transplantation, Animal, Non-U.S. Gov't, Swine, Transplantation, Inbred C57BL, Skin Transplantation, Support, Heterologous: immunology, Dopamine: analysis, Fetal Tissue Transplantation, Graft Survival, Immunoconjugates: therapeutic use, Immunosuppression: methods, Lymphocyte Function-Associated Antigen-1: immunology, Mesencephalon: transplantation, Mice
in
Transplantation
volume
75
issue
9
pages
1448 - 1454
publisher
Lippincott Williams & Wilkins
external identifiers
  • wos:000183038400006
  • pmid:12792495
  • scopus:0037572259
ISSN
1534-6080
DOI
language
English
LU publication?
yes
id
f1ab16d4-d20a-4080-86db-2c56f80bd378 (old id 116067)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12792495&dopt=Abstract
date added to LUP
2007-07-16 13:59:13
date last changed
2018-05-29 10:11:03
@article{f1ab16d4-d20a-4080-86db-2c56f80bd378,
  abstract     = {BACKGROUND: Porcine embryonic neural tissue transplanted intracerebrally could potentially relieve the symptoms of Parkinson's disease if the immune response toward the graft could be overcome. However, conventional immunosuppressive treatments have proven inefficient in preventing rejection. An alternative is blocking the costimulatory signals for lymphocyte activation. Treatment with cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA4Ig) and anti-CD40L has been successful in preventing rejection of xenografts in some experimental studies, but not all. Lymphocyte function antigen (LFA)-1 is an important costimulatory molecule for CD8+ T cells, and we hypothesize that blockade with anti-LFA-1 may enhance the efficacy of CTLA4Ig and anti-CD40L therapy. METHODS: C57BL/6 mice received intracerebral transplants of ventral mesencephalic tissue from embryonic porcine donors. CTLA4Ig, anti-CD40L, and anti-LFA-1 were administered every other day on days 0 to 8, and the transplants were studied after 4 to 6 weeks. Grafts were histologically analyzed for size, survival of dopaminergic nerve cells, and immune responses. Recipients were challenged with cultured glia cells of donor origin or an allogeneic skin graft to evaluate tolerance induction. RESULTS: Mice treated with all three substances had large grafts containing high amounts of dopamine cells but a low degree of immune response. Grafts in recipients challenged with glial cells showed an increased immunologic activity but were not rejected. Triple-treated mice showed a normal rejection process of the allogeneic skin grafts. CONCLUSION: After a short course of costimulation blocking therapy, discordant neural xenografts demonstrate long-term survival, withstand immunologic challenge, yet maintain host-versus-graft reactivity. Anti-LFA-1 complements CTLA4Ig and anti-CD40L in the induction of operational tolerance to these xenografts.},
  author       = {Larsson, Lena C and Corbascio, Matthias and Pearson, Thomas C and Larsen, Christian P and Ekberg, Henrik and Widner, Håkan},
  issn         = {1534-6080},
  keyword      = {CD40 Ligand: immunology,Brain Tissue Transplantation,Animal,Non-U.S. Gov't,Swine,Transplantation,Inbred C57BL,Skin Transplantation,Support,Heterologous: immunology,Dopamine: analysis,Fetal Tissue Transplantation,Graft Survival,Immunoconjugates: therapeutic use,Immunosuppression: methods,Lymphocyte Function-Associated Antigen-1: immunology,Mesencephalon: transplantation,Mice},
  language     = {eng},
  number       = {9},
  pages        = {1448--1454},
  publisher    = {Lippincott Williams & Wilkins},
  series       = {Transplantation},
  title        = {Induction of operational tolerance to discordant dopaminergic porcine xenografts.},
  url          = {http://dx.doi.org/},
  volume       = {75},
  year         = {2003},
}