Induction of operational tolerance to discordant dopaminergic porcine xenografts.
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/116067
- author
- Larsson, Lena C ; Corbascio, Matthias ; Pearson, Thomas C ; Larsen, Christian P ; Ekberg, Henrik LU and Widner, Håkan LU
- organization
- publishing date
- 2003
- type
- Contribution to journal
- publication status
- published
- subject
- 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
- 10.1097/01.TP.0000058807.45320.A2
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Neuronal Survival (013212041), Renal Research Unit (013242210), Neurology, Lund (013027000)
- 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
- 2016-04-01 15:20:24
- date last changed
- 2022-01-28 04:54:08
@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}}, 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}}, 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/10.1097/01.TP.0000058807.45320.A2}}, doi = {{10.1097/01.TP.0000058807.45320.A2}}, volume = {{75}}, year = {{2003}}, }