Abstract | BACKGROUND: Previous studies have shown that blockade of LIGHT, a T-cell costimulatory molecule belonging to the tumor necrosis factor (TNF) superfamily, by soluble lymphotoxin beta receptor-Ig (LTbetaR-Ig) inhibited the development of graft-versus-host disease. The cardiac allografts were significantly prolonged in LIGHT deficient mice. No data are yet available regarding the role of the LIGHT/HVEM pathway in more stringent fully allogeneic models such as skin and islet transplantation models. METHODS:
Streptozotocin-induced chemical diabetic BALB/C mice underwent transplantation with allogeneic C57BL/6 islets and were treated with LTbetaR-Ig, CTLA4-Ig or a combination of both in the early peritransplant period. RESULTS: Administration of CTLA4-Ig or LTbeta R-Ig alone only increased graft survival to 55 days and 27 days respectively, whereas simultaneous blockade of both pathways significantly prolonged the islet allograft survival for more than 100 days. Long-term survivors were retransplanted with donor-specific (C57BL/6) islets and the grafted islets remained functional for more than 100 days. All of islet allografts were protected against rejection when the mixtures of 1x10(6) CD4+ T cells from tolerant mice and islet allografts were cotransplanted under the renal capsule of the naïve BALB/c recipients. CONCLUSIONS: These data indicate that: 1) a synergistic effect for prolonged graft survival can be obtained by simultaneously blocking LIGHT and CD28 signaling in the stringent model of islet allotransplantation; 2) development of donor-specific immunological tolerance is associated with the presence of regulatory T-cell activity; and 3) local cotransplantation of the allografts with the regulatory T cells can effectively prevent allograft rejection and induce donor-specific tolerance in lymphocytes-sufficient recipients.
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Authors | Kexing Fan, Hao Wang, Huafeng Wei, Qian Zhou, Geng Kou, Sheng Hou, Weizhu Qian, Jianxin Dai, Bohua Li, Yanyun Zhang, Tongyu Zhu, Yajun Guo |
Journal | Transplantation
(Transplantation)
Vol. 84
Issue 6
Pg. 746-54
(Sep 27 2007)
ISSN: 0041-1337 [Print] United States |
PMID | 17893608
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antibodies, Monoclonal
- B7-1 Antigen
- CD28 Antigens
- Immunoconjugates
- Immunoglobulins
- Immunosuppressive Agents
- Receptors, Tumor Necrosis Factor, Member 14
- Abatacept
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Topics |
- Abatacept
- Animals
- Antibodies, Monoclonal
- B7-1 Antigen
(drug effects)
- CD28 Antigens
(drug effects)
- Graft Survival
- Immunoconjugates
(administration & dosage)
- Immunoglobulins
(administration & dosage)
- Immunosuppressive Agents
(administration & dosage)
- Islets of Langerhans Transplantation
- Mice
- Mice, Inbred BALB C
- Phenotype
- Receptors, Tumor Necrosis Factor, Member 14
(antagonists & inhibitors)
- T-Lymphocytes, Regulatory
(immunology)
- Transplantation Tolerance
(drug effects)
- Transplantation, Homologous
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