Document Detail


The effect of CD28/B7 blockade on alloreactive T and B cells after liver cell transplantation.
MedLine Citation:
PMID:  11330546     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Hepatocyte cell lines are beginning to be developed as universal donors for isolated liver cell transplantation, which is a less invasive method than orthotopic liver transplantation for treatment of metabolic liver disease. The immune response to isolated liver cell transplantation and its modification by costimulatory blockade are as yet not well delineated.
METHODS: Adenovirus expressing CTLA4Ig was used to study blockade of the costimulatory CD28/B7 pathway in murine models of hepatocyte transplantation, and the effects on alloreactive T and B cells were studied.
RESULTS: CTLA4Ig delayed rejection of subcutaneously administered C57L-derived murine hepatoma cells in CBA/J recipients for >50 days. Activation and cytokine secretion by allospecific CD4+ and CD8+ T cells were initially blocked by CTLA4Ig; delayed rejection was associated with tumor infiltration by CD8+ T cells that did not secrete interferon-gamma. CTLA4Ig failed to block transplant rejection in primed mice, indicating that memory effector T cells were resistant to its action. In contrast, CTLA4Ig suppressed both naive and memory alloreactive B cells. High levels of CTLA4Ig mediated acceptance of hepatoma cells delivered directly into the spleen. However, isolated primary C57BL/6 mouse hepatocytes delivered into the spleen were rejected with only moderately delayed kinetics.
CONCLUSIONS: Transplant antigenicity, transplant site, and CTLA4Ig dose all affected the survival of transplanted liver cells. CD8+ T cells are significant mediators of hepatocyte transplant rejection and are relatively resistant to costimulatory blockade with CTLA4Ig. Strategies to specifically antagonize CD8+ T cells or to modulate MHC class I expression in association with costimulatory blockade by CTLA4Ig may enhance the clinical feasibility of transplanting allogeneic hepatocytes.
Authors:
B Reddy; S Gupta; Y Chuzhin; A M Kalergis; L Budhai; M Zhang; G Droguett; M S Horwitz; J R Chowdhury; S G Nathenson; A Davidson
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Transplantation     Volume:  71     ISSN:  0041-1337     ISO Abbreviation:  Transplantation     Publication Date:  2001 Mar 
Date Detail:
Created Date:  2001-05-01     Completed Date:  2001-06-28     Revised Date:  2013-05-24    
Medline Journal Info:
Nlm Unique ID:  0132144     Medline TA:  Transplantation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  801-11     Citation Subset:  IM    
Affiliation:
Department of Medicine, Marion Bessin Research Liver Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, CD
Antigens, CD28 / pharmacology*
Antigens, CD80 / pharmacology*
Antigens, Differentiation / blood,  pharmacology
B-Lymphocytes / drug effects,  immunology,  physiology
CTLA-4 Antigen
Graft Rejection
Hepatocytes / transplantation*
Immunoconjugates*
Immunoglobulin G / blood,  pharmacology
Isoantigens / immunology
Liver Transplantation / immunology
Mice
Mice, Inbred C57BL
Mice, Inbred CBA
Mice, SCID
T-Lymphocytes / drug effects,  immunology,  physiology
Transplantation, Homologous / immunology
Tumor Cells, Cultured / immunology,  transplantation
Grant Support
ID/Acronym/Agency:
R01AI42295/AI/NIAID NIH HHS; R01DK46057/DK/NIDDK NIH HHS; R01DK46952/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, CD; 0/Antigens, CD28; 0/Antigens, CD80; 0/Antigens, Differentiation; 0/CTLA-4 Antigen; 0/Ctla4 protein, mouse; 0/Immunoconjugates; 0/Immunoglobulin G; 0/Isoantigens; 7D0YB67S97/abatacept

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