CTLA-4 is important in maintaining long-term survival of cardiac allografts.

Authors: Chandraker, A  Huurman, V  Hallett, K  Yuan, X  Tector, AJ  Park, CH  Lu, E  Zavazava, N  Oaks, M 
Citation: Chandraker A, etal., Transplantation. 2005 Apr 27;79(8):897-903.
Pubmed: (View Article at PubMed) PMID:15849541

INTRODUCTION: CTLA-4 is a negative regulatory molecule upregulated on activated T cells; however, its role in induction and maintenance of transplant tolerance is not well understood. METHODS: The characteristics and effects of a novel mouse anti-rat CTLA-4 antibody (Ab) (242B58) were examined using fluorescence-activated cell sorter, mixed lymphocyte reaction, enzyme-linked immunospot, signaling studies, and a rat model of cardiac transplant tolerance induced by administration of anti-CD28 Ab and cyclosporine. RESULTS: The anti-CTLA4 Ab was shown to bind to CTLA-4 but not prevent subsequent binding of B7 to CTLA-4. Binding to CTLA-4 did not result in phosphorylation of early cytoplasmic tyrosine kinases, suggesting that this is not a signaling Ab. However, its in vitro function was compatible with antagonization of the effects of CTLA-4, thereby increasing T-cell proliferation and interferon-gamma production in mixed lymphocyte reaction and enzyme-linked immunospot assays, respectively. Administration of 242B58 to animals treated with anti-CD28 Ab and cyclosporine either at the time of transplantation or various time-points up to 33 days posttransplantation did not result in immediate rejection, but rather caused a delayed severe acute allograft rejection at approximately 45 days posttransplant. CONCLUSIONS: Our results seem to be a reflection of the unique properties of the 242B58 Ab, which does not antagonize B7 binding to CTLA-4 and affect its ability to out-compete CD28 for B7 binding. It does, however, seem to interfere with CTLA-4 signaling, suggesting that competition for B7 may be important in induction of tolerance, but signaling through CTLA-4 is more important in maintaining a tolerant phenotype.

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CRRD Object Information
CRRD ID: 2302005
Created: 2008-11-13
Species: All species
Last Modified: 2008-11-13
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.