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Molecular basis of cross-species reactivities of human versus porcine CTLA-4
- Source :
- Human Immunology. 74:842-848
- Publication Year :
- 2013
- Publisher :
- Elsevier BV, 2013.
-
Abstract
- The binding motif of human CTLA-4 is well known to be MYPPPY and for porcine CTLA-4 the binding motif is LYPPPY. Is this single amino acid difference of methionine (M) versus leucine (L) critical for the CTLA-4 binding? Recently, we have reported that the recombinant soluble porcine CTLA-4 was incapable of binding to human CD80. In this study we mutated L to M in the binding motif of the soluble porcine CTLA-4 and mutated M to L in the binding motif of the soluble human CTLA-4. We then analyzed how these mutations affected the binding affinity of the mutants to both porcine and human CD80(+) cells. The soluble porcine CTLA-4-L97M mutant partially lost its binding affinity to porcine CD80 compared to the wild-type and conferred very weak binding ability to human CD80. These results indicate that the L in the binding motif of porcine CTLA-4 is important for determining its binding ability to porcine CD80. Wild-type soluble human CTLA-4 binds to both human and porcine CD80 with comparable affinity, however, the soluble human CTLA-4-M97L mutant almost lost its binding ability to human CD80 and increased its binding ability to porcine CD80. These results indicate that M in the human CTLA-4 binding motif is extremely critical for its binding to human CD80. Those data suggest that the human CTLA-4 based recombinant protein drugs such as human CTLA-4-Ig can be used and/or tested in a porcine model. Conversely, the use of porcine CTLA-4 based recombinant protein drugs such as porcine CTLA-4-Ig is restricted to swine models. The difference in binding specificity of CTLA-4 observed in this study may be useful for studies such as pig to nonhuman primate xeno-transplantation. Porcine CTLA-4- and human CTLA-4-M97L mutant-based recombinant protein drugs can be used to specifically block the direct presentation by donor antigen presenting cells in pig to nonhuman primate xeno-transplantation. Human CTLA-4-M97L mutant-based recombinant protein drugs will be more ideal as it is without immunogenicity to human being.
- Subjects :
- Graft Rejection
Swine
Transplantation, Heterologous
Immunology
Mutant
chemical and pharmacologic phenomena
Plasma protein binding
Cross Reactions
Biology
Article
law.invention
chemistry.chemical_compound
Species Specificity
law
Animals
Humans
Immunology and Allergy
CTLA-4 Antigen
Protein Interaction Domains and Motifs
Antigen-presenting cell
Binding selectivity
Methionine
Immunogenicity
hemic and immune systems
Organ Transplantation
General Medicine
Molecular biology
biological factors
chemistry
Drug Design
B7-1 Antigen
Mutagenesis, Site-Directed
Recombinant DNA
Immunotherapy
Leucine
Protein Binding
Subjects
Details
- ISSN :
- 01988859
- Volume :
- 74
- Database :
- OpenAIRE
- Journal :
- Human Immunology
- Accession number :
- edsair.doi.dedup.....f14d47dc64f27685d9b27e0fc296eb30