Selection of lowly immunogenic and highly tolerogenic donor and recipient allochimeric class I major histocompatibility complex proteins
| Autor: | Stanislaw M. Stepkowski, Barton W. Trawick, John Perez, Mou-Er Wang, Barry D. Kahan, S. Janczewska, Ping Song |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Graft Rejection
Male endocrine system Time Factors Recombinant Fusion Proteins medicine.medical_treatment Major histocompatibility complex Subcutaneous injection Histocompatibility Antigens medicine Animals Transplantation Homologous Receptor Heart transplantation chemistry.chemical_classification Transplantation Polymorphism Genetic biology Interleukin Rats Inbred Strains Molecular biology Tissue Donors Protein Structure Tertiary Rats Histocompatibility Amino acid chemistry Immunology biology.protein Cytokines Heart Transplantation Transplantation Tolerance |
| Zdroj: | Transplantation. 76:1201-1207 |
| ISSN: | 0041-1337 |
| DOI: | 10.1097/01.tp.0000082544.46595.f7 |
| Popis: | Background, Ten different highly polymorphic amino acids (AAs) are located in the al (α 1h ) and a2 (α 2h ) helical regions of the class I major histocompatibility complex RT1.A n rat alloantigen. We examined the potential of α 1h -RT1.A n versus α 2h -RT1.A n polymorphic AAs to induce accelerated rejection or tolerance of heart allografts. Methods. The allochimeric α 1h 52-90 n -RT1.A c and α 2h 148-179 n -RT1.A c cDNAs were produced by the substitution of nucleotides encoding recipient RT1.A c AAs for donor RT1.A n AAs. Allochimeric and wild-type (WT)-RT1.A n proteins were generated in an Escherichia coli expression system. Results. A single portal vein administration of 100 μg α 1h 52-90 n -RT1.A c protein in combination with a 7-day course of oral cyclosporine A (4 mg/kg) induced tolerance to Brown Norway (BN) (RT1 n ) heart allografts in PVG (RT1 c ) recipients more effectively than did WT-RT1.A n protein; α 2h 148-179 n -RT1.A c protein was ineffective. However, subcutaneous injection of 100 μg WT-RT1.A n (but neither α 1h 52-90 n -RT1.A c nor α 2h 148-179 n -RT1.A c ) protein induced accelerated rejection of BN heart allografts. Untreated PVG recipients of BN heart allografts displayed activation of both interleukin (IL)-2- and interferon-γ-producing T helper (Th) 1 cells and IL-4- and IL-10-producing Th2 cells on days 5, 7, and 14 postgrafting, as measured by an enzyme-linked immunospot assay. In contrast, in comparison with rejectors, tolerant recipients showed down-regulation of Th1 cells and up-regulation of Th2 cells on days 5, 7, 14, and 200 postgrafting. Histology of heart allografts showed that tolerant BN heart allografts had no evidence of acute or chronic rejection when examined on day 100 after transplantation. Conclusions. The poorly immunogenic α 1h 52-90 n -RT1.A c allochimeric protein induces tolerance by selective activation of regulatory Th2 cells. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|