Indirect allorecognition of major histocompatibility complex allopeptides in human renal transplant recipients with chronic graft dysfunction
| Autor: | J P, Vella, M, Spadafora-Ferreira, B, Murphy, S I, Alexander, W, Harmon, C B, Carpenter, M H, Sayegh |
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| Rok vydání: | 1997 |
| Předmět: |
Adult
Graft Rejection Male Isoantigens T-Lymphocytes Molecular Sequence Data DNA HLA-DR Antigens Middle Aged Lymphocyte Activation Kidney Transplantation Coculture Techniques Peptide Fragments Major Histocompatibility Complex Creatinine Immune Tolerance Humans Drug Therapy Combination Female Amino Acid Sequence Cells Cultured Immunosuppressive Agents HLA-DRB1 Chains |
| Zdroj: | Transplantation. 64(6) |
| ISSN: | 0041-1337 |
| Popis: | It has been suggested that T cells primed by processed donor major histocompatibility complex antigen (the "indirect" pathway of allorecognition) may be responsible for mediating chronic allograft rejection. The purpose of this study was to develop a clinically useful assay to study the occurrence of indirect allorecognition during chronic rejection in humans.A panel of 20 mer peptides corresponding to the hypervariable regions of HLA-DRB1*0101, DRB1*1501, and DRB1*0301 were synthesized. Lymphocytes obtained from renal allograft recipients were cocultured with these peptides. Proliferation was assayed by DNA incorporation of [3H]thymidine, and positive proliferation was defined by a statistically significant increase in counts per minute over background with a minimum stimulation index of 2. The precursor frequency of allopeptide reactive T cells was determined by limiting dilution analysis.Lymphocytes from 82% of patients who were mismatched for at least one of the three DR molecules and had chronic allograft dysfunction specifically proliferated to the mismatched allopeptides (n=11). Proliferation was seen in only 6% of control subjects (2/33, P0.0001). The proliferative response was low grade and was best detected on day 7-8 of culture in vitro. The precursor frequency of peptide-specific T cells was more than 10-fold higher compared with controls (P0.001).These data demonstrate for the first time that T cells of patients with chronic graft dysfunction are primed to recognize and respond to specific donor-derived major histocompatibility complex allopeptides. Our results support the hypothesis that T cells primed via the indirect pathway of allorecognition may be important mediators of chronic rejection and provide the rationale to develop specific therapeutic strategies to prevent or interrupt this process. |
| Databáze: | OpenAIRE |
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