Rapamycin ameliorates the CTLA4-Ig–mediated defect in CD8+ T Cell Immunity During Gammaherpesvirus Infection
| Autor: | B. S. Wakeman, Mandy L. Ford, Maylene E. Wagener, S. H. Speck, David F. Pinelli |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
chemical and pharmacologic phenomena
CD8-Positive T-Lymphocytes Belatacept Article Virus Abatacept Mice Gammaherpesvirinae Immune system Immunity Animals Immunology and Allergy Cytotoxic T cell Medicine CTLA-4 Antigen Pharmacology (medical) Sirolimus Transplantation business.industry CD28 Herpesviridae Infections Immunology Drug Therapy Combination business Viral load Immunosuppressive Agents CD8 medicine.drug |
| Zdroj: | American Journal of Transplantation. 15:2576-2587 |
| ISSN: | 1600-6135 |
| Popis: | Latent viral infections are a major concern among immunosuppressed transplant patients. During clinical trials with belatacept, a CTLA4-Ig fusion protein, patients showed an increased risk of Epstein-Barr virus-associated posttransplant lymphoproliferative disorder, thought to be due to a deficient primary CD8(+) T cell response to the virus. Using a murine model of latent viral infection, we observed that rapamycin treatment alone led to a significant increase in virus-specific CD8(+) T cells, as well as increased functionality of these cells, including the ability to make multiple cytokines, while CTLA4-Ig treatment alone significantly dampened the response and inhibited the generation of polyfunctional antigen-specific CD8(+) T cells. However, the addition of rapamycin to the CTLA4-Ig regimen was able to quantitatively and qualitatively restore the antigen-specific CD8(+) T cell response to the virus. This improvement was physiologically relevant, in that CTLA4-Ig treated animals exhibited a greater viral burden following infection that was reduced to levels observed in untreated immunocompetent animals by the addition of rapamycin. These results reveal that modulation of T cell differentiation though inhibition of mTOR signaling can restore virus-specific immune competence even in the absence of CD28 costimulation, and have implications for improving protective immunity in transplant recipients. |
| Databáze: | OpenAIRE |
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