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“Telomerase-Based Therapy for Enhancing Immunity”

“Telomerase-Based Therapy for Enhancing Immunity”. by Steven Fauce, Ph.D. Department of Pathology and Laboratory Medicine David Geffen School of Medicine UCLA Monday, April 14, 2008; 8:00 PM Los Angeles Gerontology Research Group. Cells of the Immune System. Cells of the Immune System.

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“Telomerase-Based Therapy for Enhancing Immunity”

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  1. “Telomerase-Based Therapy for Enhancing Immunity” by Steven Fauce, Ph.D. Department of Pathology and Laboratory Medicine David Geffen School of Medicine UCLA Monday, April 14, 2008; 8:00 PM Los Angeles Gerontology Research Group

  2. Cells of the Immune System

  3. Cells of the Immune System

  4. Cells of the Immune System

  5. Cells of the Immune System

  6. Cells of the Immune System CD4+ CD8+

  7. Cells of the Immune System CD4+ CD8+

  8. CD8

  9. CD8

  10. Repeated stimulation of T cells T antigen T T T Infected Cell T T T T T T T T T T T T T T T T T T T T T T senescence

  11. Repeated stimulation of T cells T antigen T T T Infected Cell T T T T T T T T T T T T T T T T T T T T T T

  12. Repeated stimulation of T cells T antigen T T T Infected Cell T T T T T T T T T T T T T T T T T T T T T T

  13. Repeated stimulation of T cells T T T T Infected Cell Infected Cell T T T T T T T T T T T T T T T T T T T T T T

  14. Repeated stimulation of T cells T T T T Infected Cell Infected Cell T T T T T T T T T T T T T T T T Infected Cell T T T T T T senescence

  15. Replicative senescence • Irreversible state of growth arrest • Consequence of cell division • Normal human somatic cells • Altered function and gene expression • SHORTENED TELOMERES

  16. Telomeres • repeated series of DNA at chromosome ends • essential for chromosomal stability • shortens during each cell division • signals replicative senescence

  17. Telomeres

  18. Telomeres

  19. Telomeres

  20. Telomeres

  21. TELOMERASE counteracts this effect Present in germ cells, stem cells, and activated immune cells

  22. TELOMERASE counteracts this effect Present in germ cells, stem cells, and activated immune cells

  23. Telomere Length and Telomerase in Chronic Infection • Many similarities in the cells of the immune system of elderly and HIV+ • HIV-infection and AIDS has been described as premature and rapid “aging” of the immune system

  24. Hypothesis Maintaining high levels of telomerase activity in CD8 T cells may allow for increased and prolonged function of the immune system during aging or chronic viral infection

  25. hTERT Transduction CD8+ + IL-2 T APC T T APC T gag/pol/env T T gag/pol/env T T T T T hTERT T T T T T T T T puromycin

  26. hTERT-transduced CD8+ cells

  27. hTERT-transduced CD8+ cells Dagarag M, Evazyan T, Rao N, Effros RB.. J. Immunol. 2004; 173: 6303-11

  28. Anti-viral function of hTERT-transduced CD8+ T cells

  29. Anti-viral function of hTERT-transduced CD8+ T cells Dagarag M, Ng H, Lubong R, Effros RB, Yang OO.. J. Virol. 2003; 77: 3077-83.

  30. Problems with Gene Therapy

  31. Problems with Gene Therapy • Logistics • Gene control and targeting issues • Gene must be long-lived and stable after integration

  32. Problems with Gene Therapy • Logistics • Gene control and targeting issues • Gene must be long-lived and stable after integration • 2) Safety Issues • - DNA integration sites • - Possibly contribute to malignancy • - Toxicity • - Immune and inflammatory responses

  33. Geron Corporation • Initial screen of natural sources to find extracts that could be considered for use in a wide range clinical therapies

  34. Geron Corporation • Initial screen of natural sources to find extracts that could be considered for use in a wide range clinical therapies • Isolated compound (TAT2) that showed the ability to increase telomerase activity in skin cells

  35. Telomerase Activity in Immune Cells

  36. Telomerase activity in T cells

  37. Telomerase activity in T cells

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