1 / 46

Evaluation of Human Thymic Function during Health and HIV-1 Infection

Evaluation of Human Thymic Function during Health and HIV-1 Infection. Ping Ye and Denise Kirschner DIMACS Workshop 9/23/2001. Outline. Thymic function in healthy people Thymopoiesis Markers to represent recent thymic emigrants (RTE) Thymopoiesis model TREC model

valeriedawson
Download Presentation

Evaluation of Human Thymic Function during Health and HIV-1 Infection

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Evaluation of Human Thymic Function during Health and HIV-1 Infection Ping Ye and Denise Kirschner DIMACS Workshop 9/23/2001

  2. Outline • Thymic function in healthy people • Thymopoiesis • Markers to represent recent thymic emigrants (RTE) • Thymopoiesis model • TREC model • Thymic function during pediatric HIV-1 infection • HIV-1 infection • Clinical and experimental studies • Thymic infection model • Evaluation of TREC

  3. Haynes BF. Clin Immunol. 92(1):3-5,1999 The Thymus Janeway CA et al. Immunobiology 5th ed. 2001

  4. Thymopoiesis Berkowitz RD et al. J Immunol. 161(7):3702-10, 1998

  5. Recent Thymic Emigrants (RTE) • Lack of phenotypic markers for human RTE • Human RTE generally refer to T cells that have undergone only a few cellular divisions after leaving the thymus • T cell receptor excision circles (TREC) have recently been used as a measure of the number of RTE

  6. Haynes BF et al. Annu Rev Immunol. 18: 529-60, 2000 T Cell Receptor Excision Circles (TREC) Pieces of DNA fragments that are generated during TCR gene rearrangement in the thymus and then exported from the thymus to periphery within T cells episomally Janeway CA et al. Immunobiology 5th ed. 2001

  7. TREC as A Measure of RTE

  8. Parameters Estimating RTE • TREC concentration • Is affected by both RTE and peripheral T cell proliferation and death • Naïve T cells (CD45RA+, CD62L, CD95+) • May have long lifespan • May proliferate in an antigen-independent manner • May rapidly convert to memory cells • May be converted from memory cells • Thymic volume • Assuming thymic volume is proportional to RTE levels

  9. Two Questions to Address 1st Can TREC concentration be properly used as measure of RTE? 2ndWhether thymic infection with different HIV-1 strains contribute to differences in disease progression?

  10. Thymopoiesis Model Cell Source THYMUS TES(t) TN ITTP DP SP4 SP8 BLOOD/ LYMPHOID TISSUES CD4+ RTE CD8+ RTE

  11. Simulation Results for Thymopoiesis Model Thymocytes RTE/day

  12. Model Simulation Values Compared with Experimental Data

  13. SP4 SP8 TREC Model THYMUS CD4+ RTE CD8+ RTE CD4+ T cell CD8+ T cell TREC TREC BLOOD/ LYMPHOID TISSUES

  14. Simulation Results for TREC Model Douek DC et al. Nature. 369(6712):690-5, 1998. Zhang L et al. J. Exp. Med. 187(11): 1767-78, 1998

  15. Four Events Affecting TREC Concentration THYMUS SP4 SP8 1 CD4+ RTE CD8+ RTE 3 2 CD4+ T cell CD8+ T cell 4 TREC TREC BLOOD/ LYMPHOID TISSUES 1 Thymic output 2 T cell division 3 T cell death 4 TREC degradation TREC concentration is affected by

  16. TREC Can Be Equally Affected by Thymic Output and T Cell Division (at Any Age) #

  17. sjTREC cjTREC TREC Concentration during Aging Healthy Volunteers Age (years) Douek DC et al. Nature. 396(6712): 690-5, 1998

  18. Thymic Involution Induce TREC Decline (Over Entire Lifespan) TREC concentration is a good marker for RTE in healthy people

  19. SummaryThymic Function in Healthy people • Our model quantifies the number of RTE and TREC concentration over an 80-year lifespan • TREC concentration can be equally affected by thymic output and T cell division at any age • Thymic involution induces TREC concentration decline over the entire lifespan • TREC concentration is a good marker for both CD4+ and CD8+ RTE in healthy people

  20. Outline • Thymic function in healthy people • Thymopoiesis • Markers to represent recent thymic emigrants (RTE) • Thymopoiesis model • TREC model • Thymic function during pediatric HIV-1 infection • HIV-1 infection • Clinical and experimental studies • Thymic infection model • Evaluation of TREC

  21. HIV-1 Structure • Associated with AIDS • Retrovirus family • Two identical ss RNA • Enveloped virus • Antigenic variation • Infects CD4+ cells • Entry requires CD4 and coreceptor

  22. HIV-1 Entry

  23. Classification of HIV-1 Strains • R5 strain • Uses CCR5 as coreceptor • Replicates slowly and is minimally cytopathic • Is primarily transmitted • Is prevalent in the early stage of disease • X4 strain • Uses CXCR4 as coreceptor • Replicates fast and is highly cytopathic • Is rarely transmitted • Appears in approximately 50% of patients in the late stage of disease • R5X4 strain • Uses either CCR5 or CXCR4 as coreceptor • Has similar properties as the X4 strain

  24. HIV-1 Disease Progression Hypotheses for the decline of CD4+ T cells in the blood • Changes in cell migration patterns • Changes in cell life-spans • Changes in cell production by the thymus

  25. Clinical Studies of Thymic Infection with HIV-1 • TREC levels in CD4+ and CD8+ T cells decline • Naïve CD4+ and CD8+ T cell numbers decline • Thymic volume decreases • The thymus undergoes morphological changes • “Thymic dysfunction” (TD+) is described in a subset of vertically-infected infants

  26. “Thymic dysfunction” (TD+) • Two distinct modes of pediatric HIV-1 disease progression • Normal progressors10 years to AIDS(85%) • Fast progressors 2-3 years to AIDS (15%) • lower CD4+ and CD8+ counts (DiGeorge Syndrome)

  27. Experimental Studies of Thymic Infection with HIV-1 • Coreceptors • CCR5 Expressed in low levels on DP, SP4, SP8 cells • CXCR4 Expressed in high levels on ITTP, DP cells, low levels on SP4 and SP8 cells • HIV-1 strains • R5 strain Infects DP and SP4 cells Minimally cytopathic • X4 strain Infects ITTP, DP and SP4 cells Highly cytopathic • Thymocyte maturation stages • SP4,SP8 Support active viral replication • ITTP,DP Support less viral replication

  28. Two Questions to Address 1stCan TREC concentration be properly used as measure of RTE? 2nd Whether thymic infection with different HIV-1 strains contribute to differences in disease progression?

  29. R5 R5 X4 X4 Thymic Model With HIV-1 Infection Cell Source THYMUS TES(t) TN X4 ITTPX ITTP DPX DPR DP X4 R5 SP4R SP4X SP4 SP8R SP8X SP8 R5 X4 CD4+ RTE CD8+ RTE BLOOD/LYMPHOID TISSUES

  30. Virtual Pediatric Thymic Infection

  31. Simulations of CD4+ RTE Predict Bimodal Pattern of Blood CD4+ T Cell Counts

  32. Simulation Values at Year Two of Virtual Infection Compared with Experimental Data

  33. Bifurcation ParametersImplications for Treatment • Viral influx from blood into the thymus • Virulence of strains (viral infection rate and production rate) • HIV-1 induced death of uninfected thymocytes • Progenitor cells from bone marrow • Carrying capacity of the thymus

  34. sjTREC TREC Concentration during HIV-1 Infection HIV-1 Infected Subjects Age Age (years) Douek DC et al. Nature. 396(6712): 690-5, 1998

  35. Two Questions to Address 1st Can TREC concentration be properly used as measure of RTE? 2ndWhether thymic infection with different HIV-1 strains contribute to differences in disease progression?

  36. T Cell Kinetics during HIV-1 Infection We include these effects in the model to represent HIV-1 infection

  37. T Cell Counts and TREC Concentrations in HIV-1 Infected Subjects (Age 30) T cells TREC Margolick JB et al. J Acquir Immune Defic Syndr. 6(2): 153-61, 1993 Zhang L et al. J. Exp. Med. 187(11): 1767-78, 1998

  38. Model Prediction for Thymic Output during HIV-1 Infection TREC concentration is a good marker for CD4+ RTE TREC concentration is NOT a good marker for CD8+ RTE

  39. SummaryThymic Function during Pediatric HIV-1 Infection • Infection with R5 and X4 strains induces different degrees of thymic dysfunction, which is related to CD4+ T cell counts and disease progression as seen in pediatric patients • Thymic infection in pediatric patients is more severe than in adult patients, likely due to higher viral loads and a more active thymus • Suppressing viral load in blood, high drug efficacy within the thymus, and improving inherent thymic function are necessary for reconstitution of RTE levels • Protease inhibitors have high levels of efficacy directly suppressing viral replication within the thymus, while reverse transcriptase inhibitors have low efficacy • TREC concentration is a reliable marker for CD4+ RTE, but not for CD8+ RTE in HIV-1 infected subjects

  40. Conclusions • Peripheral T cell turnover should be examined together with TREC concentration as a measure of RTE • Infection with different HIV-1 strains induces different degrees of thymic dysfunction, contributing to CD4+ T cell depletion and disease progression • With adequate suppression of viral replication within both the blood and the thymus during HAART, thymic function recovery can reconstitute immune cell numbers

  41. Publications • Ping Ye and Denise Kirschner (2002). Reevaluation of T cell receptor excision circles as a measure of human recent thymic emigrants. Journal of Immunology, 168(10), 4968-4979. • Ping Ye, Athena Kourtis, and Denise Kirschner (2002). The effects of different HIV-1 strains on human thymic function. AIDS Research and Human Retroviruses, 18(17) (In press). • Ping Ye, Athena Kourtis, and Denise Kirschner . Reconstitution of thymic function in HIV-1 patients treated with highly active anti-retroviral therapy (submitted).

  42. Acknowledgments • Dr. Denise Kirschner • Collaborator: Dr. Athena Kourtis • Dr. Ramit Mehr • Kirschner lab members • Funding • NIH and Whitaker Foundation to DEK • Rackham Graduate School and Elizabeth Glaser Pediatric AIDS Foundation to PY

  43. Clinical Studies of Thymic Function during HAART • TREC levels recover • Naïve CD4+ and CD8+ T cell numbers increase • Thymic volume increases • Children with “thymic dysfunction” response well to HAART

  44. R5 X4 R5 X4 Model of Thymic Function Reconstitution during HAART Cell Source • Reduce viral influx into the thymus • Decrease viral infection and production (if thymic drug efficacy > 0%) • Decrease HIV-1 induced death of uninfected thymocytes • Increase progenitor cells from bone marrow • Increase carrying capacity of the thymus TN THYMUS TES(t) X4 ITTP ITTPX DPR DPX DP R5 X4 SP8R SP4R SP4 SP4X SP8X SP8 R5 X4 CD4+ RTE CD8+ RTE BLOOD/LYMPHOID TISSUES

  45. Simulations of pediatric thymocyte dynamics during HAART

  46. Simulations of CD4+ RTE Predict HAART Agent Thymic Efficacy RTI HAART

More Related