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

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Presentation on theme: "Evaluation of Human Thymic Function during Health and HIV-1 Infection Ping Ye and Denise Kirschner DIMACS Workshop 9/23/2001."— 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 The Thymus Janeway CA et al. Immunobiology 5 th ed Haynes BF. Clin Immunol. 92(1):3-5,1999

4 Thymopoiesis Berkowitz RD et al. J Immunol. 161(7): , 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 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 5 th ed Haynes BF et al. Annu Rev Immunol. 18: , 2000

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 1 st Can TREC concentration be properly used as measure of RTE? 2 nd Whether thymic infection with different HIV-1 strains contribute to differences in disease progression?

10 Thymopoiesis Model Cell Source THYMUS TES(t) TN BLOOD/ LYMPHOID TISSUES CD8+ RTECD4+ RTE ITTP SP4SP8 DP

11 Simulation Results for Thymopoiesis Model ThymocytesRTE/day

12 Model Simulation Values Compared with Experimental Data

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

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

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

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

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

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

19 Summary Thymic 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 progressors2-3 years to AIDS (15%) lower CD4+ and CD8+ counts (DiGeorge Syndrome)

27 Experimental Studies of Thymic Infection with HIV-1 Coreceptors CCR5Expressed in low levels on DP, SP4, SP8 cells CXCR4Expressed in high levels on ITTP, DP cells, low levels on SP4 and SP8 cells HIV-1 strains R5 strainInfects DP and SP4 cells Minimally cytopathic X4 strainInfects ITTP, DP and SP4 cells Highly cytopathic Thymocyte maturation stages SP4,SP8Support active viral replication ITTP,DPSupport less viral replication

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

29 Thymic Model With HIV-1 Infection Cell Source TN SP8 R DP R SP4 R R5 X4 ITTP X X4 SP4 SP8 DP ITTP CD4+ RTECD8+ RTE THYMUS TES(t) BLOOD/LYMPHOID TISSUES DP X SP4 X SP8 X R5 X4

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

35 Two Questions to Address 1 st Can TREC concentration be properly used as measure of RTE? 2 nd Whether 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) Margolick JB et al. J Acquir Immune Defic Syndr. 6(2): , 1993 Zhang L et al. J. Exp. Med. 187(11): , 1998 T cells TREC

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

39 Summary Thymic 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), 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 Model of Thymic Function Reconstitution during HAART 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 Cell Source TN SP8 R DP R SP4 R R5 X4 ITTP X X4 SP4 SP8 DP ITTP CD4+ RTECD8+ RTE THYMUS TES(t) BLOOD/LYMPHOID TISSUES DP X SP4 X SP8 X R5 X4

45 Simulations of pediatric thymocyte dynamics during HAART

46 Simulations of CD4+ RTE Predict HAART Agent Thymic Efficacy RTIHAART


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