Beyond “Indirect Effects” --  The Impact of Infections in             Transplantation           Jay A. Fishman, M.D. Massa...
Viruses may be dangerous . . . .                    …and not all                   viruses are the                       s...
The risks of viral infection: Whathave we been teaching? Latent  or acute “viral infection” is activated in  an immunosup...
Cytomegalovirus   Large double-stranded    DNA virus of betaherpes    group with a genome size    of 235 Kbp, coding more...
Effects of CMV in Transplantation             Latent CMV infection: D+/R-, R+ Infection               Graft rejection     ...
Disseminated CMV Liver             ColonKidney             Lung
CMV: “Indirect Effects” Probably  a misnomer Existence of indirect effects are implied based  on clinical observations, ...
HCMV Protein                                   FunctionFC Receptor homologue       Blocks antibody-dependent cytotoxicity;...
CMV “Indirect Effects”: Many    Mechanisms are CMV-specific   Upregulation of MHC class II antigens and homology    betwe...
Opportunistic Infections Promoted byCMV Infection in Transplant Patients Fungal infections   →Aspergillus spp   →Pneumocy...
Effect of anti-CMV prophylaxis onconcomitant infections                1.0                 -73%            -35%           ...
Preemptive Therapy vs ProphylaxisMeta-Analyses: Impact on CMV Disease                                       Relative Risk ...
Mortality: universal prophylaxis vs. pre-emptive therapy   Statistically significant risk reduction of mortality with uni...
CMV and Graft Dysfunction: Renal CMV Disease causes poor renal graft function at 6 mos and CMV & HHV6 are associated with...
Anti-CMV prophylaxis is associated withincreased renal graft survival at 4 years (p =0.0425)                              ...
CMV and Graft Dysfunction: Liver CMV  infection is associated with cirrhosis, graft failure, retransplantation, and death...
CMV in Heart & Lung Transplantation Obliterative             bronchiolitis (BOS) increased in:   CMV serologic R+ and D+...
CMV and Graft Dysfunction: Heart CMV  is associated with coronary allograft  vasculopathy (MT Grattan et al, J Am Med Ass...
Summary: Effects of AntiviralAgents on Allograft Injury        Valacyclovir in kidney recipients ⇒ 50% ↓ in         rejec...
How best to impact indirecteffects?   Does prophylaxis delay or prevent CMV infection and    disease? - Yes (M Halme Tran...
Mechanisms: Monocytes, Dendritic Cells   In vitro, CMV infection of human monocytes results in a transient    block in th...
How do the effects of CMV comparewith those of HCV?  HCV   reinfection is universal after liver   transplantation  What ...
Hepatitis C                 Hepatitis C virus                  (HCV) is a small (55–                  65 nm in size)     ...
Non-A Non-B Hepatitis – the early years27/42 patients with hepatic dysfunction had life-threatening infection (64.3% vs. 2...
Increased infections in liver transplant recipients  with recurrent hepatitis C virus hepatitis Singh N et al.  Transplant...
HCV in renal recipientsKaplan-Meier estimate of the cumulative probability of death due to sepsis  in HCV + and - kidney r...
Outcomes: Outcomes in hepatitis C virus–positive recipients (compared with hepatitis C virus–negative recipients) of solid...
Post-transplant Diabetes Mellitus (PTDM) In LiverTransplant Recipients: Temporal Relationship WithHepatitis C Virus Allogr...
HCV and post-transplant diabetes   Mechanisms underlying diabetogenicity of HCV are    complex:     Insulin resistance c...
Possible anti-HCV Cyclosporine Effect?             Decreased CNI metabolism                                          Calci...
PTDM is a risk factor for post-transplant    infection in HCV+ liver recipients (HR=7.18)    Cause of Death in HCV + pati...
How about HCV and Immune Function? Progression    to chronic hepatitis C appears to be related to exhaustion of adaptive ...
Are some mechanismsunderlying increased risk forinfection shared between“viruses”?
Heterologous immunity Heterologous  immunity: Immune memory responses to previously encountered pathogens which alter sub...
Heterologous Immunity and ViralInfection  Increased rejection Virally-inducedalloreactive memory may                    ...
Heterologous Immunity   T-cell responses to viral epitopes occur in a distinct    hierarchy for a given virus on a given ...
Heterologous Immunity Can   create gaps in immunity to  subsequent pathogens with shared but  non-protective epitopes? P...
T-cell depletion or Stem celltransplants for tolerance Homeostatic  proliferation to self-MHC-  peptide complexes: In pro...
Broader Concepts: The Interfaceof Innate and Adaptive Immunity
Toll-Like Receptors (TLRs) are pattern                            Heat Shock proteins,    recognition receptors    extrace...
TLR-ligation can block tolerance      induction   Tissue inflammation (infection, surgery) and injury     trafficking of...
Natural Killer Cells induce Coronary AllograftVasculopathy (CAV) in Mice without T- or B-cells ifinfected with Lymphocytic...
NK Cells, LCMV Infection:B6.RAG1-/- into CB6F1.RAG1-/-a.   No infectionb.   Controlc.   Isograftd.   Day 28 LCMVe.   Day 5...
Let’s focus for a moment on the likely purpose                   of the immune system   • The human microbiome refers to t...
The Gut Microbiome   Colon contains >1010-11 cfu commensal    bacteria/gram tissue. Note: >1000 different    microbial sp...
Role of regulatory T cells in tolerance to commensal bacteria Chyi Hsieh, Washington University, St. Louis The  colonic m...
Which antigens drive or controlhomeostatic proliferation? Depletion                                        Naïve T cells  ...
Infection and Transplantation  Pre-Transplantation            Transplant Surgery          Post-Transplantation•Organ dysfu...
Remaining Questions   Do chronic viral infections  diminished responses to    new antigens and risk for opportunistic in...
Thank you for inviting me. I would be happy to answer        questions.           If I can help:     jfishman@partners.or ...
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Jay Fishman: indirect effects and viral infections: Infection in Transplantation

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Viral infections remain among the most important challenges in the management of the transplant recipient. This observation reflects both a predisposition to viral infection by immunosuppression that targets T-cell function, the diverse population of viruses, and the impact of viruses including infection, graft rejection, and malignancies. Traditionally, the manifestations of cytomegalovirus (CMV) infection have been termed “direct” (organ-specific) and “indirect” (immune) effects. More accurate terms might be “viral cytopathic” effects and “cellular and systemic immunologic” effects. The clinical manifestations of viral CMV infections are the result of suppression of multiple host defense mechanisms, predisposing to secondary invasion by such pathogens as P. jiroveci, Candida and Aspergillus species and increasing the risk for graft loss and death. As the biology of viral infection is explored, many of these manifestations of viral infection appear to be mediated not only by T-cells but also by the innate immune system.

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  • Slide According to results from meta-analyses that have been published during the past 2 to 3 years, preemptive therapy reduces the risk of CMV disease by almost 70% to 80%. 1-4 Data from meta-analyses have also reported a significant reduction in the incidence of CMV disease using prophylaxis. These meta-analyses were conducted using data from the past one to two decades. The investigators compiled data, regardless of what type of prophylaxis was used (ie, from high-dose acyclovir to oral ganciclovir to valganciclovir). Overall, the data demonstrate that there is a 60% to 80% reduction in CMV disease using prophylactic therapy. 3-5 Eid AJ, Razonable RR. Cytomegalovirus disease in solid organ transplant recipients: advances lead to new challenges and opportunities. Curr Opin Organ Transplant. 2007;12:610-617. Stripoli GF, et al. Cochrane Database Syst Rev . 2006. Kalil A, et al. Meta-analysis: the efficacy of strategies to prevent organ disease by cytomegalovirus in solid organ transplant recipients. Ann Intern Med. 2005;143:870-880. Small LN, et al. Preventing post-organ transplantation cytomegalovirus disease with ganciclovir: a meta-analysis comparing prophylactic and preemptive therapies. Clin Infect Dis . 2006; 43:869-880. Hodson EM, et al. Cochrane Database Syst Rev . 2008;(2):CD003774.
  • Slide According to the aforementioned meta-analyses, preemptive therapy may not be helpful in preventing the indirect effects of CMV. 1-4 For example, there is no significant reduction in all-cause mortality in patients who received preemptive treatment. In contrast to the preemptive therapy, there is a noticeable reduction in all-cause mortality, as described by Hodson and Kalil, although this was not noted in the study from Small and colleagues. Eid AJ, Razonable RR. Cytomegalovirus disease in solid organ transplant recipients: advances lead to new challenges and opportunities. Curr Opin Organ Transplant. 2007;12:610-617. Stripoli GF, et al. Cochrane Database Syst Rev . 2006 Kalil A, et al. Meta-analysis: the efficacy of strategies to prevent organ disease by cytomegalovirus in solid organ transplant recipients. Ann Intern Med. 2005;143:870-880. Small LN, et al. Preventing post-organ transplantation cytomegalovirus disease with ganciclovir: a meta-analysis comparing prophylactic and preemptive therapies. Clin Infect Dis . 2006; 43:869-880. Hodson EM, et al. Cochrane Database Syst Rev . 2008;(2):CD003774.
  • Slide Additional results are shown from three separate randomized studies that compared the use of preemptive versus prophylactic treatment in renal transplant recipients. Although no significant differences were found between preemptive and prophylactic treatment in the Khoury et al. study or the Reischig et al. study, 1-2 the incidence of CMV disease was significantly lower in the prophylaxis group compared with the preemptive group ( P =0.04) among patients who received ganciclovir in the Kliem et al. study. 3 Khoury JA, et al. Prophylactic versus preemptive oral valganciclovir for the management of cytomegalovirus infection in adult renal transplant recipients. Am J Transplant. 2006;6:2134-2143. Reischig T, et al. Valacyclovir prophylaxis versus preemptive valganciclovir therapy to prevent cytomegalovirus disease after renal transplantation. Am J Transplant. 2008;8:69-77. Kliem V, et al. Improvement in long-term renal graft survival due to CMV prophylaxis with oral ganciclovir: results of a randomized trial. Am J Tranplant. 2008;8:975-983.
  • Slide These studies also reported on the incidence of allograft rejection (or failure) during the comparison of preemptive versus prophylactic therapy. As shown in the graph, the incidence of allograft rejection was 8% in the preemptive treatment group and 2% in the prophylaxis group in the Khoury study (no significant differences). 1 In contrast, Reischig and colleagues found that biopsy-proven allograft rejection was significantly increased in the preemptive therapy group (36%) compared with the prophylaxis group (15%) during treatment with valacyclovir ( P =0.034; HR=2.89, 95% CI, 1.03–8.11). 2 In a similar manner, the use of prophylaxis was associated with a significantly lower rate of graft loss over 4 years during the study by Kliem and colleagues ( P =0.04). 3 Although these findings are of concern, these data must be confirmed by further research. Khoury JA, et al. Prophylactic versus preemptive oral valganciclovir for the management of cytomegalovirus infection in adult renal transplant recipients. Am J Transplant. 2006;6:2134-2143. Reischig T, et al. Valacyclovir prophylaxis versus preemptive valganciclovir therapy to prevent cytomegalovirus disease after renal transplantation. Am J Transplant. 2008;8:69-77. Kliem V, et al. Improvement in long-term renal graft survival due to CMV prophylaxis with oral ganciclovir: results of a randomized trial. Am J Tranplant. 2008;8:975-983.
  • Unfortunately, we do not know much about the effect of antivirals at this point. Valacyclovir, the valine ester of acyclovir, is more effective than placebo in terms of prophylaxis, and it has been shown to reduce rejection rates among kidney recipients. 1 Ganciclovir is an extremely potent anti-CMV drug. When administered for 1 month to heart transplant recipients, IV ganciclovir provided a long-term benefit as evidenced by a decrease in vasculopathy in seropositive recipients. 2 To date, a trend toward a decrease in rejection has been seen with oral ganciclovir. 3,4
  • Jay Fishman: indirect effects and viral infections: Infection in Transplantation

    1. 1. Beyond “Indirect Effects” -- The Impact of Infections in Transplantation Jay A. Fishman, M.D. Massachusetts General Hospital and Harvard Medical School
    2. 2. Viruses may be dangerous . . . . …and not all viruses are the same!!
    3. 3. The risks of viral infection: Whathave we been teaching? Latent or acute “viral infection” is activated in an immunosuppressed host. These viruses do “bad things” We call these “indirect effects” – cellular proliferation, cytokine release, modulation of gene activity in the host, immunological effects. What insights are gained from studies of cytomegalovirus and other viruses including Hepatitis C virus?
    4. 4. Cytomegalovirus Large double-stranded DNA virus of betaherpes group with a genome size of 235 Kbp, coding more then 165 genes and over 70 viral proteins The majority of the tegument proteins are either structural or affect the host cell or immune response to the virus
    5. 5. Effects of CMV in Transplantation Latent CMV infection: D+/R-, R+ Infection Graft rejection Antilymphocyte antibodies Inflammation New Primary (cytokines, growth factors, NF-κB) Infection Viral Active CMV Replication Cytokines, Antigenssyndromes (viremia, tissue invasion) Allograft rejectionFever/Neutropenia Cellular Liver, Heart Systemic immune Effects suppression Lungs, RetinaGI tract, Pancreas Injury Opportunistic Adrenals, CNS infection Proliferation Allograft injury PTLD (EBV) Coronary Vasculopathy Bronchiolitis Obliterans
    6. 6. Disseminated CMV Liver ColonKidney Lung
    7. 7. CMV: “Indirect Effects” Probably a misnomer Existence of indirect effects are implied based on clinical observations, but are difficult to measure with effects of immune suppression, underlying disease, rejection → Increased rate of opportunistic infections: Aspergillus, PCP, acceleration of HCV infection in liver transplantation → Probably increased graft rejection (acute and chronic) → Vanishing bile duct syndrome (if it exists) → Co-factor in Bronchiolitis Obliterans Syndrome → Accelerated atherogenesis in cardiac allografts → Increased EBV-associated post-transplant lymphoproliferative disorders (PTLD)
    8. 8. HCMV Protein FunctionFC Receptor homologue Blocks antibody-dependent cytotoxicity; bindingTRL11/IRL11, UL118/119 nonspecific antibody coating against CD8 and NK cellsPp65 matrix Phosphorylates IE-1 protein to inhibit MHC class I-restricted antigen presentationUS3,US6, US10, US11 Block generation and export of MHC class I peptidesUS3,US6, US10, US11 Reduced expression of MHC class I peptidesUS2 Reduced antigen presentation in MHC class II pathwayMHC-I homologue UL40, Blocks NK cell activation (also: UL16, pp65)UL122 miRNA, UL142, UL141UL18 MHC class 1 homologue; reduced immune surveillanceUL20 T-cell receptor homologue; reduced antigen presentationIE86 Inactivates p53; increase smooth muscle proliferationUL33, UL33, UL78, US27, Transmembrane proteins chemokine receptors; reduced US28 interferon and chemokine effects; reduced inflammation, increased viral disseminationIL-10 homologue UL111a; Immunosuppression; reduced MHC class I/II expression andIL8 CXC-1 UL146, UL147 lymphocyte proliferation; increased neutrophil chemotaxis; reduced dendritic cell and monocyte chemotaxis and functionUL144 TNF receptor homologueUL36, UL37 Anti-apoptosis for infected cells
    9. 9. CMV “Indirect Effects”: Many Mechanisms are CMV-specific Upregulation of MHC class II antigens and homology between CMV IE antigen and MHC class-I (HLA-DRβ, Fujinami RS, et al. J Virol. 1988;62:100-105. S. Beck, Nature. 1988;331:269-272) Block of CD8+ (MHC class I) recognition of CMV Blocks CMV antigen processing and display (immediate early Ag modification, poor allo-T-cell CTL response) Increased ICAM-1, VCAM, cellular myc & fos (adhesion) Inversion of CD4/CD8 ratio (Schooley 1983, Fishman 1984) Increased cytokines: IL-1β, TNFα, IFNγ, IL-10, IL-4, IL-8, IL-2/IL-2R, C-X-C chemokines and IL-8 (Kern et al, 1996; CY Tong, 2001) Increased cytotoxic IgM (Baldwin et al, 1983) Stimulation of alloimmune response by viral proteins (Fujinami et al, 1988, Beck et al, 1988) Increased PDGF, TGFβ; autoantibodies Increased granzyme B CD8+ T-cells, γδ-T-cells
    10. 10. Opportunistic Infections Promoted byCMV Infection in Transplant Patients Fungal infections →Aspergillus spp →Pneumocystis carinii (jirovecii) →Candidemia and intra-abdominal infection after liver and pancreas transplants Bacteremia: Listeria monocytogenes Epstein-Barr virus infection (RC Walker et al, CID, 1995, 20:1346-55), HHV6/7, HHV8/KSHV HCV: risk for cirrhosis, fulminant HCV hepatitis, retransplantation, mortality
    11. 11. Effect of anti-CMV prophylaxis onconcomitant infections 1.0 -73% -35% -69% 0.8 0.65Relative risk 0.6 0.4 0.31 0.27 0.2 0.0 Placebo/no Herp. Simplex, Bacterial Pneumocystis Protozoal treatment Varic. Zoster infections infections Hodson EM et al. Lancet 2005; 365: 2105
    12. 12. Preemptive Therapy vs ProphylaxisMeta-Analyses: Impact on CMV Disease Relative Risk of CMV Disease Study Author Preemptive Therapy Antiviral Prophylaxis 0.29 0.42 Hodson et al. (0.11–0.80) (0.34–0.52) 0.28 0.20 Kalil et al. (0.11–0.69) (0.13–0.31) 0.30 0.34 Small et al. (0.15–0.60) (0.24–0.48)Hodson EM, et al. Cochrane Database Syst Rev. 2008;(2):CD003774.Kalil A, et al. Ann Intern Med. 2005;143:870-880.Small LN, et al. Clin Infect Dis. 2006;43:869-880.
    13. 13. Mortality: universal prophylaxis vs. pre-emptive therapy Statistically significant risk reduction of mortality with universal prophylaxis (Kalil et al) and all cause mortality (Hodson et al). Prophylaxis Pre-emptive 0% Mortality: risk reduction (%) -10% -6% -20% p=0.032 -30% p=ns -40% -38% -50% -60%Kalil AC et al. Ann Intern Med 2005; 143: 870; Hodson EM et al. Lancet 2005; 365: 2105
    14. 14. CMV and Graft Dysfunction: Renal CMV Disease causes poor renal graft function at 6 mos and CMV & HHV6 are associated with chronic dysfunction (3 yrs) (CY Tong et al, Transplant. 2002, 74:576-8) Acutebut not Chronic allograft rejection is reduced by CMV prevention in liver and kidney (D+/R-) Tx (D Lowance et al, NEJM 1999, 340:1462-70; E. Gane et al, Lancet 1998, 350:1729-33) HHV6 increases CMV infection and OI’s and possibly some acute rejection in renal (A. Humar, Transplant 2002, 73:599-604) & liver recipients (JA DesJardin CID 2001, 33:1358-62; PD Griffiths et al, J Antimicrob Chemother, 2000, 45 sup 29-34) HHV7 associated with increased CMV infection and with acute rejection (IM Kidd et al, Transplant 2000, 69:2400-4)
    15. 15. Anti-CMV prophylaxis is associated withincreased renal graft survival at 4 years (p =0.0425) Oral ganciclovir prophylaxis uncensored for death (%) Freedom from graft loss; 100 90 80 70 IV pre-emptive therapy 60 50 p value (Log rank test) = 0.0425 0 1 2 3 4 Time after transplantation (years) Prophylaxis reduced CMV infection by 65% (p < 0.0001) Kliem V, et al. Am J Transplant 2008; 8:975-83.
    16. 16. CMV and Graft Dysfunction: Liver CMV infection is associated with cirrhosis, graft failure, retransplantation, and death in liver recipients (KW Burak et al, Liver Transplant 2002, 8:362-9) IncreasedHCV recurrence and fibrosis after OLTx (partially due to HHV6) (A. Sanchez-Fueyo et al, Transplant 2002, 73:56-63; N Singh et al, Clin Transplant 2002, 16:92-6; HR Rosen et al, Transplant 1997, 64:721; R. Patel et al, Transplant 1996, 61:1279) Possible roles of immune suppression, CMV-induced immune suppression & HCV, CMV-induced TGFβ/fibrosis
    17. 17. CMV in Heart & Lung Transplantation Obliterative bronchiolitis (BOS) increased in:  CMV serologic R+ and D+ combinations  CMV infection raises OB to ~60%  (Zamora MR. TransID 2001; 3: 49-56 and Am J Tx 2004, 4:1219-1226) CMV disease and D+/R- status are associated with chronic rejection, bacterial and fungal pneumonia, OB and death in Lung Tx (SR Duncan 1992; NA Ettinger 1993; K Bando 1995; RE Girgis 1996; RN Husni 1998) Reduction in BOS and fungus with iv ganciclovir (SR Duncan et al, Am J Crit Care Resp Dis 1994, 150:146-152; DR Snydman NEJM 1987, 317:1049-1054; JA Wagner et al Transplant 1995, 60:1473-7; HA Valantine et al, Circulation 1999, 100:61-6; HA Valentine et al, Transplantation 2001, 72:1647-1652)
    18. 18. CMV and Graft Dysfunction: Heart CMV is associated with coronary allograft vasculopathy (MT Grattan et al, J Am Med Assoc 1989,261:3562-6) Prophylaxis using CMVIg with ganciclovir reduces cardiac transplant vasculopathy (HA Valantine et al, Circulation 1999, 100:61-6; HA Valentine et al, Transplantation 2001, 72:1647-1652)  CMVIG plus DHPG reduced CMV incidence, rejection, and death vs. DHPG alone  Coronary Tx vasculopathy reduced  Lung and heart-lung recipients had less OB, better survival, fewer infections  Less PTLD in double Rx
    19. 19. Summary: Effects of AntiviralAgents on Allograft Injury  Valacyclovir in kidney recipients ⇒ 50% ↓ in rejection  Oral ganciclovir in heart, liver, kidney recipients ⇒ ↓ trend in rejection  Prophylactic IV ganciclovir in heart recipients ⇒ long-term benefit in ↓ of vasculopathyLowance D, et al, for the International Valacyclovir Cytomegalovirus ProphylaxisTransplantation Study Group.N Engl J Med. 1999;340:1462-1470.Valantine HA, et al. Circulation. 1999;100:61-66.Ahsan N, et al. Clin Transplant. 1997;11:633-639.
    20. 20. How best to impact indirecteffects? Does prophylaxis delay or prevent CMV infection and disease? - Yes (M Halme Transplant Int 1998, S499-501; JL Kelly et al, Transplant 1995, 59:1144-7) Does prophylaxis delay or prevent CMV-mediated effects? Role of CMV may be uncertain but clinical data support this concept. Do we need to prevent other viral infections? Yes How to best use “screening tests” depends on goal of therapy - prevent CMV disease vs. asymptomatic infection & presumed indirect effects? What is the optimal regimen? Need further data.
    21. 21. Mechanisms: Monocytes, Dendritic Cells In vitro, CMV infection of human monocytes results in a transient block in the cytokine-induced differentiation of monocytes into functionally active CD1a-positive dendritic cells. Dendritic cells are potent professional antigen presenting cells and play a central role in generation and maintenance of primary T-cell responses against viral infections. Depressed immunological functions include:  impaired ability to mature in response to LPS.  reduced phagocytic capacity  Reduced migration in response to chemoattractant factors RANTES, MIP-1, and MIP-3. This inhibition was mediated by early viral replicative events, which significantly reduced the cell-surface expression of CC chemokine receptor 1 (CCR1) and CCR5 by receptor internalization. CMV infection induces secretion of inflammatory chemokines, chemokine ligand 3 (CCL3), macrophage inflammatory protein-1 (MIP- 1 ), CCL4/MIP-1ß, and CCL5/regulated on activation, normal T expressed and secreted (RANTES) HCMV-infected cells express high levels of the costimulatory molecule CD86 HCMV-infected CD1a-negative cells are unable to induce a T-cell response.S. Gredmark and C. Söderberg-Nauclér*Journal of Virology, October 2003, p. 10943-10956, Vol. 77, No. 20
    22. 22. How do the effects of CMV comparewith those of HCV?  HCV reinfection is universal after liver transplantation  What is the impact on the risk for other infections?
    23. 23. Hepatitis C  Hepatitis C virus (HCV) is a small (55– 65 nm in size) enveloped, positive- sense, single stranded RNA virus of the family Flaviviridae  The genome consists of a single open reading frame of 9600 bp. The gene product and proteins are largely required for replication and infection.
    24. 24. Non-A Non-B Hepatitis – the early years27/42 patients with hepatic dysfunction had life-threatening infection (64.3% vs. 20% in patients withouthepatitis, p<0.01)) LaQuaglia MP et al. Transplant. 32(6):504-7, 1981 Dec
    25. 25. Increased infections in liver transplant recipients with recurrent hepatitis C virus hepatitis Singh N et al. Transplantation. 61(3):402-6, 1996 Feb 15. Major Episodes Recurrent Bacterial Fungal CMV Late infections of major infection Infection Infection Infections infection (mean)Recurrent 64% 1.45 45%, 41% 18% 32% 27% HCV (14/22) 10/22 No HCV 38% 0.51 10%, 8/78 28% 6% 9% 6% (30/78) P = 0.04 P = 0.005 P = NS P = 0.10 P= P = 0.09 P = .003 0.012Rejection episodes occurring within 6 months after transplantation werealso higher in patients with recurrent HCV hepatitis (P = 0.09).
    26. 26. HCV in renal recipientsKaplan-Meier estimate of the cumulative probability of death due to sepsis in HCV + and - kidney recipients Compared with recipients without anti- HCV before transplantation, the relative risk of graft loss among recipients with anti-HCV before transplantation was 1.30 (0.66-2.58), the relative risk of death was 2.60 (1.15-5.90), the relative risk of death due to sepsis was 6.30 (1.99-20). Bouthot BA et al. Transplantation. 63(6):849-53, 1997.
    27. 27. Outcomes: Outcomes in hepatitis C virus–positive recipients (compared with hepatitis C virus–negative recipients) of solid organ transplantation (non-liver) Type of transplant OutcomeRenal Decreased long-term patient survival (follow-up >10 y) Decreased graft survival De novo or recurrent glomerulopathy Cirrhosis Posttransplant diabetesPancreas, kidney-pancreas Increased proteinuria Higher requirements for hypoglycemic agents No difference in patient, graft survival in short-term studies No long-term studiesCardiac or lung No difference in patient, graft survival in short-term studies Wells JT. Lucey MR. Said A. Clinics in No long-term studies Liver Disease. 10(4):901-17, 2006 Nov.
    28. 28. Post-transplant Diabetes Mellitus (PTDM) In LiverTransplant Recipients: Temporal Relationship WithHepatitis C Virus Allograft Hepatitis and Impact OnMortality  The prevalence of PTDM was significantly higher in HCV (+) than in HCV (-) patients (64% vs. 28%, P0.0001). Development of PTDM is an independent risk factor for mortality (hazard ratio 3.67, P<0.0001). The cumulative mortality in HCV (+) PTDM (+) versus HCV (+) PTDM (-) patients was 56% vs. 14% (P0.001).  PTDM associated with HCV recurrence did much worse (by 6.5 fold) than those with PTDM but without or prior to HCV hepatitis in graft. Normalization of liver function tests with improvement in viremia was achieved in 4 of 11 patients, who demonstrated a marked improvement in their glycemic control. Between 1991 and 1998, of 185 OLTs performed in 176 adult patients, 47 HCV (+) cases and 111 HCV (-) controls. (Transplantation 2001; 72: 1066–1072)
    29. 29. HCV and post-transplant diabetes Mechanisms underlying diabetogenicity of HCV are complex:  Insulin resistance caused by liver injury (increased expression of both insulin receptors and insulin receptor substrate-1)  Inhibitory actions of the virus on insulin regulatory pathways in the liver (downstream signaling through phosphoinositide-3 kinase was decreased in HCV+ liver cells)  Effects of immunosuppressive drugs, e.g., tacrolimus. Glucose dysregulation is an important determinant of increased morbidity and mortality in liver and kidney recipients.Lecube A, et al. High prevalence of glucose abnormalities in patients with hepatitis C virus infection: Amultivariate analysis considering the liver injury. Diabetes Care 2004; 27: 1171–1175.Aytug S, et al. Impaired IRS-1/PI3-kinase signaling in patients with HCV: A mechanism forincreased prevalence of type 2 diabetes. Hepatology 2003; 38:1384–1392.Masini M, et al. Hepatitis C virus infection and human pancreatic b-cell dysfunction. Diabetes Care 2005;28:940–941. Bloom RD. Lake JR. Am J Transplant. 6(10):2232-7, 2006 Oct.
    30. 30. Possible anti-HCV Cyclosporine Effect? Decreased CNI metabolism CalcineurinHCV Increased Replication Inhibitors Hepatic Injury Steroids Diabetes
    31. 31. PTDM is a risk factor for post-transplant infection in HCV+ liver recipients (HR=7.18) Cause of Death in HCV + patients with Infection (N=10)  Pneumonia, sepsis with Pseudomonas, Enterococcus, Torulopsis, and Candida  Enterobacter sepsis  Pneumocystis carinii pneumonia with ARDS  Sepsis with VRE, Torulopsis, and Pseudomonas infection  Sepsis with Klebsiella and Candida  Pneumonia with multiorgan failure, Candida, Aspergillus  Pneumocystis carinii pneumonia with disseminated Aspergillus  Aspiration pneumonia with ARDS and Candidemia  Klebsiella pneumonia with ARDS  Cryptococcus pneumonia with ARDS
    32. 32. How about HCV and Immune Function? Progression to chronic hepatitis C appears to be related to exhaustion of adaptive immune function. Containment of HCV infection requires a coordinated, vigorous, and sustained multispecific CD4+ and CD8+ T-cell responses to the virus. (Spangenberg HC et al. Intrahepatic CD8+ T-cell failure during chronic hepatitis C virus infection. Hepatology 2005;42:828-37; Nellore, A and Fishman JA. NK Cells, Innate Immunity and Hepatitis C Infection after Liver Transplantation. Clin Infect Dis. 2011, 52 (3): 369-377) HCV infection may enrich the hepatic regulatory T cell population which may persist after liver transplantation. Compared to uninfected recipients, OLT recipients with HCV have enhanced peripheral Foxp3+ CD4+CD25+ T cell population. The mechanisms are uncertain. (Ciuffreda D et al. Liver Transpl 2010;16:49-55; Carpentier A et al. Increased expression of regulatory Tr1 cells in recurrent hepatitis C after liver transplantation. Am J Transplant 2009;9:2102-12.) HCVis associated with decreased numbers of peripheral dendritic cells in patients with chronic and post-transplant HCV infection.
    33. 33. Are some mechanismsunderlying increased risk forinfection shared between“viruses”?
    34. 34. Heterologous immunity Heterologous immunity: Immune memory responses to previously encountered pathogens which alter subsequent immune responses to unrelated pathogens or grafts.  Responses may be mediated by TNFα, IFNγ  In some cases: Memory CD4+ cells mediate bacterial  virus cross reactivity CD8+ cells mediate virus  virus cross reactivity
    35. 35. Heterologous Immunity and ViralInfection  Increased rejection Virally-inducedalloreactive memory may Rejection and create a barrier to transplantation tolerance or treatment increase induce graft rejection orreplication and (AB Adams et viral autoimmunity al, JCI 2003:111:1887-95) risk for opportunistic  Alloreactive T-cells are activated by viral infections infection. (Yang H and Welsh RM JI 1986: 1186-1193; Braciale TJ et al J Exp Med 1981, 153:1371-76; Chen HD 2001, Nat Imm 2:1067-76)  Allo-cross reactivity of CMV and EBV (Adams AB et al. Immunol Rev 2003, 196:147-160.)  Pre-existing alloreactive memory T-cells increase rejection rate (Heeger PS et al. JI 1999, 163:2267-75) Differences by virus type, persistence, latency?
    36. 36. Heterologous Immunity T-cell responses to viral epitopes occur in a distinct hierarchy for a given virus on a given MHC background (“public specificity”) The hierarchy of T-cell responses are governed by the competition between epitopes for presentation by MHC, the availability of nontolerized T cells capable of responding to the epitopes, and the competition between T cells binding to domains on the antigen-presenting cells (Yewdell JW, Bennink JR: Annu Rev Immunol 1999, 17:51-88.) Due to elevated frequencies of antigen-specific memory T cells and their elevated activation state, infection of a host with a virus that encodes an epitope cross-reactive with that memory pool might recruit those T cells into a vigorous immune response but would suppress responses to other epitopes. (Brehm MA et al. Nat Immunol 2002, 3:627-634; Klenerman P, Zinkernagel RM: Nature 1998, 394:482-485.)
    37. 37. Heterologous Immunity Can create gaps in immunity to subsequent pathogens with shared but non-protective epitopes? Process is dependent on the sequence of infections and can be either beneficial or detrimental to the host
    38. 38. T-cell depletion or Stem celltransplants for tolerance Homeostatic proliferation to self-MHC- peptide complexes: In process of repopulation, T-cell repertoire (TCR) may be narrowed to reflect memory (prior exposures) but may not respond well to new, subsequent exposures (SJ Lin Blood. 112(3):680-9, 2008; M Cornberg J Clin Invest. 116(5):1443-56, 2006)
    39. 39. Broader Concepts: The Interfaceof Innate and Adaptive Immunity
    40. 40. Toll-Like Receptors (TLRs) are pattern Heat Shock proteins, recognition receptors extracellular matrix proteins, collagens, β- defensin, nuclear Promote allograft rejection via signal protein HMGB1, transduction (usually MyD88 and/or Trif) oligonucleotides, DNA, RNA, … pathways – ligands may include products of cellular damage (damage-associated molecular patterns, DAMPs) or inflammation Likely designed for microbial products – so more bacteria, viruses, fungi, or nucleic acids  more stimulation and So dirty surgery, vascular catheters left in too long, viral activation ….  TLR activation
    41. 41. TLR-ligation can block tolerance induction Tissue inflammation (infection, surgery) and injury  trafficking of T-cells Listeria monocytogenes (intracellular bacterium)  IFNβ blocks heart and skin tolerance (T Wang et al, AJT, 10:1524, 2010) Staphylococcus aureus (but not Pseudomonas aeruginosa)  IL-6 (EB Ahmed et al, AJT, 11:936, 2011) Newcastle disease virus  IFNα by dendritic cells (DC) and macrophages (Y Kumagi et al, Immunity, 27:240, 2007)Mechanism: Non-specific stimulation (cytokines, chemokines)of T-cells or increased antigen presentation by APCs?
    42. 42. Natural Killer Cells induce Coronary AllograftVasculopathy (CAV) in Mice without T- or B-cells ifinfected with Lymphocytic Choriomenigitis VirusParental C57BL/6.RAG1-/- (H2Db) hearts were transplanted into (C57BL/6 x BALB/c.RAG1-/-) F1 (H2Dbxd) recipients. Recipients were sacrificed on post-operative day 56 with beating hearts. Mice were infected IP with 2.25 x 10e5 PFU of LCMV Armstrong strain. Infected hearts had a mean of 518,725 copies of LCMV per nanogram tissue RNA. LCMV inoculation alone: 6 of 8 recipients infected with LCMV developed florid CAV lesions. Controls: viral media injection 1 in 15 developed lesions of CAV LCMV inoculation with anti-NK1.1 mAb administration to deplete NK cells. None of the 6 mice infected with LCMV and treated with anti-NK1.1 mAb developed CAV. Conclusion: NK cells appear to mediate the development of CAV induced by LCMV infection.
    43. 43. NK Cells, LCMV Infection:B6.RAG1-/- into CB6F1.RAG1-/-a. No infectionb. Controlc. Isograftd. Day 28 LCMVe. Day 56 LCMVf. NK Cell depletedg. NK Cell infiltrateh. Smooth muscle cell proliferationi. Macrophages
    44. 44. Let’s focus for a moment on the likely purpose of the immune system • The human microbiome refers to the community of microorganisms, including prokaryotes, viruses, and microbial eukaryotes, that populate the human body. • From an initial genome sequencing project at NIH of 178 microbial genomes – 547,968 predicted polypeptides that correspond to the gene complement of these strains – 30,867 polypeptides, of which 29,987 (approximately 97%) were previously unidentified ("novel") polypeptides from the microbiome of the gastrointestinal tract • Simple math – there are 100 trillion •Phylogenetic tree of human 16S rDNA organisms in the GI tract. It is likely sequences Organisms sequenced as part that humans were developed to of the Human microbiome project are support bacterial growth!! highlighted in blue.Science. 2010 May 21;328(5981):994-9.
    45. 45. The Gut Microbiome Colon contains >1010-11 cfu commensal bacteria/gram tissue. Note: >1000 different microbial species from >10 different divisions colonize the GI tract, but just two bacterial divisions—the Bacteroidetes and Firmicutes— and one member of the Archaea appear to dominate, together accounting for >98% of the 16S rRNA sequences obtained from this site.
    46. 46. Role of regulatory T cells in tolerance to commensal bacteria Chyi Hsieh, Washington University, St. Louis The colonic microbial and Treg TCR repetoires are unique and may play central roles in the pathogenesis of autoimmunity, inflammatory bowel disease, and in determination of immunity to self and non-self antigens Likely includes “sampling” of GI flora by dendritic cell processes  presentation
    47. 47. Which antigens drive or controlhomeostatic proliferation? Depletion Naïve T cells Does T-cell depletioncells Memory T and reconstitution or costimulatory blockade in the face of cross- IL-7/MHC reacting antigen alter immunity Lymph nodes Memory T to the graft and reduce cells immune competence? Spleen Slow Homeostatic Gut Proliferation Memory T cells From: Tchao and Turka, AJT Fast Homeostatic Proliferation 2012; 12: 1079–1090 Costimulation + Commensal bacteria
    48. 48. Infection and Transplantation Pre-Transplantation Transplant Surgery Post-Transplantation•Organ dysfunction • Infection (technical) •Depletion and Immune•Colonization (ICU) • Tissue injury reconstitution• Antimicrobials • Organ dysfunction •Immunosuppression• Infections •Community exposures• Vaccination •Opportunistic infectionImmune memory • Ligands for Pattern • Heterologous or cross-reactive• Heterologous or cross- recognition receptors  memoryreactive cytokines, chemokines  Rejection• Narrowed immune •Pathogen & Allograft • Failed costimulatory blockaderesponses derived antigens • Narrowed immune responses•Stimulation by “Latent or • Damage-associated (infections)persistent infections” molecular patterns • Stimulation by new or “persistent • Alloimmune stimulation  infections” (graft injury)  cytokines, decreased tolerance chemokines • Enhanced antigen • Increased effector over Treg cells presentation
    49. 49. Remaining Questions Do chronic viral infections  diminished responses to new antigens and risk for opportunistic infections via compression of the T-cell repertoire? How much virus/replication is needed for various effects? Role of asymptomatic viral replication? Altered response to subsequent cross-reacting infections:  Suppression by regulatory T-cells  Excessive cytokine responses  Chronic cytokine release  bias of T-cells to effector and fewer memory cells (lower quality memory responses) Do vaccines make this process worse? Role of innate immune function (NK and plasmacytoid dendritic cells, other subpopulations) Homeostatic proliferation: Do we provoke graft rejection by altering gut flora or antiviral prophylaxis?
    50. 50. Thank you for inviting me. I would be happy to answer questions. If I can help: jfishman@partners.or g

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