* Watch the video at the end of the presentation
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.
Acute kidney injury in critically ill patients in the new millenium: definiti...
Jay Fishman: indirect effects and viral infections: Infection in Transplantation
1. Beyond “Indirect Effects” --
The Impact of Infections in
Transplantation
Jay A. Fishman, M.D.
Massachusetts General Hospital and
Harvard Medical School
2. Viruses may be dangerous . . . .
…and not all
viruses are the
same!!
3. The risks of viral infection: What
have 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. 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
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. HCMV Protein Function
FC Receptor homologue Blocks antibody-dependent cytotoxicity; binding
TRL11/IRL11, UL118/119 nonspecific antibody coating against CD8 and NK cells
Pp65 matrix Phosphorylates IE-1 protein to inhibit MHC class I-restricted
antigen presentation
US3,US6, US10, US11 Block generation and export of MHC class I peptides
US3,US6, US10, US11 Reduced expression of MHC class I peptides
US2 Reduced antigen presentation in MHC class II pathway
MHC-I homologue UL40, Blocks NK cell activation (also: UL16, pp65)
UL122 miRNA, UL142, UL141
UL18 MHC class 1 homologue; reduced immune surveillance
UL20 T-cell receptor homologue; reduced antigen presentation
IE86 Inactivates p53; increase smooth muscle proliferation
UL33, UL33, UL78, US27, Transmembrane proteins chemokine receptors; reduced
US28 interferon and chemokine effects; reduced
inflammation, increased viral dissemination
IL-10 homologue UL111a; Immunosuppression; reduced MHC class I/II expression and
IL8 CXC-1 UL146, UL147 lymphocyte proliferation; increased neutrophil
chemotaxis; reduced dendritic cell and monocyte
chemotaxis and function
UL144 TNF receptor homologue
UL36, UL37 Anti-apoptosis for infected cells
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. Opportunistic Infections Promoted by
CMV 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
12. Preemptive Therapy vs Prophylaxis
Meta-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. 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. 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. Anti-CMV prophylaxis is associated with
increased 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. 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. 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. 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. Summary: Effects of Antiviral
Agents 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 vasculopathy
Lowance D, et al, for the International Valacyclovir Cytomegalovirus Prophylaxis
Transplantation 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. How best to impact indirect
effects?
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. 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. How do the effects of CMV compare
with those of HCV?
HCV reinfection is universal after liver
transplantation
What is the impact on the risk for other
infections?
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. Non-A Non-B Hepatitis – the early years
27/42 patients with hepatic dysfunction had life-
threatening infection (64.3% vs. 20% in patients without
hepatitis, p<0.01))
LaQuaglia MP et al.
Transplant. 32(6):504-7,
1981 Dec
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 0.012
Rejection episodes occurring within 6 months after transplantation were
also higher in patients with recurrent HCV hepatitis (P = 0.09).
26. HCV in renal recipients
Kaplan-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. Outcomes: Outcomes in hepatitis C virus–positive
recipients (compared with hepatitis C virus–negative
recipients) of solid organ transplantation (non-liver)
Type of transplant Outcome
Renal
Decreased long-term patient survival (follow-up >10 y)
Decreased graft survival
De novo or recurrent glomerulopathy
Cirrhosis
Posttransplant diabetes
Pancreas, kidney-
pancreas Increased proteinuria
Higher requirements for hypoglycemic agents
No difference in patient, graft survival in short-term
studies
No long-term studies
Cardiac 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. Post-transplant Diabetes Mellitus (PTDM) In Liver
Transplant Recipients: Temporal Relationship With
Hepatitis C Virus Allograft Hepatitis and Impact On
Mortality
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. 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: A
multivariate 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 for
increased 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.
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. 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.
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. Heterologous Immunity and Viral
Infection 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. 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. 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. T-cell depletion or Stem cell
transplants 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)
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. 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. Natural Killer Cells induce Coronary Allograft
Vasculopathy (CAV) in Mice without T- or B-cells if
infected with Lymphocytic Choriomenigitis Virus
Parental 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. NK Cells, LCMV Infection:
B6.RAG1-/- into CB6F1.RAG1-/-
a. No infection
b. Control
c. Isograft
d. Day 28 LCMV
e. Day 56 LCMV
f. NK Cell depleted
g. NK Cell infiltrate
h. Smooth muscle
cell proliferation
i. Macrophages
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. 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. 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. Which antigens drive or control
homeostatic 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. 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 infection
Immune memory • Ligands for Pattern • Heterologous or cross-reactive
• Heterologous or cross- recognition receptors memory
reactive cytokines, chemokines Rejection
• Narrowed immune •Pathogen & Allograft • Failed costimulatory blockade
responses 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. 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. Thank you for inviting me. I
would be happy to answer
questions.
If I can help:
jfishman@partners.or
g
Notes de l'éditeur
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