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Epstein-Barr Virus: Cancer and Immunosuppression. Jeffrey I. Cohen Head, Medical Virology Section Laboratory of Clinical Infectious Diseases NIH. Pathogenesis of EBV Infection. Cohen NEJM 2000. Cellular Immune Responses Are Critical For Control of EBV.

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epstein barr virus cancer and immunosuppression

Epstein-Barr Virus: Cancer and Immunosuppression

Jeffrey I. Cohen

Head, Medical Virology Section

Laboratory of Clinical Infectious Diseases

NIH

slide3

Cellular Immune Responses Are Critical For Control of EBV

Early IM: NK cells

non-HLA specific CTLs

Late IM: HLA-restricted CTLs (CD8 and CD4):

Lytic epitopes - up to 40% of CD8 cells

Latent epitopes - up to 2% of CD8 cells

Healthy EBV seropositive persons:

Latent epitopes- 4% of CD8 cells

Lytic epitopes- 0.1 to 5% of CD8 cells

slide4

EBV Transforms B Cells In Vitro and the Cells Express Limited Viral and Cellular Proteins

EBV LCLs

EBV Latency Proteins

Cell Genes Induced

Rickinson and Kieff, Fields Virology

slide5

EBV Latency Proteins

Cohen NEJM 2000

slide6

LMP-1 is the EBV Oncogene

Oncogene Expression in transgenic mice leads to B cell lymphoma; expression in fibroblasts leads to tumors in nude mice

B Cell Proliferation Upregulates adhesion molecules, CD23, CD40, IL-6, IL-10, etc. Activates NF-B

Inhibits apoptosisUpregulates Bcl-2, A20, Mcl-1

H & E

LMP-1

(Kulwichit et al PNAS 1998)

slide7

LMP-1 Mimics constitutively form of CD40 in B cells

Thorley-Lawson, Nature Rev Immunol, 2001

slide8

Activation of NF-B in Tumor from Patient with Post-Transplant EBV Lymphoproliferative Disease

Lane 1: EBV- B cell

Lane 2: EBV+ B cell

Lane 3: EBV- LPD

Lane 4: EBV+ LPD

Liebowitz NEJM 1998

slide9

Diseases Associated with EBV

EBV in B Cell

Infectious mononucleosis

X-Linked Lymphoproliferative Disease

Chronic active EBV

Hodgkin Disease

Burkitt Lymphoma

Lymphoproliferative disease

EBV in Other Cells

Nasopharyngeal carcinoma

Gastric carcinoma

Nasal T/NK cell lymphomas

Peripheral T cell lymphomas

Oral hairy leukoplakia

Smooth muscle tumors in transplant patients

slide10

Diseases Driven by Epstein-Barr Virus

Infectious mononucleosis

Chronic Active EBV

X-linked lymphoproliferative disease

Lymphoproliferative disease

Oral hairy leukoplakia

Hodgkin disease EBV EBV-Driven

Nasopharyngeal carcinoma Gene Cell

T cell lymphoma Expression Proliferation

Burkitt lymphoma

slide11

Patterns of EBV Latent Infection

  • Latency
  • TypeEBEREBNA-1EBNA-2EBNA-3LMP-1LMP-2Disease
  • 1 + + - - - - BL
  • + + - - + + NPC, HD
  • + + + + + + IM, LPD
  • Other + +/- - - - +/- Carrier
slide12

Burkitt Lymphoma

EBV+: 90% of cases in developing countries – jaw tumors

20% cases in US – children with abdominal tumors

AIDS patients – tumors in lymph nodes

EBV may be one “hit” but all tumors have c-myc translocations

Dysregulation of c-myc oncogene

Only EBV EBNA-1 expressed

Therapy: Chemotherapy

slide13

Hodgkin Disease

EBV+: 60-70% of cases in developing countries

35-50% cases in US

EBV in Reed-Sternberg cells

Therapy: Chemotherapy, radiation

Anti-EBV CTLs effective in some cases

LMP-1 expression

ebv associated smooth muscle tumors
EBV-Associated Smooth Muscle Tumors

Occur in transplant recipients, AIDS patients, congenitial immunodeficiency

Pathology: leiomyosarcomas and leiomyomas in various organs (especially transplant) and lymph nodes

Some tumors regress with reduced immunosuppression

slide15

EBV Lymphoproliferative Disease

Occurs with immunodeficiency (AIDS, congenital) or after transplantation, RA and MTX

Symptoms: Infectious Mononucleosis Mass lesions in organs (less often lymph nodes)

Risk Factors: Primary infection GVHD with increased immune suppression T cell depleted bone marrow CMV

Cohen NEJM 2000

risk for ebv ptld
Risk for EBV PTLD
  • Primary infection- higher viral loads, no memory T cells to EBV
  • CMV infection
  • Polymorphisms corresponding to low production of IFN-, TNF-; high levels of IL-10
  • Level of intensity of T cell immunosuppression
slide17

EBV Viral Load is Increased in Patients

with Lymphoproliferative Disease

Riddler, Blood 1994

Viral Load Used to Monitor Transplant Patients: Increased EBV load at onset of LPD Used to initiate preemptive therapy

slide18

Treatment of EBV Lymphoproliferative Disease

  • Reduce immunosuppression- Early, polymorphic lesions often responsive Later monomorphic lesions can have chromosomal changes
  • Excise localized lesions
  • Radiation therapy (for CNS lesions) or chemotherapy
  • Anti-CD20 monoclonal antibody (rituximab)
  • Interferon-
  • For stem cell transplant recipients: donor lymphocyte infusions or donor EBV-specific cytotoxic T cell infusions
  • For solid organ transplant recipients: autologous or HLA-matched, EBV-specific, cytotoxic T cell infusions
slide19
Cutaneous Lymphomas Associated with EBV-infected T cellsNon-immunosuppressed Patients More often in Asians
  • Hydroa vacciniforme: vesciulopapular lesions on face and hands, fever, can progress to T cell lymphoma
  • Angiocentric NK/T cell lymphomas:ulcers, vesicles, nodules, papules on nose, checks, lips, extremities, trunk
  • EBV subcutaneous T cell lymphoma: plaques, fever, hepatosplenomegaly, pancytopenia, panniculitis, hemophagocytosis
slide20

Cutaneous Lymphomas Associated with EBV-infected B cellsImmunosuppressed Patients

  • Cutaneous ulcerated nodules- B cell lymphomas after transplant or in patients with AIDS
  • Cutaneous B cell lymphomas in patients with rheumatoid arthritis or polymyositis receiving methotrexate- resolution in some after drug stopped
ebv lpd more common at sites with chronic inflammation
EBV LPD More Common at Sites with Chronic Inflammation
  • Disease more frequent in transplanted organ Higher frequency of EBV+ cells

Antigenic stimulation with B cell proliferation

Cytokine activation in organ

  • Reports of EBV+ pyothorax-associated pleural lymphomas at site of pleural inflammation after tuberculosis (Arch Pathol Lab Med. 1996)
  • Report of 3 cases of EBV+ large B cell lymphomas in patients with chronic inflammation (osteomyelitis- tumor at site of bone, chronic venous ulcers- tumor at site of ulcer) (J Pathol. 1997 )
immunosuppressive agents associated with ebv lpd
Immunosuppressive Agents Associated with EBV LPD
  • Steroids and Azathioprine
  • Methotrexate: Patients with RA, Polymyositits
  • Antibodies: ATG: anti-thymocyte globulin ALG: anti-lymphocyte globulin OKT3: anti-CD3
  • Calcineurin inhibitors: cyclosporine, tacrolimus
  • Sirolimus
slide23

CY (100 g/ml)

Prednisone (10 m)

Prednisone (1 m)

CY (10 g/ml)

MPA (100 g/ml)

MPA (10 g/ml)

MTX (50 g/ml)

AZA (10 g/ml)

AZA (1 g/ml)

CsA (10 g/ml)

CsA (1 g/ml)

MTX (5 g/ml)

_

DRUG:

BMRF1

-actin

Methotrexate, but not other Immunosuppressants, Induces EBV Lytic Replication

Feng et al JNCI 2004

calcineurin inhibitors and ptld cyclosporine tacrolimus
Calcineurin Inhibitors and PTLD: Cyclosporine, Tacrolimus
  • Inhibit generation of cytotoxic activity
  • Induce expression of IL-6 and TGF- that supports B cell activation and proliferation
  • Enhance survival of EBV-transformed cells in vitro by protecting from Fas-mediated apoptosis
  • Lower doses of cyclosporine allow T cell responses to EBV in vitro and are associated with lower rates of lymphoma than higher doses
  • In children tacrolimus is associated with a higher risk of LPD than cyclosporine in some, but not all studies.
slide25

Risk of PTLD in Pediatric Liver Transplant Recipients for Primary Tacrolimus Therapy

Cacciarelli et at Pediatric Transplantation 2001

kaposi s sarcoma at the site of topical tacrolimus
Kaposi’s Sarcoma at the Site of Topical Tacrolimus

28 yo AIDS patient on HAART (CD 143) with psoriasis and seborrheic dermatitis treated with topical tacrolimus 0.1% ointment to axilla, groin, head for 1 month

Developed KS at these sites and in lungs while on tacrolimus

Cho et al. J. Am Acad Dermatol. 50:149-50, 2004

lymphoma at site of atg or alg injections
Lymphoma at Site of ATG or ALG Injections

AgeTransplantAT/LGSites of LymphomaRef

  • kidney horse buttock, nodes 1
  • kidney horse buttock, nodes, liver 2

32 heart rabbit thigh, brain, lung, nodes 3

  • heart rabbit thigh, chest wall, 3

abdominal nodes

1. Deodhar et al N Engl J Med 280:1104-6, 1969

2. Cotton et al. Transplantation 16:154-7, 1973; follow-up Herrera et al. Mil Med. 146:652-4, 1981

3. Weintraub and Warnke Transplantation 33:347, 1982

slide28

Lymphoma at Site of ALG(Cotton et al 1973; Herrera et al 1981)

47 y.o. renal transplant recipient

thoracic duct canulation before and 3 wks after transplant to deplete lymphocytes; prednisone, azothioprine

Horse ALG i.m. in buttocks post transplant on x 14 d, 3 x/wk x 1 yr

6 months after last ALG nodule at site >reticulum cell sarcoma (no EBV studies), immunosuppression reduced, radiation to site;

One year later draining lymph nodes had histiocytic lymphoma, radiation (no EBV studies)

2 years later died of bacteremia-lymphoma in liver

lymphoma at site of alg deodhar et al 1969
Lymphoma at Site of ALG(Deodhar et al 1969)

32 y.o. renal transplant recipient on azathioprine and prednisone

Rejection 7 months after transplant: treated with actinomycin C and graft irradiation

Horse ALG i.m. in buttocks: 6 weeks later nodule at site, enlarge over 10 months; excised-reticulum cell sarcoma with lymph node involvement (no EBV studies); died of OI

lymphoma at site of alg weintraub and warnke 1982
Lymphoma at Site of ALG(Weintraub and Warnke 1982)

7 patients with NHL/182 heart transplants, 2 developed lymphoma at site of ATG

  • 32 yo cardiac transplant recipient underwent two allogeneic heart transplants

Developed high grade immunoblastic lymphoma in thigh at site of rabbit ATG, later in brain and lung

  • 18 yo cardiac transplant recipient underwent two allogeneic heart transplants

Developed large noncleaved cell lymphoma in thigh at site of rabbit ATG, later chest wall and abdomen

summary ebv lpd in persons receiving immunosuppressants
Summary: EBV LPD in Persons Receiving Immunosuppressants
  • Most early, polymorphic lesions are EBV driven, and may respond to reduction in immunosuppression
  • Later monomorphic lesions may have chromosomal changes and often require chemotherapy
  • More common with primary EBV infection
  • May have genetic component (cytokine polymorphisms)
  • More common at site of chronic inflammation
  • Some occur at sites of local immunosuppression: ATG or ALG injection sites – all patients on other immunosuppression