Cancer and Immunosuppression Pathogenesis of EBV Infection Cohen NEJM 2000 Early IM NK cells nonHLA specific CTLs Late IM HLArestricted CTLs CD8 and CD4 ID: 595606
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Slide1
Epstein-Barr Virus: Cancer and Immunosuppression Slide2
Pathogenesis of EBV Infection
Cohen
NEJM 2000Slide3
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
Cellular Immune Responses Are Critical For Control of EBVSlide4
EBV Transforms B Cells In Vitro and the Cells Express Limited Viral and Cellular Proteins
Rickinson and Kieff, Fields Virology
EBV LCLs
EBV Latency Proteins
Cell Genes InducedSlide5
EBV Latency Proteins
Cohen NEJM 2000Slide6
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-
BInhibits apoptosis Upregulates Bcl-2, A20, Mcl-1
LMP-1 is the EBV Oncogene
LMP-1
H & E
(Kulwichit et al PNAS 1998)Slide7
LMP-1 Mimics constitutively form of CD40 in B cells
Thorley-Lawson, Nature Rev Immunol, 2001Slide8
Liebowitz NEJM 1998
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+ LPDSlide9
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
Diseases Associated with EBVSlide10
Diseases Driven by Epstein-Barr Virus
Infectious mononucleosisChronic Active EBV X-linked lymphoproliferative disease Lymphoproliferative diseaseOral hairy leukoplakia
Hodgkin disease EBV EBV-Driven
Nasopharyngeal carcinoma Gene Cell
T cell lymphoma Expression Proliferation
Burkitt lymphomaSlide11
Latency
Type
EBER
EBNA-1 EBNA-2 EBNA-3 LMP-1 LMP-2 Disease1 + + - - - - BL + + - - + + NPC, HD + + + + + + IM, LPD
Other + +/- - - - +/- Carrier
Patterns of EBV Latent InfectionSlide12
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 translocationsDysregulation of c-myc oncogene
Only EBV EBNA-1 expressedTherapy: Chemotherapy
Burkitt Lymphoma
Slide13
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
Hodgkin Disease
LMP-1 expressionSlide14
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 immunosuppressionSlide15
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 2000Slide16
Risk for EBV PTLDPrimary infection- higher viral loads, no memory T cells to EBVCMV infection
Polymorphisms corresponding to low production of IFN-
, TNF-; high levels of IL-10
Level of intensity of T cell immunosuppressionSlide17
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 therapySlide18
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 infusionsSlide19
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, hemophagocytosisSlide20
Cutaneous Lymphomas Associated with EBV-infected B cells
Immunosuppressed 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 stoppedSlide21
EBV LPD More Common at Sites with Chronic InflammationDisease 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 )Slide22
Immunosuppressive Agents Associated with EBV LPDSteroids and AzathioprineMethotrexate: Patients with RA, Polymyositits
Antibodies: ATG: anti-thymocyte globulin ALG: anti-lymphocyte globulin OKT3: anti-CD3
Calcineurin inhibitors: cyclosporine, tacrolimus
SirolimusSlide23
Methotrexate, but not other Immunosuppressants, Induces EBV Lytic Replication
BMRF1
CY (100
g/ml)
Prednisone (10
m)
_
AZA (1
g/ml)
CsA (1
g/ml)
CY (10
g/ml)
MPA (10
g/ml)
Prednisone (1
m)
MTX (5
g/ml)
AZA (10
g/ml)
CsA (10
g/ml)
MPA (100
g/ml)
MTX (50
g/ml)
DRUG:
-actin
Feng et al JNCI 2004Slide24
Calcineurin Inhibitors and PTLD: Cyclosporine, TacrolimusInhibit generation of cytotoxic activityInduce 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 dosesIn 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 2001Slide26
Kaposi’s Sarcoma at the Site of Topical Tacrolimus
Cho et al. J. Am Acad Dermatol. 50:149-50, 2004
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 tacrolimusSlide27
Lymphoma at Site of ATG or ALG InjectionsAge
Transplant
AT/LG Sites of Lymphoma Ref kidney horse buttock, nodes 1 kidney horse buttock, nodes, liver 232 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, 1982Slide28
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 yr6 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 liverSlide29
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 OISlide30
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 abdomenSlide31
Summary: EBV LPD in Persons Receiving ImmunosuppressantsMost 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 inflammationSome occur at sites of local immunosuppression: ATG or ALG injection sites – all patients on other immunosuppression