Epstein-Barr Virus: Cancer and Immunosuppression .

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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 Jeffrey I. Cohen Head, Medical Virology Section Laboratory of Clinical Infectious Diseases NIH

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Pathogenesis of EBV Infection Cohen NEJM 2000

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Cellular Immune Responses Are Critical For Control of EBV Early IM: NK cells non-HLA particular CTLs Late IM: HLA-confined CTLs (CD8 and CD4): Lytic epitopes - up to 40% of CD8 cells Latent epitopes - up to 2% of CD8 cells Healthy EBV seropositive people: Latent epitopes-4% of CD8 cells Lytic epitopes-0.1 to 5% of CD8 cells

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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

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EBV Latency Proteins Cohen NEJM 2000

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LMP-1 is the EBV Oncogene Expression in transgenic mice prompts B cell lymphoma; expression in fibroblasts prompts tumors in bare mice B Cell Proliferation Upregulates grip particles, CD23, CD40, IL-6, IL-10, and so forth. Enacts NF- B Inhibits apoptosis Upregulates Bcl-2, A20, Mcl-1 H & E LMP-1 (Kulwichit et al PNAS 1998)

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LMP-1 Mimics constitutively type of CD40 in B cells Thorley-Lawson, Nature Rev Immunol, 2001

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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

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Diseases Associated with EBV in B Cell Infectious mononucleosis X-Linked Lymphoproliferative Disease Chronic dynamic EBV Hodgkin Disease Burkitt Lymphoma Lymphoproliferative ailment EBV in Other Cells Nasopharyngeal carcinoma Gastric carcinoma Nasal T/NK cell lymphomas Peripheral T cell lymphomas Oral bushy leukoplakia Smooth muscle tumors in transplant patients

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Diseases Driven by Epstein-Barr Virus Infectious mononucleosis Chronic Active EBV X-connected lymphoproliferative sickness Lymphoproliferative illness Oral bristly leukoplakia Hodgkin malady EBV-Driven Nasopharyngeal carcinoma Gene Cell T cell lymphoma Expression Proliferation Burkitt lymphoma

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Patterns of EBV Latent Infection Latency Type EBER EBNA-1 EBNA-2 EBNA-3 LMP-1 LMP-2 Disease 1 + - BL + - + NPC, HD + IM, LPD Other +/ - +/ - Carrier

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Burkitt Lymphoma EBV+: 90% of cases in creating nations – jaw tumors 20% cases in US – youngsters with stomach tumors AIDS patients – tumors in lymph hubs EBV might be one "hit" yet all tumors have c-myc translocations Dysregulation of c-myc oncogene Only EBV EBNA-1 communicated Therapy: Chemotherapy

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Hodgkin Disease EBV+: 60-70% of cases in creating nations 35-half cases in US EBV in Reed-Sternberg cells Therapy: Chemotherapy, radiation Anti-EBV CTLs powerful in a few cases LMP-1 look

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EBV-Associated Smooth Muscle Tumors Occur in transplant beneficiaries, AIDS patients, congenitial immunodeficiency Pathology: leiomyosarcomas and leiomyomas in different organs (particularly transplant) and lymph hubs Some tumors relapse with decreased immunosuppression

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EBV Lymphoproliferative Disease Occurs with immunodeficiency (AIDS, intrinsic) or after transplantation, RA and MTX Symptoms: Infectious Mononucleosis Mass sores in organs (less regularly lymph hubs) Risk Factors: Primary contamination GVHD with expanded resistant concealment T cell exhausted bone marrow CMV Cohen NEJM 2000

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Risk for EBV PTLD Primary contamination higher viral burdens, no memory T cells to EBV CMV disease Polymorphisms relating to low generation of IFN-, TNF-; large amounts of IL-10 Level of force of T cell immunosuppression

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EBV Viral Load is Increased in Patients with Lymphoproliferative Disease Riddler, Blood 1994 Viral Load Used to Monitor Transplant Patients: Increased EBV stack at onset of LPD Used to start preemptive treatment

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Treatment of EBV Lymphoproliferative Disease Reduce immunosuppression-Early, polymorphic sores frequently responsive Later monomorphic sores can have chromosomal changes Excise confined injuries Radiation treatment (for CNS sores) or chemotherapy Anti-CD20 monoclonal counter acting agent (rituximab) Interferon- For immature microorganism transplant beneficiaries: giver lymphocyte imbuements or benefactor EBV-particular cytotoxic T cell implantations For strong organ transplant beneficiaries: autologous or HLA-coordinated, EBV-particular, cytotoxic T cell mixtures

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Cutaneous Lymphomas Associated with EBV-tainted T cells Non-immunosuppressed Patients More frequently in Asians Hydroa vacciniforme: vesciulopapular sores on face and hands, fever, can advance to T cell lymphoma Angiocentric NK/T cell lymphomas:ulcers, vesicles, knobs, papules on nose, checks, lips, furthest points, trunk EBV subcutaneous T cell lymphoma: plaques, fever, hepatosplenomegaly, pancytopenia, panniculitis, hemophagocytosis

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Cutaneous Lymphomas Associated with EBV-tainted B cells Immunosuppressed Patients Cutaneous ulcerated knobs B cell lymphomas after transplant or in patients with AIDS Cutaneous B cell lymphomas in patients with rheumatoid joint pain or polymyositis getting methotrexate-determination in some after medication halted

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EBV LPD More Common at Sites with Chronic Inflammation Disease more incessant in transplanted organ Higher recurrence of EBV+ cells Antigenic incitement with B cell expansion Cytokine initiation in organ Reports of EBV+ pyothorax-related pleural lymphomas at site of pleural irritation after tuberculosis (Arch Pathol Lab Med. 1996) Report of 3 instances of EBV+ huge B cell lymphomas in patients with ceaseless irritation (osteomyelitis-tumor at site of bone, constant venous ulcers-tumor at site of ulcer) (J Pathol. 1997 )

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Immunosuppressive Agents Associated with EBV LPD Steroids and Azathioprine Methotrexate: Patients with RA, Polymyositits Antibodies: ATG: against thymocyte globulin ALG: hostile to lymphocyte globulin OKT3: hostile to CD3 Calcineurin inhibitors: cyclosporine, tacrolimus Sirolimus

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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, however not different Immunosuppressants, Induces EBV Lytic Replication Feng et al JNCI 2004

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Calcineurin Inhibitors and PTLD: Cyclosporine, Tacrolimus Inhibit era of cytotoxic movement Induce articulation of IL-6 and TGF- that backings B cell actuation and multiplication Enhance survival of EBV-changed cells in vitro by shielding from Fas-intervened apoptosis Lower measurements of cyclosporine permit T cell reactions to EBV in vitro and are connected with lower rates of lymphoma than higher dosages In kids tacrolimus is connected with a higher danger of LPD than cyclosporine in a few, yet not all studies.

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Risk of PTLD in Pediatric Liver Transplant Recipients for Primary Tacrolimus Therapy Cacciarelli et at Pediatric Transplantation 2001

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Kaposi\'s Sarcoma at the Site of Topical Tacrolimus 28 yo AIDS tolerant on HAART (CD 143) with psoriasis and seborrheic dermatitis treated with topical tacrolimus 0.1% balm to axilla, crotch, set out toward 1 month Developed KS at these locales and in lungs while on tacrolimus Cho et al. J. Am Acad Dermatol. 50:149-50, 2004

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Lymphoma at Site of ATG or ALG Injections Age Transplant AT/LG Sites of Lymphoma Ref kidney horse butt cheek, nodes 1 kidney horse butt cheek, hubs, liver 2 32 heart rabbit thigh, mind, lung, hubs 3 heart rabbit thigh, mid-section divider, 3 stomach hubs 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

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Lymphoma at Site of ALG (Cotton et al 1973; Herrera et al 1981) 47 y.o. renal transplant beneficiary thoracic pipe canulation before and 3 wks after transplant to exhaust lymphocytes; prednisone, azothioprine Horse ALG i.m. in backside post transplant on x 14 d, 3 x/wk x 1 yr 6 months after last ALG knob at site >reticulum cell sarcoma (no EBV ponders), immunosuppression decreased, radiation to site; after one year depleting lymph hubs had histiocytic lymphoma, radiation (no EBV concentrates on) after 2 years kicked the bucket of bacteremia-lymphoma in liver

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Lymphoma at Site of ALG (Deodhar et al 1969) 32 y.o. renal transplant beneficiary on azathioprine and prednisone Rejection 7 months after transplant: treated with actinomycin C and unite irradi

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