The etiology and pathogenesis of mycosis fungoides (MF) and its leukemic variant, the Sezary syndrome have remained in question. While adult T cell leukemia/lymphoma (ATLL) is known to be caused by infection with the Human T Lymphotropic Virus Type I (HTLV-I), the majority of patients with MF have no antibodies and their malignant cells (Sezary cells), have not yet been shown to harbor the virus. The P.I. has succeeded in culturing the blood lymphocytes of patients with MF and has detected virus particles resembling HTLV-I in cultured cells of practically all patients. Most of these cultures have become immortalized. The particles in some specimens react with antisera to HTLV-I/II, whereas in other cultures, they are not reactive. Recently, utilizing a variety of specific primers and probes, it has been shown by PCR that the blood cells of 45/50 consecutive MF patients harbor HTLV-I sequences, whereas the cells of one patient proved to harbor a deleted proviral sequence specific for HTLV-II. Therefore, a role for HTLV or incomplete forms of these viruses in the pathogenesis of MF is entertained. This project will examine the mechanism(s) by which this retrovirus affects the evolution of the disease. Firstly, the cell(s) which harbor the virus in vivo will be identified. It is not known whether the neoplastic CD4+ cell is infected per se, or whether it is transformed indirectly. Therefore, freshly isolated specimens of MF blood, skin and lymph nodes will be fractionated to enrich for various subpopulations of lymphocytes, monocytes, dendritic and Langerhans cells. The populations found to harbor proviral sequences by PCR will then be subjected to in situ hybridization combined with histochemistry or, if the signal proves to be too weak, in situ PCR and immunoelectron microscopy will be done to identify the infected cell. Conversely, the pathogenic effect of HTLV- I/II will be studied in vitro. To this end, normal CD4-positive lymphocytes, monocytes, Langerhans, and dendritic cells will be cocultured with irradiated bona fide HTLV-infected cell lines, virus=containing MF cultures and the alleged HTLV transforming protein, tax. If the target cells become infected in vitro, the effect on their physiology (e.g. cytokine production, cytotoxicity) and parameters of transformation (immortalization, karyotypic changes and rearrangement of the T cell receptor beta chain) will be assessed. The infectivity of MF cells and/or their cultures will also be tested in rabbits. In addition, ultrastructural and freeze-fracture analyses of HTLV-I/II and their effect on mammalian cell membranes during viral uptake, proliferation, and polykaryon formation will be analyzed. These studies may help elucidate when, in its evolution, the inexorably fatal course of MF may be arrested.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA058519-01A3
Application #
2099194
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1994-12-15
Project End
1997-11-30
Budget Start
1994-12-15
Budget End
1995-11-30
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
New York
State
NY
Country
United States
Zip Code
10012
Zucker-Franklin, D; Pancake, B A; Brown, W H (2002) Prevalence of HTLV-I Tax in a subset of patients with rheumatoid arthritis. Clin Exp Rheumatol 20:161-9
Zucker-Franklin, D; Kosann, M K; Pancake, B A et al. (1999) Hypopigmented mycosis fungoides associated with human T cell lymphotropic virus type I tax in a pediatric patient. Pediatrics 103:1039-45
Zucker-Franklin, D; Pancake, B A (1998) Human T-cell lymphotropic virus type 1 tax among American blood donors. Clin Diagn Lab Immunol 5:831-5
Zucker-Franklin, D; Pancake, B A; Marmor, M et al. (1997) Reexamination of human T cell lymphotropic virus (HTLV-I/II) prevalence. Proc Natl Acad Sci U S A 94:6403-7
Pancake, B A; Zucker-Franklin, D (1996) The difficulty of detecting HTLV-1 proviral sequences in patients with mycosis fungoides. J Acquir Immune Defic Syndr Hum Retrovirol 13:314-9
Pancake, B A; Wassef, E H; Zucker-Franklin, D (1996) Demonstration of antibodies to human T-cell lymphotropic virus-I tax in patients with the cutaneous T-cell lymphoma, mycosis fungoides, who are seronegative for antibodies to the structural proteins of the virus. Blood 88:3004-9
Pancake, B A; Zucker-Franklin, D; Marmor, M et al. (1996) Determination of the true prevalence of infection with the human T-cell lymphotropic viruses (HTLV-I/II) may require a combination of biomolecular and serological analyses. Proc Assoc Am Physicians 108:444-8
Bogen, S A; Pelley, D; Charif, M et al. (1996) Immunophenotypic identification of Sezary cells in peripheral blood. Am J Clin Pathol 106:739-48
Khan, Z M; Sebenik, M; Zucker-Franklin, D (1996) Localization of human T-cell lymphotropic virus-1 tax proviral sequences in skin biopsies of patients with mycosis fungoides by in situ polymerase chain reaction. J Invest Dermatol 106:667-72
Zucker-Franklin, D (1996) Megakaryocyte and platelet structure in thrombocytopoiesis: the effect of cytokines. Stem Cells 14 Suppl 1:1-17