Cutaneous T cell lymphoma (CTCL) is a clonally-derived, skin-invasive malignancy of CD4+ helper T lymphocytes. During the early stages of disease, the immune system of patients with CTCL appears normal; however, certain advanced forms of CTCL, such as the Sezary syndrome (SS), which is associated with a typical constellation of cellular and humoral immune abnormalities. These include depressed T-cell responses to antigens, impaired cellular cytotoxicity, elevated serum IgE and IgA, eosinophilia, and decreased T-cell interleukin-2 receptor expression. The scope of these abnormalities is strikingly similar to the in vitro activities of interleukins 4 and 5 (IL-4 & IL-5). In this regard, discrete subsets of murine T-helper cells that produce IL-4 and IL-5 (Th2 cells) or IL-2 and interferon-gamma (IFN-gamma) (Th1 cells) in a mutually exclusive secretion pattern have been described. Furthermore, cytokines produced by one subset can provide a negative feedback signal to the reciprocal subset. Preliminary studies using enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR) assays indicate that peripheral blood lymphocytes (PBLs) of patients with SS produce significantly more IL-4, and significantly less IL-2 and IFN-gamma, and contain significantly more messenger RNA (mRNA) specific for IL-4 and IL- 5 than do PBL from patients with limited plaque CTCL and from normal controls. Furthermore, short-term culture of SS PBL with small doses of IFN-gamma completely suppressed IL-4 production in vitro. Based upon these observations, it is our hypothesis that (1) CTCL represents a proliferation of IL-4 and IL-5-producing Th2-like cells, that (2) abnormal production of IL-4 and IL-5 by the malignant T-cells is associated with the observed immune abnormalities that occur with advancing stage of disease, and that (3) IFN-gamma treatment of the malignant T-cells can inhibit the abnormal IL-4 production. By use of ELISA and PCR, we propose to confirm that the malignant T-cell in CTCL is a Th2-like cell that is overproducing IL-4 and IL-5 and that has a defective capacity to product IL-2 and IFN-gamma. We propose to correlate the clinical progression of disease and the presence of immune abnormalities with abnormal cytokine regulation by the malignant T-cells. Furthermore, through an examination of pre- and post-transcriptional events, the effects of IFN-gamma on the regulation of IL-4 production will be studied. Lastly, recent findings indicate that IL-12, a potent inducer of IFNgamma and cytolytic lymphocyte activity, and, an antagonist of IL-4, may be an ideal candidate cytokine for immunotherapy of SS. The results of this study will enhance our understanding of the mechanisms involved in disease progression in CTCL, will elucidate the role of cytokines int he immune abnormalities, and will permit the development of therapeutic strategies utilizing biological response modifiers, including IFNgamma, IFNalpha, and IL-12, to counteract the abnormal cytokine production.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA058841-02
Application #
2099467
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1993-07-12
Project End
1996-06-30
Budget Start
1994-07-01
Budget End
1995-06-30
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Dermatology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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