CYTOKINE IMBALANCE IN POST TRANSPLANT LYMPHOMA

Epstein-Barr virus (EBV) is associated with the development of an aggressive B cell lymphoproliferative disorder (BLPD) in organ and bone marrow transplant recipients as well as individuals with congenital or acquired immunodeficiency (ID) syndromes. When polyclonal, BLPD may regress with withdrawal of immunosuppression, however, when monoclonal, BLPD acts malignant being unusually resistant to conventional therapy and frequently is fatal. Predisposing factors for BLPD include immunosuppression/deficiency, chronic antigenic stimulation, and cytokine imbalance. Although the nature of immune defects predisposing to BLPD are unknown, aberrant T cell responses have been implicated. Since BLPD occurs in both profound and mild ID, additional factors are likely involved. Possibly disturbed immunoregulation leads to excessive or deficient lymphokine production in response to antigenic stimulation resulting in inappropriate growth of EBV infected B cells. Determination of serum levels of major regulators of B cell proliferation (interferon alpha (IFN- a), IL-4 and IgE) in patients with BLPD, show that they have significantly reduced IFN-a and significantly elevated IL-4 and IgE, suggesting that unbalanced proportions of lymphokines favoring B cell proliferation may contribute to the development of BLPD. Supporting this hypothesis is the recent success in treatment of BLPD with IFN-a and intravenous immunoglobulin. Recently, it has been found that immunodeficient CB-17 (scid) mice injected with human peripheral blood develop human EBV associated B cell tumors identical to BLPD. We propose to use this model to investigate factors related to the development of BLPD and to define how cytokines regulate B cell growth in BLPD. The long-term objective is to explore prophylactic and therapeutic approaches which ultimately may be applied to patients. The study involves 3 phases: 1) establishment of the CB-17 scid/hu mouse model; 2) use this model to evaluate factors contributing to the risk for BLPD in humans including: immunosuppression (Cyclosporine A and OKT3); chronic antigenic stimulation (irradiated allogenic cells); and cytokine imbalance (IL-4); and 3) evaluation of IFN-a and anti-IL-4 moAb as prophylaxis or treatment of BLPD. Serum cytokine levels and T cell subsets will be monitored and tumors evaluated for EBV genome by Southern analysis, clonality by gene rearrangement and histology by light microscopy. Correlation of cytokine levels with incidence, time to onset and nature of tumors will better define the role cytokines play in the pathophysiology and management of BLPD.