have been immortalized by repetitive culturing in vitro in the presence of IL-2 
(25). B cell responses in vitro are also enhanced by IL-2 (26). Interleukin-2 can 
also stimulate secretion by T cells of other lymphokines including gamma 
interferon. 
2.4 Interleukin-2 in Human Studies 
Within the last ten years, Rosenberg et al have conducted several studies with 
systemic IL-2 in order to enhance lymphocyte function (14-16). Indeed, tumors 
such as renal cell carcinoma and melanoma have shown activity to intravenous 
IL-2 with a 20-30% response rate (15). The major effect of IL-2 was on the 
expansion of effector cell populations which have the capability to kill the tumor 
cells in vitro. However, because of the short serum half life of IL-2, high doses 
have to be used which are very toxic. Hypotension and capillary leak syndrome 
with decreased systemic vascular resistance can lead to interstitial pulmonary 
edema, pre-renal azotemia, cardiac arrhythmias, and myocardial infarction (14- 
lb). 
2.5 Gene Transfer in Animal Models 
Several laboratories have shown that the introduction of cytokine genes, such as 
IL-2 (17,19), IL-4 (33), IFN-gamma (34, 18), TNF (35) and GM-CSF (36) into 
tumor cells leads to their rejection in an immunologically competent host. 
Secretion of GM-CSF or IL-4 leads to a localized inflammatory response at the 
tumor site without induction of immunological memory (33,36). IL-2, interferon- 
gamma, and tumor necrosis factor on the other hand induce a long lasting 
cellular immune response which leads to the rejection of potentially lethal tumor 
challenges at a later time point (17,34,35). Initial studies by Tepper (33) 
demonstrated the potent effect of localized IL-4 secretion at the tumor site 
characterized by an accumulation of eosinophils and macrophages. Fearon (19) 
introduced the IL-2 gene into a poorly immunogenic murine colon carcinoma. 
The IL-2 secreting tumors were rejected and induced an effective cytolytic T cell 
response. Depletion of CD 8+ cells in vivo abrogated the cellular antitumor 
response implicating the pivotal role of class I restricted CD 84- cells. 
To approximate more closely the physiologic mode of cytokine secretion in the 
course of an immune response, the IL-2 gene was directly introduced into a 
murine fibrosarcoma cell line (CMS5). In this way a localized secretion of low 
levels of cytokine was achieved which led to the regression of the tumor (17,18). 
While control mice were killed by tumor within 45 days, mice carrying the IL-2 
secreting tumor not only rejected the implanted tumor and were cured, but also 
developed immunological memory. Lethal doses of tumor cells implanted after 
several months were rejected, while unrelated tumor grew and killed these mice, 
demonstrating the specificity of the response. In addition, lymphocytes taken 
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Recombinant DNA Research, Volume 15 
