IN-VIVO REGULATION OF TRANSFORMING GROWTH-FACTOR-BETA-1 TRANSCRIPTIONBY IMMUNOTHERAPY - INTERLEUKIN-2 IMPAIRS INTERFERON-ALPHA-STIMULATED INCREASE IN STEADY-STATE MESSENGER-RNA LEVELS OF TRANSFORMING GROWTH-FACTOR-BETA-1

Recombinant interleukin-2 (rIL-2) in combination with recombinant inte rferon ex (rIFN alpha) has been shown to mediate significant antitumor al effects in some patients with advanced renal cell cancer or maligna nt melanoma. The therapeutic effects may be partially modulated by sec ondarily induced cytokines, especially with regard to in vivo lymphocy te activation. To investigate possible negative effects on lymphocyte activation during immunotherapy, we designed a study on transcription of transforming growth factor beta 1 (TGF beta 1), a known inhibitor o f lymphocyte function, in patients undergoing treatment with daily alt ernating administration of rIFN alpha and rIL-2. Here we present data on gene expression of TGF beta 1. Kinetic mRNA studies revealed an inc rease of TGF beta 1 mRNA in peripheral mononuclear cells 12 h after su bcutaneous injection of rIFN alpha. The following intravenous rIL-2 ad ministration significantly decreased the amounts of TGF beta 1 specifi c mRNA. in contrast to the effect of the first dose, subsequent applic ation of rIFN alpha did not enhance TGF beta gene expression during rI FN alpha/lL-2 therapy. The diminished TGF beta 1 gene expression retur ned to pretreatment levels 1-7 days after the last rIL-2 administratio n. When IL-2 expression was studied, increase in IL-2 mRNA was concomi tant with a decrease in TGF beta 1 transcripts. Our results indicate a complex regulatory effect on secondarily induced cytokines such as TG F beta 1 by immunotherapeutic approaches. The rIL-2-mediated down-regu lation of increased TGF beta 1 steady-state mRNA levels following rIFN alpha may represent a positive immune regulatory effect on cytotoxic cells. Furthermore this effect may modulate proliferation of neoplasti c tissues.