Bulgarini D

Interleukin-2 bolus therapy induces immediate and selective disappearance from peripheral blood of all lymphocyte subpopulations displaying natural killer activity: role of cell adhesion to endothelium.

As early as 10-15 min after the start of a 30 min interleukin-2 (IL-2) infusion, a rapid, virtually complete disappearance of all natural killer (NK) lymphocyte subpopulations (including both CD3- CD56+ and CD3+ CD56+ cells with either alpha/beta or gamma/delta T-cell receptor) was observed from peripheral blood. In contrast, the number of T lymphocytes (CD3+ CD56-) was unmodified for at least 2 h after IL-2 injection. The IL-2-induced, rapid disappearance from peripheral blood of NK and NK-like lymphocytes may be related to their massive adherence to the activated endothelium. In this regard, IL-2 infusion caused a very rapid rise of tumour necrosis factor-alpha (TNF-alpha) plasma concentration, whereas other cytokines, such as interferon-gamma (IFN-gamma), were induced only at later times. In vitro experiments indicated that IL-2, either alone or better combined with TNF-alpha, exerts a rapid and selective stimulatory effect on NK adhesion to endothelial cells. On the basis of these findings, we suggest that the activation of NK lymphocytes induced by IL-2, alone or combined with TNF-alpha, plays a key role in mediating the massive and selective adherence of NK and NK-like cells following IL-2 bolus infusion.

IL-2 induces the release of secondary cytokines which stimulate the cytotoxic activity of either NK or CD8(+) lymphocytes.

The therapeutic potential of interleukin-2 (IL-2) for the treatment of human cancer has been extensively investigated (cfr. 1). In cell cultures IL-2 activates not only the lymphocytes which mediate MHC-restricted recognition of specific target cells, but also the natural killer (NK) lymphocytes which lyse in vitro particular tumor targets, The lymphokine-activated killer (lAK) cells, obtained by culturing peripheral blood lymphocytes (PBL) with IL-2 (2) exhibit the capacity of lysing a wide range of fresh and cultured malignant cells and virally-transformed normal tissues with minimal destruction of normal cells (2). Clinical trials have shown that significant anti-tumor responses are observed in a minority of patients with disseminated malignancies following infusion of large dosages of 11-2, combined or not with IAK cells (3). However severe toxicity is associated with high-dose IL-2 therapy (3). The administration of IL-2 results in a series of typical modifications of circulating blood cells. Thus IL-2 has a pronounced effects on the number of circulating lymphocytes: lymphopenia develops early after initiation of bolus IL-2 infusion and persists during the entire period of IL-2 administration. Within 24-48 h after discontinuance of IL-2, a marked rebound lymphocytosis develops (4); the level of rebound is doseand schedule-related (4). Furthermore, IL-2 infusion also elicits a series of secondary effects on the hematopoietic system: i) a progressive anemia may develop, which often requires blood transfusion; ii) thrombocytopenia is occasionally monitored; iii) eosinophilia often occurs, particularly after prolonged IL-2 administration (5). Prelimirary studies suggested that these hematological changes were associated with a decline in circulating erythroid (BFU-E) and granulocyte-macrophage (CFU-GM) progenitors (5). In the present study we have investigated the mechanisms responsible for IL-2-induced hematological modifications and the possible role of secondary IL-2-induced cytokines in the activation of cytotoxic lymphocytes.