Release of interleukin-2-like material by b-chronic lymphocytic leukemia cells. An autocrine or paracrine model of production and utilization?

In a series of untreated patients with B-cell chronic lymphocytic leukemia (B-CLL), the capacity of the neoplastic B-cell population to release an interleukin-2 like factor (IL-21f) was assessed. While unstimulated purified leukemic B-cells showed no IL-21f production, in 16 of the 27 cases tested (59.2%) significant amounts of IL-21f (4.3–125 U) were released following activation with phytohemagglutinin (PHA) and the phorbol ester 12- O-tetradecanoylphorbol-13-acetate (TPA). In seven further cases (25.9%), small quantities of IL-21f (0.2–1.7 U) were detected, while only in four (14.8%) no release was found. In 11 of the 20 cases (55%), PHA alone was also capable of inducing the production of limited amounts of IL-21f (0.4–8 U). Only small amounts were released from B lymphocytes isolated from normal tonsils both with PHA and PHA plus TPA. Further purification using a fluorescence activated cell sorter suggests that the IL-21f is truly produced by leukemic B cells and blocking experiments with the PC-61 monoclonal antibody indicate that IL-21f and IL-2 use the same cell membrane receptor. However, co-cultures of leukemic B cells with small amounts of autologous or allogeneic T lymphocytes enhanced the amount of IL-21f released into the supernatant to values markedly higher than those released by T- or B cells alone. Unlike normal B lymphocytes, unstimulated purified leukemic B cells from 17 out of 23 B-CLL cases (73.9%) were capable of absorbing variable amounts of exogenous IL-2. In addition, in six of the 11 cases tested (54.5%) IL-2 alone was capable of producing a 2–4 fold increase of thymidine uptake. In six out of eight cases (75%), a 2–5 fold enhancement of the proliferative response was observed when the leukemic B cells were co-stimulated with Staphylococcus aureus Cowan 1 (SAC) and IL-2. Moreover, when the cells were pre-activated with SAC or with PHA plus TPA and then further stimulated with IL-2, a 2–20 fold increase in proliferative response was found in the majority of cases studied. These findings indicate that elevated quantities of IL-21f may be released in B-CLL particularly due to the B- and T cell interconnections, and that the leukemic B cells appear capable of absorbing IL-2 and of proliferating after costimulation with IL-2. It is suggested that in B-CLL a paracrine or possibly autocrine system of IL-2 production and utilization may occur, which may play a contributory role in the expansion of the disease.