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Abstract
Adoptive immunotherapy with lymphokine activated killer (LAK) cells and recombinant interleukin-2 (IL-2) is successful in a variety of tumour models in both the normal and the immunocompromised mouse. We investigated the effects of an immune response to an allogeneic challenge on the metabolism of IL-2. Serum IL-2 levels at different time points after the administration of 20,000 units of IL-2 intraperitoneally were 2-4 fold higher in normal mice than in recently alloimmunized mice. In an intraperitoneal tumour model the alloimmunization of mice with allogeneic P815 tumour cells or splenocytes IP prior to the intraperitoneal inoculation of syngeneic tumour significantly diminished the anti-tumour effects of IL-2 and LAK cell immunotherapy in 7 consecutive experiments. High doses of IL-2 or pretreatment with cyclophosphamide restored the efficacy of IL-2 and LAK cell immunotherapy. From these results we hypothesize that T cells, activated by the allogeneic challenge, consume IL-2 and thus inhibit the effects of IL-2 and LAK cell treatment by competitive inhibition. LAK cell activity with reduced levels of IL-2 cannot be maintained and anti-tumour effects are lost. High doses of IL-2 were shown to overcome the competition for IL-2. Alternatively activated T-cells could be eliminated by pretreatment with cyclophosphamide and anti-tumour effects restored. These results are important in that they provide an alternative explanation as to the mechanism of non-specific cell mediated suppression and may in part explain the failure of some cancer patients to respond to treatment with IL-2 plus LAK immunotherapy.
Highlights
Blood collected at each time point was pooled and their serum frozen for IL-2 determinations at a later time
We concluded from these experiments that IL-2 consumption is increased in mice actively engaged in an alloimmune response
In order to determine the optimal time for assessment of the interaction of an immune response and i.p. immunotherapy with IL-2 we studied the kinetics of the cytolytic responses generated after i.p. allogeneic tumour challenge
Summary
MiceC57BL/6 (BL/6) (H-2b) female mice were obtained from Jackson Laboratory (Bar Harbor, ME) and used 9-12 weeksCorrespondence: P.H. C57BL/6 (BL/6) (H-2b) female mice were obtained from Jackson Laboratory (Bar Harbor, ME) and used 9-12 weeks. They were maintained on laboratory chow and acidified water ad libitum in a pathogen free environment. Single cell suspensions were obtained by excising the tumour, mincing the tissue in Hanks balanced salt solution (HBSS, Biofluids, Rockville, MD) followed by repeated treatment at 37°C with 0.25% trypsin without calcium or magnesium (Biofluids, Rockville, MD). After 3min of stirring, the supernatant was discarded and an equal vol of fresh trypsin was added to the flask. For the three 8 min periods the supernatants, containing released tumour cells, were collected, and fresh trypsin again added back to the tumour. The supernatants were pooled in ice-cold HBSS. The cells were passed through a 100 gauge nylon mesh (Tobler, Ernst & Traber Co., Elmsford, NY), washed three times in HBSS and live cells counted in 0.08% trypan blue
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