Down‐regulation of peripheral blood cell interferon receptors in chronic myelogenous leukemia patients undergoing human interferon (HuIFNα) therapy

Abstract

Our interest in studying interferon (IFN) receptor activity in peripheral blood cells (PBCs) from patients with chronic myelogenous leukemia (CML) receiving therapeutic doses of partially purified leukocyte IFN (IFNα) stems from a need for more adequate monitoring of IFN therapy. The binding of ³⁵S-labelled recombinant DNA-derived leukocyte clone A IFN (³⁵SrlFNαA) to PBCs from 8 patients with CML was determined before and during IFNα treatment. The patients′ mean pretherapy binding level (0.049 femtomoles of bound ³⁵S-rlFNαA) was in the range of values obtained from 4 normal donors (mean of 0.054 femtomoles bound). Within 24 hr of the first IFNα dose, the mean femtomoles bound decreased 10-fold and remained low during the course of IFNα treatment. In I/I patient, we demonstrated that this decreased binding was due to a loss in number of IFN receptors. The apparent number of receptors after 5 doses of IFNα decreased from approximately 600 receptors per cell at pretherapy to approximately 75 receptors per cell, with no difference in the dissociation constants (1.13 × 10−¹⁰M, 0.968 × 10−¹⁰M, before and during treatment, respectively). In 4/4 patients, we demonstrated indirectly that the decreased binding was not due to receptor saturation as a result of residual circulating IFNα. In 3/3 patients, we demonstrated a gradual recovery of binding capacity after incubating the patients′ PBCs at 37°C. Within 2–7 days in vivo recovery of binding, comparable to pretherapy levels, was observed in 3/3 patients whose IFNα therapy was discontinued. Combining all these data, we conclude that in both responding and nonresponding patients with CML, IFNα exposure induces decreased binding of labelled IFN when a single recombinant DNA-derived IFN species is used. We feel the supporting data indicate that the decreased binding capacity may be due to receptor down-regulation. In the limited number of patients studied thus far, there was no correlation between clinical hematologic response and occurrence of down-regulation, however, down-regulation of cell surface receptors may be required to sustain a biological effect. Further studies of both the kinetics of down-regulation and activation of key enzyme systems are required to fully evaluate the relevance of these findings.