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Effects of alpha-interferon on MHC unrestricted cytotoxicity in chronic myelogenous leukemia
A Meseri-Delwail1, V Delwail, A Brizard
1URA CNRS 1172, IBMIG, Poitiers, France.
Insights
Alpha-interferon (alpha-IFN) enhances natural killer (NK) and lymphokine-activated killer (LAK) activities in chronic myelogenous leukemia (CML) patients, correlating with cytogenetic remission. However, lymphoid blast crisis can occur despite high NK/LAK activity, suggesting immune escape mechanisms.
Area of Science:
- Immunology
- Hematology
- Oncology
Background:
- Alpha-interferon (alpha-IFN) can induce lymphokine-activated killer (LAK) cytotoxicity without interleukin-2 (IL2).
- The mechanism by which alpha-IFN reduces Philadelphia chromosome-positive (Ph1+) clones in chronic myelogenous leukemia (CML) is not fully understood.
- Investigating the role of natural killer (NK) and LAK activity in alpha-IFN's therapeutic effect on CML is crucial.
Purpose of the Study:
- To determine if alpha-interferon's efficacy in reducing Ph1+ clones in CML patients is mediated by NK or LAK activity.
- To assess the correlation between NK and LAK activities and cytogenetic remission in alpha-IFN-treated CML patients.
- To investigate the immune status of CML patients experiencing lymphoid versus nonlymphoid blast crisis during alpha-IFN therapy.
Main Methods:
- NK and LAK cytotoxicity assays were performed using NK-sensitive (K562) and NK-resistant (Raji) cell lines.
- Effector cells were patient blood mononuclear cells (MC) without in vitro activation.
- Target-cell colony-growth inhibition assay was used to measure cytotoxicity.
Main Results:
- Cytogenetic remission in alpha-IFN-treated CML patients was significantly associated with enhanced NK and LAK activities.
- Some patients developed lymphoid blast crisis despite high NK/LAK activity and partial/total cytogenetic remission.
- Most patients with nonlymphoid blast crisis had 100% Ph1+ cells and defective NK and/or LAK activity.
Conclusions:
- Alpha-interferon likely exerts an indirect, complex effect on CML cells mediated by immune surveillance cells.
- Enhanced NK and LAK activities correlate with therapeutic response in CML patients treated with alpha-IFN.
- Lymphoid blast crisis may represent a form of immune escape from LAK cytotoxicity in CML.
Abstract:
The capacity of alpha-interferon (alpha-IFN) to induce lymphokine activated killer (LAK) cytotoxicity in the absence of interleukin-2 (IL2) has prompted us to test whether its ability to reduce dramatically the number of Ph1+ clones in chronic myelogenous leukemia (CML) patients is in part mediated through the generation of natural killer (NK) or LAK activity. The latter were tested using NK-sensitive (K562) and NK-resistant (Raji) cell lines in a target-cell colony-growth inhibition assay. Effector cells (E) were patient blood mononuclear cells (MC) without in vitro activation prior to their coculture with targets (T). Here we report that cytogenetic remission in alpha-IFN-treated patients is associated with significantly enhanced NK and LAK activities. Nevertheless, some patients under alpha-IFN therapy were found to develop lymphoid blast crisis despite high levels of NK and LAK activities, and partial or total cytogenetic remission. In contrast, most of the patients who developed nonlymphoid blast crisis presented 100% Ph1+ cells and displayed defective NK and/or LAK activity. These observations could favor the hypothesis that there is an indirect but complex effect of alpha-IFN on leukemic cells, mediated by cells involved in immune surveillance; and also that lymphoid blast cells may actually escape LAK cytotoxicity.