Influence of low dose rIL-2 treatment on endogenous cytokine production, expression of surface IL-2R and the level of soluble IL-2R in patients with minimal residual disease.

This study was designed to investigate the immunomodulatory effect of low-dose IL-2 therapy (100 microg/day for 3 weeks) on interferon (IFN), tumor necrosis factor (TNF) production in vivo and in vitro and on the expression of IL-2Ralpha/beta and soluble form of IL-2Ralpha. Patients enrolled in the study suffered from multiple myeloma (MM), Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) All of them were in remission after chemotherapy or radiotherapy. Our results indicated that IL-2 given subcutaneously at a low dose of 100 microg/day for 3 weeks induced IFN-gamma and TNF-alpha in plasma (measured 24 hrs after the last dose of IL-2) and affected the ability of blood leukocytes to produce cytokines. Production of IFN-gamma induced in vitro with PHA was enhanced, but TNF-alpha production induced by lipopolysaccharide (LPS) and virus (Newcastle Disease Virus) was depressed. The expression of both: surface IL-2R, especially beta subunit on total population of lymphocytes and NK cells, and soluble form of IL-2R, of chain were significantly enhanced after low-dose IL-2 therapy. Low dose IL-2 therapy was well tolerated by all patients, and side effects not exceeding II grade of toxicity according to WHO scale were observed. Five patients with MM relapsed 3-10 month after cessation of IL-2 therapy, but all patients with Hodgkin's and non-Hodgkin's lymphomas are still in remission (20 months of observation).

[1]  T. Mosmann Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. , 1983, Journal of immunological methods.

[2]  D. Goeddel,et al.  Human tumor necrosis factor. Production, purification, and characterization. , 1985, The Journal of biological chemistry.

[3]  D. Nelson,et al.  Soluble interleukin 2 receptors are released from activated human lymphoid cells in vitro. , 1985, Journal of immunology.

[4]  D. Goeddel,et al.  Effect of interleukin 2, interferon-gamma, and mitogens on the production of tumor necrosis factors alpha and beta. , 1985, Journal of immunology.

[5]  R. Foà,et al.  High serum levels of soluble interleukin 2 receptor in patients with B chronic lymphocytic leukemia. , 1987, Blood.

[6]  C. Pui,et al.  High serum interleukin-2 receptor levels are related to advanced disease and a poor outcome in childhood non-Hodgkin's lymphoma. , 1987, Blood.

[7]  Kendall A. Smith,et al.  Interleukin-2: inception, impact, and implications. , 1988, Science.

[8]  J. Mier,et al.  IL-2 stimulates the production of IL-1 alpha and IL-1 beta by human peripheral blood mononuclear cells. , 1988, Journal of immunology.

[9]  F. Behm,et al.  Serum interleukin 2 receptor levels in childhood acute lymphoblastic leukemia. , 1988, Blood.

[10]  R. Foà,et al.  Production of tumor necrosis factor-alpha by B-cell chronic lymphocytic leukemia cells: a possible regulatory role of TNF in the progression of the disease. , 1990, Blood.

[11]  L A Rubin,et al.  The soluble interleukin-2 receptor: biology, function, and clinical application. , 1990, Annals of internal medicine.

[12]  H. Zwierzina,et al.  Detection of soluble IL‐2 receptor in the serum of patients with myelodysplastic syndromes: induction under therapy with GM‐CSF , 1991, British journal of haematology.

[13]  S. Voss,et al.  Characterization of the interleukin 2 receptors (IL-2R) expressed on human natural killer cells activated in vivo by IL-2: association of the p64 IL-2R gamma chain with the IL-2R beta chain in functional intermediate-affinity IL-2R , 1992, The Journal of experimental medicine.

[14]  L. Larsson,et al.  Interleukin-2 enhances the production of tumor necrosis factor-alpha in activated B-type chronic lymphocytic leukemia (B-CLL) cells. , 1993, Leukemia.

[15]  G. Gusella,et al.  IL-2 Up-regulates but IFN-γ suppresses IL-8 expression in human monocytes , 1993 .

[16]  V. Diehl,et al.  Serum Cytokine Levels in Cancer Patients Treated with Different Schedules of Ultra‐Low-Dose Interleukin‐2 , 1994, Journal of immunotherapy with emphasis on tumor immunology : official journal of the Society for Biological Therapy.

[17]  B. Coiffier,et al.  Interleukin-2 treatment in lymphoma: a phase II multicenter study. , 1994, Blood.

[18]  J. Daniluk,et al.  Interferon production by peripheral blood cells of patients with alcoholic liver disease (ALD). , 1994, Archivum immunologiae et therapiae experimentalis.

[19]  R. Hein,et al.  Low‐dose recombinant interleukin‐2 therapy in advanced multiple myeloma , 1995, British journal of haematology.

[20]  P. Dietrich,et al.  Low‐dose IL‐2 treatment: Activation of discrete T‐ and NK‐cell sub‐populations in vivo , 1995, International journal of cancer.

[21]  T. Robak Cytokines in the treatment of hematological disorders: recent progress and perspectives. , 1996, Archivum immunologiae et therapiae experimentalis.

[22]  A. Nagler,et al.  Immunotherapy with recombinant human interleukin-2 and recombinant interferon-alpha in lymphoma patients postautologous marrow or stem cell transplantation. , 1997, Blood.

[23]  H. Ben-bassat,et al.  Interleukin‐2 (IL‐2) Receptor α, β and γ Subunit Expression as a Function of B‐Cell Lineage Ontogeny: the Use of IL‐2‐PE664Glu to Characterize Internalization via IL‐2 Receptor Subunits , 1997 .