title: Dysregulation of lymphocyte interleukin-12 receptor expression in Sézary syndrome.
abstract: Initial phase I and II clinical trials with recombinant human interleukin-12 have demonstrated the therapeutic efficacy of this cytokine in early stage cutaneous T cell lymphoma as compared with more advanced stages such as the leukemic Sézary syndrome. In an effort to optimize the use of recombinant human interleukin-12, using flow cytometry we studied the regulation of the interleukin-12 receptor beta1 (high affinity chain) and beta2 (chain necessary for interleukin-12 signal transduction) on normal volunteer CD4+ and CD8+ T cells and CD4+ and CD8+ cells from eight patients with different degrees of leukemic involvement with Sézary syndrome. The beta1 chain was not readily detectable on resting normal and T cells from Sézary patients, but expression was induced following T cell activation with phytohemagglutinin. Similarly, the beta2 chain was not detectable on resting normal volunteer T cells, but could be induced following phytohemagglutinin stimulation. Moreover, the beta2 chain on normal volunteer T cells was markedly upregulated following short-term culture with interferon-gamma or recombinant human interleukin-12. CD8+ T cells routinely exhibited a greater expression of beta2 than did CD4+ T cells. In marked contrast, both CD4+ and CD8+ T cells from patients with Sézary syndrome and a high tumor cell burden (> 50% circulating atypical Sézary T cells) failed to express the beta2 chain under any culture conditions. Although, culture with anti-interleukin-10 also markedly increased beta2 expression on normal volunteer T cells, this failed to induce expression on either CD4+ or CD8+ T cells from Sézary patients and a high tumor burden. Investigation of patients with Sézary syndrome and a low tumor cell burden (< 15% circulating Sézary T cells) revealed a pattern of beta2 expression that was intermediate between advanced Sézary syndrome and normal volunteers. Both CD4+ and CD8+ peripheral blood T cells from these earlier stage patients were induced to express the beta2 chain, although at a lower frequency of positivity than T cells from normals, following culture with phytohemagglutinin, interferon-gamma, recombinant human interleukin-12, or anti-interleukin-10. These results indicate that short-term culture with interferon-gamma and recombinant human interleukin-12 potently upregulates beta2 chain expression on T cells from normal volunteers, whereas a similar, but less marked effect occurs on T cells from Sézary syndrome patients and a low circulating tumor cell burden. In contrast, the beta2 chain appears to be suppressed on both CD4+ and CD8+ T cells from Sézary patients with a heavy circulating tumor cell burden and it is not induced by interferon-gamma or recombinant human interleukin-12. Therefore, recombinant human interleukin-12 is likely to be most effective for early stage cutaneous T cell lymphoma due to a greater display of beta2 receptors on responding CD8+ anti-tumor cytotoxic T cells.
authors.affiliation: Department of Dermatology, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Zaki
authors.forename: R B
authors.initials: RB
authors.lastname: Shane
authors.forename: Y
authors.initials: Y
authors.lastname: Geng
authors.forename: L C
authors.initials: LC
authors.lastname: Showe
authors.forename: S E
authors.initials: SE
authors.lastname: Everetts
authors.forename: D H
authors.initials: DH
authors.lastname: Presky
authors.forename: M
authors.initials: M
authors.lastname: Wysocka
authors.forename: J S
authors.initials: JS
authors.lastname: Moore
authors.forename: A H
authors.initials: AH
authors.lastname: Rook
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000494:pharmacology; D009360:Neoplastic Cells, Circulating; D010835:Phytohemagglutinins; D018123:Receptors, Interleukin / Q000096:biosynthesis*; D053707:Receptors, Interleukin-12; D012751:Sezary Syndrome / Q000276:immunology* / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D012878:Skin Neoplasms / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; C508438:IL12RB1 protein, human; C508439:IL12RB2 protein, human; D010835:Phytohemagglutinins; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma