In 24 patients with cutaneous T-cell lymphomas (CTCL) the clinical course was documented by determination of a tumour burden index (TBI) on entering the study and six months later. In addition to the first TBI, soluble interleukin-2 receptor levels (slL-2R) in the serum were determined using an ELISA technique in 23 patients. In 18 patients natural killer cell (NK) activity was assessed by a 4 h chromium-51 release assay. Statistical analysis revealed a negative correlation between NK activity and an increase of TBI as well as NK activity and slL-2R. Furthermore, there was a strong positive correlation between the increase of TBI and slL-2R. slL-2R and NK activity might be prognostic factors in CTCL patients

Becker, Jürgen C.

Burg, Günter

Dummer, Reinhard

Nestle, Frank

Röger, Jürgen

Schäfer, Erwin

Vogt, Thomas

Wiede, Johannes

English

University of Regensburg Publication Server

EUROPEAN JOURNAL OF DERMATOLOGY Volume 1 • Number 1 • October 1991 EDITORIAL Why create a new journal of dermatology in 1991 ? Jean Thivolet REVIEW ARTICLE Skin ceramides : structure and function M. Kerscher H.C. Korting M. Schafer-Korting CLINICAL REPORTS Primary cutaneous B-cell lymphoma as first manifestation of acquired immuno-deficiency syndrome A. Vicente E. Campo R. Marti A. Azon T. Estrach M.Lecha J. Palou J.M. Mascaro Acute monoblastic leukemia and histiocytosis X : a case report and review of the literature F. Cambazard L. Misery J. Kanitakis E. Archimbaud C. Hermier Acanthosis nigricans and insulin resistance in obese patients : a frequent but underestimated dermato-endocrinopathy V. Martin Ch. Thivolet L. Bajard L. Thomas M. Faure Occupational allergic contact dermatitis from iatrogenic sensitization by a new acrylate dentin adhesive L Kanerva K. Turjanmaa R. Jolanki T. Estlander CASE REPORTS Digital extraskeletal chondroma A.L. Claudy W. Godard L. Jacquelin Infundibular keratosis : a distinctive infundibular tumour M.J. Lopez Redondo C. Schoendorff L. Requena G. Roustan E. Sanchez Yus F. Sanchez de Paz Polyeponychia bolboides : an unusual manifestation of factitious disorder ? R. Happle A. Chang INVESTIGATIVE REPORTS Conversion of human epidermal Langerhans cells into interdigitating cells in vitro is not associated with functional maturation M.B.M. Teunissen J. Wormmeester H.A.H. Rongen M l . Kapsenberg, J.D. Bos Levels of immunoreactive interleukin 1 a and p in basal, suprabasal and cornified epidermal cell subpopulations of normal human epidermis. Comparison with keratinocytes cultured in defined medium H. Gatto J. Viae A. Reano M.Charveron SHORT COMMUNICATION Increased binding sites of dansylated cyclosporin A in psoriatic epidermis grafted onto nude mice during cyclosporin A treatment A. Urabe J. Nakayama H. Terao Y. Ori THESIS Cyclosporin A in the treatment of psoriasis F. Henle Sensory neuromediators in human skin/role in inflammation and other disorders J. Wallengren JohnLibbey I EUROTEXT Fin Investigative Report European Journal of Dermatology 1991; 1 :135-138 REINHARD DUMMER (U) FRANK NESTLE(1) JOHANNES WIEDE(1) ERWIN SCHAFER(2) JORGEN ROGER(1) JORGEN C. BECKER(1) THOMAS VOGT (1 ) GUNTER BURG'1'3' ( 1 department of Dermatology, Univer-sity of Wurzbura Medical School, D 8700 Wurzburg, Germany. ( 2 ,Department of Nuclear Medicine, University of Wurzburg Medical School, D 8700 Wurzburg, Germany. ( 3 )Department of Dermatology, Univer-sity of Zurich Medical School, Gloria-strasse 31, CH 8091 Zurich, Switzer-land. Reprints: R. Dummer ( 3 ). EJD n°2, vol. 1, november 1991 Coincidence of increased soluble interleukin-2 receptors, diminished natural killer cell activity and progressive disease in cutaneous T-cell lymphomas In 24 patients with cutaneous T-cell lymphomas (CTCL) the clinical course was documented by determination of a tumour burden index (TBI) on entering the study and six months later. In addition to the first TBI, soluble interleukin-2 receptor levels (slL-2R) in the serum were determined using an ELISA technique in 23 patients. In 18 patients natural killer cell (NK) activity was assessed by a 4 h chromium-51 release assay. Statistical analysis revealed a negative correlation between N K activity and an increase of TBI as well as NK activity and slL-2R. Furthermore, there was a strong positive correlation between the increase of TBI and slL-2R. slL-2R and NK activity might be prognostic factors in CTCL patients. Keywords: cutaneous T-cell lymphomas, soluble interleukin-2 recep-tor, natural killer cell activity, prognostic factors. Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of lym-phoproli ferative disorders originat-ing in the skin. In general , the term desig-nates a cl inical ly, histologically and phe-notypically var iable spectrum of diseases which are slowly progressive and show striking interindividual differences [1]. An increased risk of second malignancy [2] and a decrease in natural kil ler cell activity [3, 4] indicate imbalanced im-munofunctions in these patients. Recently, we and others [5, 6] reported elevated serum levels of soluble interleukin-2 receptors (TAC-protein) in some of these patients. Yet, the b io logical relevance of this phenomenon is unclear. In the present study we analysed the interactions of N K activity, slL-2R and the cl inical outcome in CTCL patients. Table I. Patients characteristics: slL-2R, NK activity, and clinical course described by A TBI Pat. (n = 24) Stage TNM[19] Histol. diagnosis Pretreatment therapy during follow-up period (6 months) slL-2R (U/ml) (n = 23) Spec, lysis (%) (n = 18) A TBI (n = 24) GE IIA low-grade peripheral e.b.r e. ster. e. ster. 1690 5.0 18 HE MB low-grade peripheral e. ster. e. ster. 385 13.0 5 WA IA low-grade peripheral e. ster. e. ster. 405 16.5 0 BA IIA low-grade peripheral e. ster. e. ster. 330 4.0 0 H O IIB high-grade peripheral MTX, IFN-a MTX, e. ster. 538 30.7 0 PUVA ST IIB low-grade peripheral BCNU, topical, BCNU topical 3000 6.4 30 e. ster. e. ster. Tl III low-grade peripheral e. ster. BCNU topical 1320 4.0 12 KA IIA low-grade peripheral e. ster., IFN-a e. ster. 3570 6.0 20 KAI IIB high-grade peripheral PUVA, e. ster. e. ster. 10700 6.0 20 KE IIA low-grade peripheral e. ster. e. ster. 1190 21.9 20 SCH IA low-grade peripheral e. ster. e. ster. 950 10.5 0 H O IVB low-grade peripheral PUVA, e. ster. e. ster., MTX 9230 n.d. 40 BCNU, MTX I RE IIA high-grade peripheral e. ster. e. ster. 720 15.0 0 TR IA low-grade peripheral PUVA, e. ster. IFN-a, e. ster. 800 42.3 0 GEI IIB high-grade peripheral e. ster. e. ster. 570 n.d. 0 BET IIA low-grade peripheral none PUVA 7330 2.3 20 HER IA low-grade peripheral PUVA, e. ster. e. ster. 1110 6.9 0 KG IB low-grade peripheral e. ster. e. ster. 650 24.7 2 prednimustine VA IIB low-grade peripheral e. ster. e. ster. 300 22.5 0 GR IA low-grade peripheral e. ster. BCNU topical 790 n.d. 0 D O IVA low-grade peripheral PUVA, e. ster. e. ster. 12300 n.d. 40 KUN IVA low-grade peripheral PUVA, e. ster. e. ster. 1190 n.d. 40 Yl IA low-grade peripheral PUVA, e. ster. e. ster. 510 n.d. 0 WAL IA high-grade peripheral none e. ster. n.d. 19.8 0 MTX: methothrexate, BCNU: carmustine, IFN-a: interferon-a2a, e. ster.: external steroids, e.b.r.: electron beam radiation, n.d.: not done. Patients and methods Patients Twenty four patients with histologically proven CTCL in different stages were investigated. Before entering the study, systemic treatment had been stopped for at least two weeks. Physical examinations were done on day 0 and repeated six months later (for al l 24 patients). Staging procedures and histological c lassi f ica-tion were done accord ing to the recom-mendations for staging and therapy of cutaneous lymphomas of the European Organ iza t ion for Research and Treat-ment of Cancer , cutaneous lymphoma project group [7]. O n day 0. per ipheral b lood mononuclear cells for Cr release assay were taken in 18 patients, and serum samples were col lected in 23 patients. Patients' characteristics includ-ing pretreatment and therapy during the fol low-up per iod are summarized in Table I. Therapy in the fo l low-up per iod was app l ied accord ing to the cl in- ical necessities. number of patients 10 10 slL-2R < 1000 U slL-2R > 1000 U patients with progressive disease (ATBI > 10) patients with stable disease (ATBI < 10) Figure 1. Clinical outcome according to soluble interleukin-2 receptor serum levels. References 1- Burg G, Braun-Falco O. Cutaneous lym-phomas, pseudolymphomas and related dis-orders. Berlin, Heidelberg, New York, Tokyo: ^ringer 1983. 2. Kantor AF, Rochelle EC, Vonderheid EC, von Scott EJ, Fraumeni JF. Risk of second Malignancy after cutaneous T-cell lympho-mas. Cancer 1989; 63: 1612-1615. 3. Laroche L, Kaiserlian D. Decreased natural killer cell activity in cutaneous T-cell lympho-mas. N Engl J Med 1983; 306: 101 -102. Levy S, Tempe JL, Caussade P, Aleksijevic A, Grosshans E, Mayer S, Lang JM. Stage related decrease in natural killer cell activity •n untreated patients with mycosis fungoides. Cancer Immunol Immunother 1984; 18: 138-140. 5. Kaudewitz P, Josimovic-Alasevic O, Diamantstein T, Eckert F, Klepzig K, Burg G. Soluble IL-2 receptor serum levels in cuta-neous T-cell lymphomas: Correlation with cli-nical stage and IL-2 receptor status in cutane-ous infiltrates. J Invest Dermatol 1988; 91: 386-387. 6. Dummer R, Nestle F, Schafer E, Wiede J, Roger J, Hartmann A, Burg G. Influence of soluble interleukin-2 receptors and soluble CD 8 proteins on natural killer cell activity and clinical course in cutaneous T-cell lymphoma Patients. Arch Dermatol Res 1990; 8: 557-558. 7. Kerl K, Sterry W. Classification and staging, h: Burg G, Sterry W, eds. EORTC/BMFT Cuta-neous Lymphoma Project Group: Recommen-dations for staging and therapy of cutaneous lymphomas. 1987; 1-10. B. Goldstein AM, Marcon L, Cullen BR, Nel-son DL. A competive enzyme-linked immuno-assay (ELISA) for the measurement of soluble human interleukin-2 receptors (IL-2R, Tac-protein). J Immunol Methods 1988; 107:103-109. °. Yamada S, Ruscetti FW, Overton WA, Her-bermann RB, Birchenall-Sparks MC, Ortaldo JR. Regulation of human large granular lym-phocyte growth by recombinant interleukin 2: Induction of interleukin-2 receptor and prom-otion of growth of cells with enhanced cytoto-xicity. J Leak Biol 1987; 41: 505-517. Clinical course In order to estimate the cutaneous tumour mass in a semiquantitative manner, a tumour burden index was introduced. Physical examinations were done by one investigator, only. The percentage of involved skin was documented using the rule of the nines. Speci-f ic skin lesions were differentiated in patches (flat lesions, diameter larger than 1 cm), p la -ques (flat or slightly elevated lesions with increased consistency) and tumours (large nodular lesions, diamter larger than 1 cm) [7]. The extension of tumours, patches and plaques was noted and the tumour burden index (TBI) was calculated as: tumour plaque patch TBI = x% x 4 + x% x 2 + x% x 1 x% = involved skin in % Under these conditions the maximal achievable TBI was 400. In our patients the TBI was 41 ± 59 (mean ± standard deviat ion, minimal 2, maximal 280). The cl inical course of progressing patients was determined by the difference of the tumour burden index (A TBI) at day 0 and six months later. It was calculated as: A TBI = TBI 6 - TBI 0 ; TBI* = after six months, TBI 0 = TBI day 0. Patients with a stable disease or regress-Statistical tests A computerized correlation analysis was performed using a new statistical prog-ramme (MEDAS) developed by Grund C , Haubitz I. and Rausche A . Institute for Biostatistics, University of Wurzburg. Correlat ion between slL-2R and N K acti-vities was analysed by the calculat ion of Spearman's correlat ion coefficient, p. Correlat ion between ATBI and slL-2R and N K activity, respectively, was deter-mined by the calculat ion of Kendal 's cor-relation coefficient, r. Results The results of slL-2R, N K activity and cl inical course are summarized in Table I. Statistical analysis of our data revealed correlations between N K activity, slL-2R and disease progression, which was descr ibed by the ATBI . There was a negative correlation between N K activity and ATBI (r = -0 .3492 , P< 0.05). A strong positive cor-relation was found between slL-2R and Soluble interleukin-2 receptors Soluble interleukin-2 receptors (slL-2R) in the serum were determined by sandwich ELISA (T Cel l Sciences Inc., Cambr idge, USA) [8]. The test employs two non-competing murine monoclonal anti-bodies to the a-chain of human IL-2R. It was done according to the manufactur-er's instructions. The microtiter plates were read at 490 nm using a Dynatech MR 700 microplate reader. Units of slL-2R were calculated from a standard curve constructed on the basis of a supernatant from phytohemagglutinin-stimulated peripheral b lood mononuclear cells. Interassay variation was 5%. Natural killer cell activity Peripheral mononuclear cells (PMC) were separated by Ficol l -Hypaque cen-trifugation. N K activity was determined in a 4 h 5 1 C r release assay as previously descr ibed [9], using the NK-sensit ive erythroblastoma cell line K562 as target cells. The effectontarget ratio was 40 : 1. Spon-taneous release was assessed by incubating label led K 562 in medium alone, and total release was evaluated by a solution of SDS. After harvesting the supernatants using a Skatron filterstick system, radioactivity was measured in a Pharmacia gamma-counter. Specific lysis (SL) was calculated as: 0.3492, P < 0.05). A strong positive corre-lation was found between slL-2R and ATBI (r = 0.6091, P < 0.0005). N o corre-lation between staging and slL-2R or staging and N K activity was observed. N K activity and slL-2R showed a negative correlation (p = - 0 . 5 4 2 3 , P < 0.03). Analysing the reliability of slL-2R as a prognostic factor, we suggest that a ATBI of at least 10 should be considered as a significant change. Moreover , slL-2R should exceed the upper normal range by a factor of 2 (> 1000 U/ml). Under these conditions the specificity of slL-2R for tumour progression was 90.0% (n = 11). There was no false-posit ive value, indicating high sensitivity (Fig. 1). Discussion Recent reports of successful transplanta-tion of cutaneous lymphomas on natural kil ler cel l-depleted severe combined immunodeficient (SCID) mice [10] as well SL(7 ) M e a n experimental release - mean spontaneous release ^ M e a n total release - mean spontaneous release References 10. Charley MR, Tharp M, Locker J, Deng J-S, Goslen JB, Mauro T, McCoy P, Abel I E, Jega-sothy B. Establishment of a human cutaneous T-cell lymphoma in C.B.-17 SCID mice. J Invest Dermatol 1990; 94: 381-384. 11. Gause A, Roschansky V, Tschiersch A, Schmits R, Diehl V, Pfreundschuh M. The prog-nostic value of low pretreatment serum interleukin-2 receptor (slL-2R) in patients with Hodgkin's disease (HD). J Cancer Res Clin Oncol 1990; 116: 320S. 12. Wagner DK, Kiwanuka J, Edwards BK, Rubin LA, Nelson DL, Magrath IT. Soluble interleukin-2 receptor levels in patients with undifferentiated and lymphoblastic lympho-mas: Correlation with survival. J Clin Oncol 1987; 5: 1262-1274. 13. Kapp A, Piskorski A, Schopf E. Elevated levels of interleukin-2 receptor in sera with atopic dermatitis and psoriasis. Br J Dermatol 1988;119:707-710. 14. DiGiovine FS, Duff GW. Interleukin-l: the first interleukin. Immunol Today 1990; 11:13-20. 15. Tron VA, Rosenthal DR, Sauder DN. Epi-dermal interleukin-l is increased in cuta-neous T-cell lymphoma. J Invest Dermatol 1988; 90: 378-381. 16. Dummer R, Wiede J, Nestle F, Schafer E, Burg G. Diminished natural killer cell activity in mycosis fungoides patients can be partially restored by IL-2. J Invest Dermatol 1989; 93: 298. 17. Rubin LA, Jay G, Nelson DL. The released interleukin-2 receptor binds interleukin-2 efficiently. J Immunol 1986; 137: 3841-3844. 18. Symons JA, Wood NC, Di Giovine FS, Duff GW. Soluble IL-2 receptor in rheumatoid arthritis: Correlation with disease activity, IL-1 and IL-2 inhibition. J Immunol 1988; 141: 2612-2618. 19. Bunn PA, Lamberg SI. Report of the com-mittee on staging and classification of cuta-neous T-cell lymphomas. Cancer Treat Rep 1979; 63:725-728. as an enhanced risk of developing secon-dary neoplasias [2] point to impaired immunofunctions in CTCL patients. A n a -lysing N K activity and cl inical course in these patients we found a correlat ion between the decrease of N K activity and the progression of the disease. W e con-clude that N K activity might be a prognos-tic factor for CTCL patients. Elevated levels of slL-2R were found in the serum of patients suffering from lym-phoprol i ferative disorders [5,6,11,12] as well as in the serum of patients suffering from inflammatory skin diseases [13]. Regarding the strong correlation between tumour progression in CTCL pa -tients and slL-2R, we suggest that this soluble protein may be of high prognostic value. This is consistent with the detection of slL-2R as an unfavourable prognostic sign in other lymphoproli ferative disor-ders such as Hodgkin 's disease [11] and lymphoblastic lymphomas [12]. From an immunological point of view, the negative correlation between slL-2R and N K activities offers interesting perspec-tives. Under physiologic circumstances, membrane-bound and soluble forms of the T A C protein are observed after T-cell stimulation, for example by antigen pre-senting cells and interleukin 1. As a con-sequence, the stimulated T lymphocytes produce interleukin-2 [14]. In CTCL patients this mechanism seems to be dis-turbed. In some CTCL patients, interleukin 1 [15] might enhance expression of T A C protein, albeit, without addit ional induc-tion of interleukin-2, which is able to res-tore diminished N K activity [16] and is known to be a potent stimulating cytokine for N K activity [9]. This d iscordance could be an important factor for tumour spread-ing. W e propose, that slL-2R might be responsible for the decreased N K activity by neutralizing interleukin-2 [17, 18] • Abbreviations CTCL: cutaneous T-cell lymphoma. SCID: severe combined immune deficiency. slL-2R: soluble interleukin-2 receptor. N K : natural ki l ler cel l . TBI: tumour burden index. Zusammenfassung Bei 24 Patienten mit cutanem T-Zell Lymphom (CTCL) wurde der klinische Ver lauf mittels eines "Tumor burden index (TBI)" bei Beginn der Beobach-tung und sechs Monate spdter doku-mentiert. Zusammen mit dem ersten TBI wurde der losl iche Interleukin-2 Rezeptor (slL-2R) im Serum mittels ELISA und die naturliche Ki l lerzel l -(NK-) Aktivitat der peripheren mono-nukledren Zel len mittels "Cr-51 Release A s s a y " bestimmt. Die statistis-che Auswertung der drei Parameter e rgab eine negative Korrelat ion zwis-chen NK-Akt iv i tat und Zunahme des TBI, sowie zwischen NK-Akt iv i tat und slL-2R. Auf ierdem fand sich eine hoch-signifikante Korrelat ion zwischen sIL-2R und Zunahme des TBI. slL-2R und NK-Akiv i td t sind mogl icherweise von prognostischer Bedeutung bei Patien-ten mit CTCL . European Cytokine Network Number of issues : 6 Subscriptions Subscriptions can be paid by check made out to European Cytokine Network. Orders for subscription should be filled out and sent, together with chek and signature, to : John Libbey Eurotext, 6, rue Blanche - 91210 Montrouge, France. Tel. : (33.1) 47.35.85.52 Telefax: (33.1)46.57.10.09 Inquiries AH questions concerning subscriptions and mailing should be sent to the above address. Subscription rates France Individual 800 FF Institutional 1 000 FF Students 500 FF Rest of Rest of Europe World US $ 135 US $ 150 US $ 180 US $ 195 US$ 90 US$105 Prices are for a one-year subscription (1 volume of 6 issues) and include postage and handling charges. Advertizing rates available on request. 

Coincidence of increased soluble interleukin-2 receptors, diminished natural killer cell activity and progressive disease in cutaneous T-cell lymphomas

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Coincidence of increased soluble interleukin-2 receptors, diminished natural killer cell activity and progressive disease in cutaneous T-cell lymphomas

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