Histological and ultrastructural changes were investigated in lung, liver, and heart of mice given interleukin-2 (IL-2), either alone or in combination with other cytokines. IL-2 induced a vascular leak syndrome (VLS) of a moderate degree with infiltration of lymphoid cells, moderate endothelial damage. mild hepatic parenchymal damage, and minimal myocardial alterations. Interferon-a (IFN-α) produced infiltration mainly of monocytes/macrophages in liver and heart; endothelial cell damage was absent in lung and heart and minimal in liver. Interleukin-1α (IL-1α) caused an increased number of neutrophils in liver and lung; VLS and parenchymal cell and endothelial damage were not found. The VLS and the cellular damage caused by the combination of IL-2 and IFN were much more severe than those produced by IL-2 alone. In animals treated with IL-2, IFN-α, and IL-1α, VLS was minimal and parenchymal and endothelial cell damage were less severe than after IL-2 alone or IL-2 plus IFN-α. Taken together, these observations show that IL-1α reduces ultrastructural changes produced by IL-2 and IFN-α. This reduction may be clinically useful in the treatment of neoplasms.
Anderson TD and Hayes TJ (1989). Toxicity of human recombinant interleukin-2 in rats: Pathologic changes are characterized by marked lymphocytic and eosinophilic proliferation and multisystem involvement. Lab. Invest. 60: 331-346.
2.
Anderson TD, Hayes TJ, Gately, MK, Bontempo JM, Stern LL, and Truitt GA (1988). Toxicity of human recombinant interleukin-2 in the mouse is mediated by interleukin-activated lymphocytes. Lab. Invest. 59: 598-612.
3.
Aronson FR, Libby P., Brandon EP, Janicka MW, and Mier JW (1988). Il-2 rapidly induces natural killer cell adhesion to human endothelial cells. J. Immunol. 141: 158-163.
4.
Behling UH (1983). The radioprotective effect of bacterial endotoxin . In: Beneficial Effects of Endotoxins, A Nowotny (ed). Plenum Press, New York, pp. 127-147.
5.
Brunda MJ, Bellantoni D., and Sulich V. (1987). In vivo anti-tumor activity of combinations of interferon alpha and interleukin-2 in a murine model. Correlation of efficacy with the induction of cytotoxic cells resembling natural killer cells. Int. J. Cancer40: 365-371.
6.
Brunda MJ, Rosenbaum D., and Stern, L. (1984). Inhibition of experimentally-induced murine metastases by recombinant alpha interferon: Correlation between the modulatory effect of interferon treatment on natural killer cell activity and inhibition of metastases. Int. J. Cancer34: 421-426.
7.
Brunda MJ, Sulich V., and Bellantoni D. (1987). The anti-tumor effect of recombinant interferon alpha or gamma is influenced by tumor location. Int. J. Cancer40:807-810.
8.
Brunda MJTarnowski D. and Davatelis ( 1986). Interaction of recombinant interferons with recombinant interleukin-2: Differential effects of natural killer cell activity and interleukin-2-activated killer cells. Int. J. Cancer37: 787-793.
9.
Budd GTOsgood B.Barna B.Boyett JMFinke J., Medendorp SVMurthy S.Novak D.Sergi J.Tubbs R., and Bukowski RM (1989). Phase I clinical trial of interleukin-2 and α-interferon: Toxicity and immunologic effects. Cancer Res.49: 6432-6436.
10.
Byars N., Schreiber AB, Allison AC and Modabber F.( 1984). Interleukin-1 containing conditioned media stimulate the proliferation of capillary endothelial cells. Fed. Proc . 43: 462.
11.
Cameron RB, McIntosh JK, and Rosenberg SA (1988). Synergistic antitumor effects of combination immunotherapy with recombinant interleukin-2 and a recombinant hybrid α-interferon in the treatment of established murine hepatic metastases. Cancer Res. 48: 5810-5817.
12.
Chikkala NF , Lewis I., Ulchaker J., Stanley J., Tubbs R., and Finke JH (1990). Interactive effects of α-interferon A/D and interleukin-2 on murine lymphokine activated killer activity: Analysis at the effector and precursor level. Cancer Res. 50: 1176-1182.
13.
Cotran RS and Pober JS (1989). Effects of cytokines on vascular endothelium: Their role in vascular and immune injury. Kidney Int. 35: 969-975.
14.
Damle NK and Doyle LV (1987). IL-2 activated human killer lymphocytes but not their secreted mediate increase in albumin flux across cultured endothelial monolayers. Implications for vascular leak syndrome. Culture142: 2660-2669.
15.
Damle NK, Doyle LV, Bender JR, and Bradley EC (1987). Interleukin-2 activated human lymphocytes exhibit enhanced adhesion to normal vascular endothelial cells and cause their lysis . J. Immunol. 138: 1779-1785.
16.
DeWit R. , Boucher CA, Veenhof KHN, Schattenkerk Jkme, Bakker PJM, and Danner SA (1988). Clinical and virological effects of high-dose recombinant interferon-α in disseminated aids-related kaposi's sarcoma. Lancet2: 1214-1217.
17.
Duke SS, King LS, Jones MR, Newman JHBrigham KL, and Forbes JT (1989). Human recombinant interleukin-2 activated sheep lymphocytes lyse sheep pulmonary microvascular endothelial cells. Cell. Immunol. 122: 188-199.
18.
Ernstoff MS , Nair S.Bahnson RR, Miketic LMBanner B., Gooding W.Day R., Whiteside T., Hakala T., and Kirkwood JM (1990). A phase IA trial of sequential administration recombinant DNA-produced Interferons: Combination recombinant interferon gamma and recombinant interferon alfa in patients with metastatic renal cell carcinoma. J. Clin. Oncol . 8: 1637-1649.
19.
Ettinghausen SE, Lipford EH III, Mule JJ and Rosenberg SA (1985). Systematic administration of recombinant interleukin-2 stimulates in vivo lymphoid cell proliferation in tissues. J. Immunol. 135: 1438-1497.
20.
Ettinghausen SELipford EH III.Mule JJ, and Rosenberg SA (1985). Recombinant interleukin-2 stimulates in vivo proliferation of adoptively transferred lymphokine-activated killer (LAK) cells. J. Immunol. 135:3623-3635.
21.
Ettinghausen SEPuri RK and Rosenberg SA (1988). Increased vascular permeability in organs mediated by the systemic administration of lymphokine-activated killer cells and recombinant interleukin-2 in mice. J. Natl. Cancer Inst. 80: 177-188.
22.
Fujita S., Puri RK, Yu Z-X., Travis WD, and Ferrans VJ (1991). An ultrastructural study of in vivo interactions between lymphocytes and endothelial cells in the pathogenesis of the vascular leak syndrome induced by interleukin-2. Cancer68: 2169-2174.
23.
Gately MK, Anderson TD, and Hayes TJ (1988). Role of asialo-GM1-positive lymphoid cells in mediating the toxic effects of recombinant IL-2 in mice. J. Immunol. 141: 189-200.
24.
Glauser FL, DeBlois G., Bechard D., Fowler AA, Merchant R., and Fairman RP (1988). Review: Cardiopulmonary toxicity of adoptive immunotherapy . Am. J. Med. Sci. 296: 406-412.
25.
Glauser FL, DeBois GG, Bechard DE, Merchant RE, Grant AJ, and Fowler AA (1988). A comparison of cardiopulmonary effects of continuous versus bolus infusion of recombinant interleukin-2 in sheep. Cancer Res. 48: 2221-2225.
26.
Gresser I., Maury C., and Brouty-Boye D. (1972). Mechanism of the antitumor effect of interferon in mice. Nature (London) 239: 167-168.
27.
Grunberg SW , Kempf RA, Itri LM, Ventun CL, Boswell WD Jr, and Mitchell MS (1985). Phase II study of recombinant alpha interferon in the treatment of advanced non-small cell lung carcinoma. Cancer Treat. Rep . 69: 1031-1032.
28.
Gulick T., Chung MK, Pieper SJ, Lange LG, and Schreiner GF (1989). Interleukin 1 and tumor necrosis factor inhibit cardiac myocyte β-adrenergic responsiveness. Proc. Natl. Acad. Sci. 86: 6753-6757.
29.
Iigo M., Sakurai M., Tumura T., Saijo N., and Hoshi A. (1988). In vivo antitumor activity of multiple injections of recombinant interleukin-2, alone and in combination with three different types of recombinant interferon, on various syngeneic murine tumors. Cancer Res.48: 260-264.
30.
Itoh S., Matsuo S., Shimoji K., Oda T., Sasaki I., and Katayama I. (1989). The effect of α-interferon on the liver in a patient with hairy cell leukemia: Light and electron microscopic studies . Am. J. Gastroenterol. 84: 942-947.
31.
Kragel AH, Travis WD, Feinberg L., Pittaluga S., Striker LM, Roberts WCLotze MT, Yang JJ and Rosenberg SA (1990). Pathologic findings associated with interleukin-2 based immunotherapy for cancer: A postmortem study of 19 patients. Human Pathol. 21 : 493-502.
32.
Kragel AH, Travis WD, Steis RGRosenberg SA, and Roberts WC (1990). Myocarditis or acute myocardial infarction associated with interleukin-2 therapy for cancer. Cancer66: 1513-1516.
33.
Lane HC, Feinberg J., Davey V., Deyton L., Baseler M., Manischewitz J., Masur H., Kovacs JA, Herpin B., Walker R., Metcalf JA, Salzman N., Quinnan G., and Fauci AS (1988). Anti-retroviral effects of interferon-α in AIDS-associated Kaposi's sarcoma. Lancet2: 1218-1222.
34.
Lee RE, Lotze MT, Skibber JM, Tucker E., Bonow RO, Ognibene FP, Carrasquillo JA, Shelhamer JH, Parillo JE, and Rosenberg SA (1989). Cardiorespiratory effects of immunotherapy with interleukin-2. J. Clin. Oncol. 7: 7-20.
35.
Lee SH, Chiu H., Rinderknecht E., Sabo W., and Stebbing N. (1983). Importance of treatment regimen of interferon as an antitumor agent. Cancer Res. 43: 4172-4175.
36.
Lotze MT, Chang AE, Seipp CA, Simpson C., Vetto JT, and Rosenberg SA (1986). High-dose recombinant interleukin-2 in the treatment of patients with disseminated cancer. J. Am. Med. Assoc.256: 3117-3124.
37.
Lotze MT, Matory YL, Rayner AA, Ettinghausen SE, Vetto JT, Seipp CA, and Rosenberg SA (1986). Clinical effects and toxicity of interleukin-2 in patients with cancer. Cancer58: 2764-2772.
38.
Lynch DH, Rubin AS, Miller RE, and Williams DE (1993). Protective effects of recombinant human interleukin-1α in doxorubicin-treated normal and tumor-bearing mice. Cancer Res. 53: 1565-1570.
39.
Mule JJ, Shu S., and Rosenberg SA (1985). The antitumor efficacy of lymphokine-activated killer cells and recombinant interleukin-2 in vivo. J. Immunol . 135: 646-652.
40.
Mule JJ, Yang J., Shu S., and Rosenberg SA (1986). The anti-tumor efficacy of lymphokine-activated killer cells and recombinant interleukin-2 in vivo: Direct correlation between reduction of established metastases and cytolytic activity of lymphokine-activated killer cells. J. Immunol. 136: 3899-3909.
41.
Neta R., Douches S., and Oppenheim JJ (1986). Interleukin-1 is a radioprotector. J. Immunol. 136: 2483-2485.
42.
Nora R., Abrams JS, Tait NS, Hiponia DJ, and Silverman HJ (1989). Myocardial toxic effects during recombinant interleukin-2 therapy. J. Natl. Cancer Inst. 81: 59-63.
43.
Oldham RR (1982). Toxic effects of interferon. Science219: 902.
44.
Osanto S., Cluitmans FHM, Franks CR, Bosker HA, and Cleton FJ (1988). Myocardial injury after interleukin-2 therapy . Lancet2: 48-49.
45.
Papa MZ, Mule JJ, and Rosenberg SA (1986). Antitumor efficacy of lymphokine-activated killer cells and recombinant interleukin-2 in vivo: Successful immunotherapy of established pulmonary metastases from weakly immunogenic and nonimmunogenic murine tumors of three distinct histological types. Cancer Res. 46: 4973-4978.
46.
Pasini FL, DiPerri T., van der Plas K., Palmer P., and Franks CR (1989). Myocardial injury after interleukin-2 therapy . Lancet1: 674.
47.
Peace DJ and Cheever MA (1989). Toxicity and therapeutic efficacy of high-dose interleukin-2: In vivo infusion of antibody to NK-1 attenuates toxicity without compromising efficacy against murine leukemia. J. Exp. Med.169: 161-173.
48.
Pober JS and Cotran RS (1991). What can be learned from the expression of endothelial adhesion molecules in tissues? Lab. Invest. 64: 301-305.
49.
Puri RK, Fox BA, Spiess PJ, Weber J., and Rosenberg SA (1989). In-vivo proliferation of adoptively transferred tumor infiltrating lymphocytes in response to systemic administration of interleukin-2 . FASEB J.3A: 828.
50.
Puri RK and Leland P. (1991). In vivo treatment with interferon causes augmentation of IL-2 induced lymphokine activated killer cells in the organs of mice. Clin. Exp. Immunol. 85: 317-325.
51.
Puri RK and Rosenberg SA (1989). Combined effects of interferon-α and interleukin-2 on the induction of a vascular leak syndrome in mice. Cancer Immunol. Immunother. 28: 267-274.
52.
Puri RK, Travis WD, and Rosenberg SA (1989). Decrease in interleukin 2-induced vascular leakage in the lungs of mice by administration of recombinant interleukin 1 alpha in vivo. Cancer Res. 49: 969-976.
53.
Puri RK, Travis WD, and Rosenberg SA (1990). In-vivo administration of interferon-α and interleukin-2 induced proliferation of lymphoid cells in the organs of mice . Cancer Res. 50: 5543-5550.
54.
Quesada JR, Reuben J., Manning JT, Hersh EM, and Gutterman JU (1984). Alpha interferon for induction of remission in hairy-cell leukemia. N. Eng. J. Med. 310: 15-18.
55.
Quesada JR, Talpaz M., Rios A., Kurzrock R., and Gutterman JU (1986) Clinical toxicity of interferons in cancer patients: A review. J. Clin. Oncol. 4: 234-243.
56.
Rosenberg SA , Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S., Linehan WM, Robertson CN, Lee RE, Rubin JT, Seipp CA, Simpson CG, and White DE (1987). A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N. Eng. J. Med.316: 889-897.
57.
Rosenberg SA , Lotze MT, Muul LM, Leitman S., Chang AE, Ettinghausen SE, Matory YL, Skibber JM, Shiloni E.Vetto JTSeipp CASimpson C. and Reichart CM (1985). Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer . N. Eng. J. Med.313: 1485-1492.
58.
Rosenstein M.Ettinghausen SE and Rosenberg SA (1986). Extravasation of intravascular fluid mediated by the systemic administration of recombinant interleukin-2 . J. Immunol. 137: 1735-1742.
59.
Samlowski WEWard JHCraven CM and Freed-man RA (1989). Severe myocarditis following high-dose interleukin-2 administration. Arch. Pathol. Lab. Med. 113: 838-841.
60.
Schmidt JA, Mizel SB, Cohen P., and Green I.( 1988). Interleukin-1, a potential regulator of fibroblast proliferation . J. Immunol. 128: 2177-2182.
61.
Sone S., Utsugi T., Nii A., and Ogura T. (1988). Differential effects of recombinant interferons α, β, and γ on induction of human lymphokine (IL-2)-activated killer activity . J. Natl. Cancer Inst. 80: 425-431.
62.
Sonnenblick M. and Rosin A. (1991). Cardiotoxicity of interferon . Chest99: 557-561.
63.
Summerville LFJ and Massaro D. (1980). Protection from oxygen toxicity with endotoxin. J. Clin. Invest. 65: 1104-1110.
64.
White CW, Ghezzi P., Dinarello CA, Caldwell SA, McMurtry IF, and Repine JE (1987). Recombinant tumor necrosis factor/cachectin and interleukin-1 pretreatment decreases lung oxidized glutathione accumulation, lung injury, and mortality in rats exposed to hyperoxia. J. Clin. Invest. 79: 1868-1873.
65.
Yi ES and Ulich TR (1992). Endotoxin, interleukin-1, and tumor necrosis factor cause neutophil-dependent microvascular leakage in postcapillary venules. Am. J. Pathol. 140: 656-663.
66.
Zbinden G. (1990). Effects of recombinant human alpha-interferon in a rodent cardiotoxicity model. Toxicol. Lett. 50: 25-35.
67.
Zhang J., Yu Z-X., Hilbert SL, Yamaguchi M., Chadwick, DP, Herman EH, and Ferrans VJ (1993). Cardiotoxicity of human recombinant interleukin-2 in rats: A morphological study. Circulation87: 1340-1353.
