Abstract
Groups of 8 to ten SCID (CB.17 scid/scid) or NOD/SCID (NOD/LtSz- scid/scid) mice were injected i.v. with two million human HSB-2 T-ALL cells on day 1 (SCID-HSB-2 and NOD/SCID-HSB-2 mice) and treated later with 3 i.v. 10 μg doses of the anti-CD7 antibody HB2 on days 7, 9 and 11 or with a single 10 μg dose of HB2-SAPORIN or a 7.4 μg dose of HB2-F(ab)2-SAPORIN immunotoxin (IT) on day 7. Treatment of SCID-HSB-2 mice with HB2-SAPORIN led to a significant prolongation in the time to development of signs and symptoms of disease compared with PBS sham-treated controls with 80% of animals surviving disease-free. In contrast treatment with HB2-F(ab)2-SAPORIN was significantly less effective in SCID-HSB-2 mice with 80% of animals in this treatment group developing leukaemia over the course of the study. HB2 antibody treatment of SCID-HSB-2 mice also led to a significant prolongation in time to leukaemia development compared with sham-treated controls with 37% of animals in this treatment group disease-free at termination of the study. In contrast HB2 antibody treatment of NOD/SCID-HSB-2 mice had no therapeutic effect in these animals and the therapeutic effectiveness of both HB2-SAPORIN and HB2-F(ab)2-SAPORIN ITs was similar and significantly reduced compared to the effect observed in SCID-HSB-2 mice. It was initially thought that the lack of therapeutic effect of antibody and IT in NOD-SCID-HSB-2 mice might relate to their putative lack of NK cells but flow cytometric and functional studies with NOD-SCID mouse splenocytes revealed that these animals do have some functional NK cells though fewer in number and possibly lower in functionality than those of SCID mice. We reason that the complete lack of therapeutic effect of HB2 antibody and the reduced effect of HB2-SAPORIN in NOD/SCID mice is due to the reduced cytolytic activity of NOD/SCID NK cells which is probably below a certain critical threshold value in these animals. We conclude from this that immunotherapeutics like HB2-SAPORIN would be more accurately assessed for intrinsic potency in NOD/SCID mice where the effects of NK cell and possibly other non-adaptive immune mechanisms would not have a significant influence. © 2000 Cancer Research Campaign http://www.bjcancer.com
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References
Adams RA, Pothier L, Flowers A, Lazarus H, Farber S and Foley GE (1970) The question of stemlines in human acute leukemia. Comparison of cells isolated in vitro and in vivo from a patient with acute lymphoblastic leukemia. Experimental Cell Research 62: 5–10
Baxter AG and Cooke A (1993) Complement lytic activity has no role in the pathogenesis of autoimmune diabetes in NOD mice. Diabetes 42: 1574–1578
Bhatia M, Wang JCY, Kapp U, Bonnet D and Dick JE (1997) Purification of primitive human hematopoietic cells capable of repopulating immune-deficient mice. PNAS 94: 5320–5325
Bosma GC, Custer RP and Bosma MJ (1983) A severe combined immunodeficiency mutation in the mouse. Nature 301: 527–530
Cesano A, O'Connor R, Lange B, Finan J, Rovera G and Santoli D (1991) Homing and progression patterns of childhood acute lymphoblastic leukaemias in severe combined immunodeficient mice. Blood 77: 2463–2474
Christianson SW, Shultz LD and Leiter EH (1993) Adoptive transfer of diabetes into immunodeficient NOD-scid/scid mice. Relative contributions of CD4+ and CD8+ T-cells from diabetic versus prediabetic NOD. NON-Thy-1a donors. Diabetes 42: 44–55
Cikes M, Friberg S and Klein G (1973) Progressive loss of H-2 antigens with concomitant increase of cell-curface antigen(s) determined by Moloney Leukemia Virus in cultured murine lymphomas. Journal of National Cancer Instute 50: 347–362
Custer RP, Bosma GC and Bosma MJ (1985) Severe combined immunodeficiency (SCID) in the mouse. Pathology, reconstitution, neoplasms. Am J Pathol 120: 464–477
Dick JE (1996) Normal and leukemic human stem cells assayed in SCID mice. Semin Immunol 8: 197–206
Dorshkind K, Keller GM, Phillips RA, Miller RG, Bosma GC, O'Toole M and Bosma MJ (1984) Functional status of cells from lymphoid and myeloid tissues in mice with severe combined immunodeficiency disease. J Immunol 132: 1804–1808
Dorshkind K, Pollack SB, Bosma MJ and Phillips RA (1985) Natural killer cells are present in mice with severe combined immunodeficiency. Journal of Immunology 134: 3798–3801
Flavell DJ (1996) Modelling human leukaemia and lymphoma in severe combined immunodeficient (Scid) mice: practical applications. Haematological Oncology 14: 67–82
Flavell DJ, Boehm DA, Noss A and Flavell SU (1997) Comparison of the potency and therapeutic efficacy of the anti-CD7 immunotoxin HB2-Saporin constructed with one or two saporin moieties per immunotoxin molecule. British Journal of Cancer 75: 1035–1043
Flavell DJ, Warnes S, Noss A and Flavell SU (1998) Host-mediated antibody dependent cellular cytotoxicity (ADCC) contributes to the in vivo therapeutic efficacy of an anti-CD7-saporin immunotoxin in a SCID mouse model of human T-ALL. Cancer Research 58: 5787–5794
Kamel-Reid S, Letarte M, Sirard C, Doedens M, Grunberger T, Fulop G, Freedman MH, Phillips RA and Dick JE (1989) A model of human acute lymphoblastic leukemia in immune-deficient SCID mice. Science 246: 1597–1600
Kamel-Reid S, Letarte M, Doedens M, Greaves A, Murdoch B, Grunberger T, Lapidot T, Thorner P, Freedman MH, Phillips RA and Dick JE (1991) Bone marrow from children in relapse with pre-B acute lymphoblastic leukaemia proliferates and disseminates rapidly in SCID mice. Blood 78: 2973–2981
Kataoka S, Satoh J, Fujiya H, Toyota T, Suzuki R, Itoh K and Kumagai K (1983) Immunologic aspects of the nonobese diabetic (NOD) mouse. Abnormalities of cellular immunity. Diabetes 32: 247–253
Kollmann TR, Kim A, Zhuang X, Hachamovitch M and Goldstein H (1994) Reconstitution of SCID mice with human lymphoid and myeloid cells after transplantation with human fetal bone marrow without the requirement for exogenous human cytokines. PNAS 91: 8032–8036
Kotloff DB, Bosma MJ and Ruetsch NR (1993) Scid mouse pre-B cells with intracellular μ chains: analysis of recombinase activity and IgH gene rearrangements. Int Immunol 5: 383–391
Lapidot T, Pflumio F, Doedens M, Murdoch B, Williams DE and Dick JE (1992) Cytokine stimulation of multilineage hematopoiesis from immature human cells engrafted in SCID mice. Science 255: 1137–1141
Morland BJ, Barley J, Boehm D, Flavell SU, Ghaleb N, Kohler JA, Okayama K, Wilkins B and Flavell DJ (1994) Effectiveness of HB2(anti-CD7)-saporin immunotoxin in an in vivo model of human T-cell leukaemia developed in severe combined immunodeficient mice. British Journal of Cancer 69: 279–285
Pilarski LM, Hipperson G, Seeberger K, Pruski E, Coupland RW and Belch AR (2000) Myeloma progenitors in the blood of patients with aggressive or minimal disease: engraftment and self-renewal of primary human myeloma in the bone marrow of NOD SCID mice. Blood 95: 1056–1065
Prochazka M, Gaskins HR, Shultz LD and Leiter EH (1992) The non-obese diabetic scid mouse:model for spontaneous thymomagenesis associated with immunodeficiency. PNAS 89: 3290–3294
Serreze DV and Leiter EH (1988) Defective activation of T suppressor cell function in nonobese diabetic mice. Potential relation to cytokine deficiencies. J Immunol 140: 3801–3807
Serreze DV, Gaskins HR and Leiter EH (1993) Defects in the differentiation and function of antigen presenting cells in NOD/Lt mice. J Immunol 150: 2534–2543
Shpitz B, Fernandes BJ, Mullen JBM, Roder JC and Gallinger S (1994) Improved engraftment of human tumours in SCID mice pretreated with radiation and anti-asialo GMI. Anticancer Research 14: 1927–1934
Shultz L, Schweitzer PA, Christianson SW, Gott B, Schweitzer IB, Tennent B, McKenna S, Mobraaten L, Rajan TV, Greiner DL and Leiter EH (1995) Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice. The Journal of Immunology 154: 180–191
Thorpe PE, Brown ANF, Jr, JAGB Foxwell BMJ and Stirpe F (1985) An immunotoxin composed of monoclonal anti-Thy 1.1 antibody and a ribosome-inactivating protein from Saponaria officinalis: potent antitumor effects in vitro and in vivo. Journal of National Cancer Institute 75: 151–159
Wang JCY, Lapidot T, Cashman JD, Sirard C, Doedens M, Laraya P, Addy L, Minden M, Keating A, Eaves AC, Eaves CJ and Dick JE (1995) Engraftment of primitive normal and leukemic hematopoetic cells from chronic phase CML patients in immunodeficient mice. Blood 86: 601a
Workman P, Twentyman P, Balkwill F, Balmain A, Chaplin D, Double J, Embleton J, Newell D, Raymond R, Stables J, Stephens T and Wallace J (1998) United Kingdom Co-ordinating Committee on Cancer Research (UKCCCR) guidelines for the welfare of animals in experimental neoplasia (second edition). Br J Cancer 77: 1–10
Yu J, Dialynas DP, Shao LE, Lee MJ, Gold DP and Yu AL (1999) Fetal cord blood facilitates engraftment of primary childhood T-cell acute lymphoblastic leukaemia in immunodeficient mice and enhances leukaemia colony formation in vitro. Proc Am Assoc Cancer Res 40: 660 (abstract #4352)
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Flavell, D., Warnes, S., Noss, A. et al. Anti-CD7 antibody and immunotoxin treatment of human CD7+T-cell leukaemia is significantly less effective in NOD/LtSz-scid mice than in CB.17 scid mice. Br J Cancer 83, 1755–1761 (2000). https://doi.org/10.1054/bjoc.2000.1565
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DOI: https://doi.org/10.1054/bjoc.2000.1565
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