IL-6 is a multifunctional cytokine that is implicated in the pathophysiology of several malignant diseases including MM, an incurable malignant plasma cell disorder. IL-6 is known to enhance proliferation, differentiation and survival of malignant plasma cells in MM through an autocrine and/or a paracrine mechanism that involves the inhibition of apoptosis of the malignant cells, induction of resistance to chemotherapy and contribution to angiogenesis. Moreover, elevated levels of IL-6 in serum of patients with MM correlate with disease activity, unfavorable prognosis and refractoriness to standard therapy. Blocking IL-6 has been postulated to be an effective therapy (Klein et al, 1995) and several studies have investigated the effect of blocking IL-6 on MM cells and cell lines both in vitro and in vivo. However, the lack of a reliable IL-6 dependent MM model has hindered these efforts. Recently, mouse plasmacytomas were described as appropriate models to study the biology of human MM (
Iankov et al., Immunobiology 2004; 208(5)
). The current study describes a new in vivo IL-6 dependent mouse plasmacytoma model in SCID mice. Mice were inoculated subcutaneously with 1 x 106 7TD1 cells, an IL-6 dependent mouse hybridoma/plasmacytoma cell line. Three days after tumor inoculation, mice were treated 2x/week i.p. with either PBS or 25 mg/kg of anti-mouse IL-6 (R & D systems, Clone MP520F3) or control mAb. Thirteen days after tumor implantation the mean tumor volume in the control mAb group and PBS group was 3204 +/− 360 SEM mm3, n = 10; and 2430 +/− 189 SEM mm3, n = 10, respectively. The mean tumor volume in the anti-IL-6 treated group was 635 +/− 149 SEM mm3, n = 10. Serum was tested by ELISA for levels of IL-6 and IgM (a mAb that is produced by 7TD1 cell line). IL-6 serum level was undetectable in naïve non-tumor bearing SCID mice. The IL-6 levels in the PBS treated group and control mAb group were 121 +/− 32 pg/ml and 125 +/− 14 pg/ml, respectively. IL-6 levels in animals treated with rat-anti- mouse IL-6 were not detected due to interference of the mAb with the ELISA. Serum IgM levels in optical density (OD) were 0.02 +/− 0.005 in the naïve non-tumor bearing animals, 0.80 +/− 0.02 in the PBS group, 0.77 +/− 0.03, in the control mAb group, and 0.19 +/− 0.17 in the rat anti-mouse IL-6 group. In conclusion the current study showed that 7TD1cells could be grown in SCID mice. Serum levels of both IgM and IL-6 were significantly elevated in the PBS and control mAb treated tumor-bearing animals. There was a significant reduction in the IgM levels in the rat anti-mouse IL-6 treated group (P <0.0001), a positive correlation between final tumor weight and serum IgM level (P < 0.0001, r2 = 0.782) and a 74% inhibition of tumor growth relative to either control mAb or vehicle control (P <0.0001). Taken together the current study introduces a new IL-6 dependant mouse plasmacytoma model that can be used to study the biology of MM and to test the efficacy of IL-6 blocking agents in vivo.
