Cyclophosphamide induces type I interferon and augments the number of CD44(hi) T lymphocytes in mice: implications for strategies of chemoimmunotherapy of cancer.
نویسندگان
چکیده
In a previous study, we reported that a single injection of cyclophosphamide (CTX) in tumor-bearing mice resulted in tumor eradication when the animals were subsequently injected with tumor-sensitized lymphocytes. Notably, CTX acted by inducing bystander effects on T cells, and the response to the combined CTX/adoptive immunotherapy regimen was inhibited in mice treated with antibodies to mouse interferon (IFN)-alpha/beta. In the present study, we have investigated whether CTX induced the expression of type I IFN, and we have characterized the CTX effects on the phenotype of T cells in normal mice. CTX injection resulted in an accumulation of type I IFN messenger RNA in the spleen of inoculated mice, at 24 to 48 hours, that was associated with IFN detection in the majority of the animals. CTX also enhanced the expression of the Ly-6C on spleen lymphocytes. This enhancement was inhibited in mice treated with anti-type I IFN antibodies. Moreover, CTX induced a long-lasting increase in in vivo lymphocyte proliferation and in the percentage of CD44(hi)CD4(+) and CD44(hi)CD8(+ )T lymphocytes. These results demonstrate that CTX is an inducer of type I IFN in vivo and enhances the number of T cells exhibiting the CD44(hi) memory phenotype. Since type I IFN has been recently recognized as the important cytokine for the in vivo expansion and long-term survival of memory T cells, we suggest that induction of this cytokine may explain at least part of the immunomodulatory effects observed after CTX treatment. Finally, these findings provide a new rationale for combined treatments with CTX and adoptive immunotherapy in cancer patients. (Blood. 2000;95:2024-2030)
منابع مشابه
Cancer Therapy: Clinical Cyclophosphamide Induces a Type I Interferon–Associated Sterile Inflammatory Response Signature in Cancer Patients' Blood Cells: Implications for Cancer Chemoimmunotherapy
Purpose: Certain chemotherapeutics, particularly cyclophosphamide, can enhance the antitumor efficacy of immunotherapy. A better understanding of the cellular and molecular basis of cyclophosphamide-mediated immunomodulation is needed to improve the efficacy of chemoimmunotherapy. Experimental Design: Transcript profiling and flow cytometry were used to explore cyclophosphamideinduced immunoadj...
متن کاملCyclophosphamide induces a type I interferon-associated sterile inflammatory response signature in cancer patients' blood cells: implications for cancer chemoimmunotherapy.
PURPOSE Certain chemotherapeutics, particularly cyclophosphamide, can enhance the antitumor efficacy of immunotherapy. A better understanding of the cellular and molecular basis of cyclophosphamide-mediated immunomodulation is needed to improve the efficacy of chemoimmunotherapy. EXPERIMENTAL DESIGN Transcript profiling and flow cytometry were used to explore cyclophosphamide-induced immunoad...
متن کاملImmunotherapeutic effects of pentoxifylline in type 1 diabetic mice and its role in the response of T-helper lymphocytes
Objective(s):Pentoxifylline is an immunomodulatory and anti-inflammatory agent and is used in vascular disorders. It has been shown that pentoxifylline inhibits proinflammatory [d1] cytokines production. The purpose of this study was to investigate the therapeutic effects of pentoxifylline on the treatment of autoimmune diabetes in mice. Materials and Methods: Diabetes was induced by multiple l...
متن کاملThe Protective Effects of Origanum vulgare L. Extract on Genetic Damage of Cyclophosphamide in Mice Blood Lymphocytes Using Micronucleus Test
Despite its various clinical applications, cyclophosphamide (CP), an alkylating chemotherapeutic agent, has demonstrated numerous side effects, including genetic toxicity. This study investigated the protective action of Origanum vulgare L., a powerful antioxidant plant, on the genotoxicity of CP in the mice blood lymphocytes. The mice were pretreated orally with different doses of (50, 100, 20...
متن کاملT Cell Stimulation In Vivo by Lipopolysaccharide (LPS)
Lipopolysaccharide (LPS) from gram-negative bacteria causes polyclonal activation of B cells and stimulation of macrophages and other APC. We show here that, under in vivo conditions, LPS also induces strong stimulation of T cells. As manifested by CD69 upregulation, LPS injection stimulates both CD4 and CD8(+) T cells, and, at high doses, stimulates naive (CD44(lo)) cells as well as memory (CD...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Blood
دوره 95 6 شماره
صفحات -
تاریخ انتشار 2000