Angioimmunoblastic T-cell lymphoma mice model
Introduction
Angioimmunoblastic T-cell lymphoma (AITL) represents a distinct clinicopathological entity among nodal peripheral T-cell lymphomas. A complex network of interactions between AITL tumor cells and the various reactive cellular components of the tumor microenvironment forms the clinical and histological features of AITL [1]. Because of its complexity, analysis of the immunopathogenesis of AITL in vitro seems to be impossible. On the other hand, recent advances in the development of novel mouse models, in which human hematopoietic and/or immune systems could be reconstituted, have contributed to analyzing the pathogenesis of various human diseases and evaluating the effects of therapeutic agents [2], [3], [4], [5], [6]. In the present study, we aimed to establish a novel AITL mouse model in which both primary tumor cells of human AITL and microenvironmental reactive cells engraft and interact with each other, using NOD/Shi-scid, IL-2Rγnull (NOG) mice [7], [8] as recipients, and analyzed the immunopathogenesis of AITL.
Section snippets
Human cells
The donors of tumor cells provided written informed consent before sampling in accordance with the Declaration of Helsinki. The present study was approved by the institutional ethics committee of Nagoya City University Graduate School of Medical Sciences.
Animals
NOG mice were purchased from the Central Institute for Experimental Animals and used at 6–8 weeks of age. All of the in vivo experiments were performed in accordance with the United Kingdom Coordinating Committee on Cancer Research Guidelines
Establishment of the primary AITL cell-bearing NOG mouse model
Microscopic images of the affected lymph node of AITL patient 1 are shown in Fig. 1A. There was marked proliferation of arborizing high endothelial venules (HEV). There was polymorphic infiltrate composed of small to medium-sized lymphocytes with clear to pale cytoplasm, distinct cell membranes and minimal cytological atypia. The neoplastic cells were admixed with variable numbers of small reactive lymphocytes, eosinophils, plasma cells, and histiocytes. These histological findings are typical
Discussion
The recent identification of CD4+ TFH cell as the cell of origin of AITL provides a rationale to explain some of the clinical and histological features of AITL. A fundamental function of TFH cells is regulation of B cell-mediated humoral immunity. It has been known that in humanized NOG mice reconstituted with human CD34+ hematopoietic stem cells, there was little IgG production because of the inappropriate differentiation of human B cells in the mouse environment [17], [18], [19], [20].
Grants support
The present study was supported by Grants-in-Aid for Young Scientists (A) (No. 22689029, T. Ishida), Scientific Research (B) (No. 22300333, T. Ishida, and R. Ueda), and Scientific Support Programs for Cancer Research (No. 221S0001, T. Ishida) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Grants-in-Aid for National Cancer Center Research and Development Fund (No. 21-6-3, T. Ishida), and Health and Labour Sciences Research Grants (H22-Clinical Cancer
Conflicts of interest
Nagoya City University Graduate School of Medical Sciences has received research grant support from Kyowa Hakko Kirin for works provided by Takashi Ishida. No other conflict of interest relevant to this article is reported.
Acknowledgements
We thank Ms. Chiori Fukuyama for her excellent technical assistance, and Ms. Naomi Ochiai for her excellent secretarial assistance.
Authors’ contributions. F.S., T.I., R.U., and H.I. designed the research. F.S., T.I., A.I., F.M., A.M., and H.T. performed the experiments. All of the authors analyzed and interpreted the data. F.S. and T.I. wrote the paper, and all of the other authors contributed to writing the paper.
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