References

scbmt

БИОМЕДИЦИНА

Journal Biomed

2074-59822713-0428

Scientific center of biomedical technologies of Federal Medical and Biological Agency

10.33647/2074-5982-15-4-67-81

scbmt-152

Research Article

МЕТОДЫ БИОМЕДИЦИНСКИХ ИССЛЕДОВАНИЙ

METHODS OF BIOMEDICAL RESEARCHES

ГУМАНИЗИРОВАННЫЕ МЫШИ: МЕТОДЫ ПОЛУЧЕНИЯ, МОДЕЛИ И ИСПОЛЬЗОВАНИЕ В ЭКСПЕРИМЕНТАЛЬНОЙ ОНКОЛОГИИ (ОБЗОР)

HUMANIZED MICE: CREATION, MODELS AND USE IN EXPERIMENTAL ONCOLOGY (REVIEW)

Кит

О. И.

Kit

O. I.

д.м.н., проф., чл.-корр. РАН, Заслуженный врач РФ,

344037, Ростов-на-Дону, ул. 14-я линия, д. 63

Dr. Sci. (Med.), Prof., Corresponding Member of the Russian Academy of Sciences, Honored Doctor of the Russian Federation,

344037, Rostov-on-Don, 14-ya liniya str., 63

onko-sekretar@list.ru

Максимов

А. Ю.

Maksimov

A. Yu.

д.м.н., проф.,

344037, Ростов-на-Дону, ул. 14-я линия, д. 63

Dr. Sci. (Med.), Prof.,

344037, Rostov-on-Don, 14-ya liniya str., 63

rnioi@list.ru

Протасова

Т. П.

Protasova

T. P.

к.б.н.,

344037, Ростов-на-Дону, ул. 14-я линия, д. 63

Cand. Sci. (Biol.),

344037, Rostov-on-Don, 14-ya liniya str., 63

protasovatp@yandex.ru

Гончарова

А. С.

Goncharova

A. S.

к.б.н.,

344037, Ростов-на-Дону, ул. 14-я линия, д. 63

Cand. Sci. (Biol.),

344037, Rostov-on-Don, 14-ya liniya str., 63

fateyeva_a_s@list.ru

Кутилин

Д. С.

Kutilin

D. S.

к.б.н.,

344037, Ростов-на-Дону, ул. 14-я линия, д. 63

Cand. Sci. (Biol.),

344037, Rostov-on-Don, 14-ya liniya str., 63

k.denees@yandex.ru

Лукбанова

Е. А.

Lukbanova

E. A.

344037, Ростов-на-Дону, ул. 14-я линия, д. 63

344037, Rostov-on-Don, 14-ya liniya str., 63

katya.samarskaya@yandex.ru

ФГБУ «Ростовский научно-исследовательский онкологический институт» Минздрава РоссииРоссияRostov Research Institute of Oncology of the Ministry of Health of the Russian FederationRussian Federation

2019

30112019

046781

2019

Кит О.И., Максимов А.Ю., Протасова Т.П., Гончарова А.С., Кутилин Д.С., Лукбанова Е.А.

Kit O.I., Maksimov A.Y., Protasova T.P., Goncharova A.S., Kutilin D.S., Lukbanova E.A.

Данная работа распространяется под лицензией Creative Commons Attribution 4.0.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://journal.scbmt.ru/jour/article/view/152

В лабораториях разных стран ведется постоянная работа по улучшению существующих, а также созданию новых биологических объектов, моделирующих различные заболевания человека. Иммунодефицитные мыши, которым трансплантированы функциональные клетки и ткани человека, а также трансгенные животные, в геноме которых интегрированы соответствующие человеческие гены — то есть «гуманизированные мыши», — все чаще выступают в качестве тест-систем в различных биомедицинских исследованиях. Модели гуманизированных мышей постоянно совершенствуются и в настоящее время используются для изучения биологических реакций человека, в качестве доклинических инструментов для тестирования лекарственных средств, для выявления патогенетических механизмов широкого спектра заболеваний. В частности, такие животные играют все более важную роль в изучении специфических для человека инфекционных агентов, а также широко применяются в исследованиях биологии рака и разработках новых противоопухолевых воздействий. Кроме того, гуманизированные мыши все чаще используются в качестве трансляционных моделей во многих областях клинических исследований, включая трансплантологию, иммунологию и онкологию. В конечном счете использование гуманизированных животных может привести к внедрению действительно «персонализированной» медицины в клиническую практику. В данном обзоре обсуждаются современные достижения в получении и использовании гуманизированных мышей, подчеркивается их полезность для изучения патогенеза, а также разработки новых методов лечения онкологических заболеваний человека.

Research laboratories in various countries are constantly endeavouring to improve the existing and to create new biological objects to simulate various human diseases. Immunodefi cient mice with transplanted human functional cells and tissues, as well as transgenic animals with the relevant human genes integrated in their genome — i. e. humanized mice — are increasingly used as test systems in biomedical studies. Humanized mouse models are constantly being improved to fi nd application in studies investigating human biological reactions and identifying the pathogenetic mechanisms behind a wide range of diseases, or as preclinical tools for medicine testing. In particular, such animals play an increasingly important role both in studies of human-specifi c infectious agents, cancer biology research and in the development of new antitumour agents. In addition, humanized mice are increasingly used as translational models in many areas of clinical research, including transplantology, immunology and oncology. Ultimately, the use of humanized animals can lead to the introduction of a truly personalized medicine into clinical practice. In this review, we discuss modern advances in the creation and use of humanized mice, emphasizing their usefulness for the pathogenesis study, as well as the development of new methods for human cancer treatment.

гуманизация животныхксенотрансплантацияиммунодефицитные мышимоделирование заболеваний человеказлокачественные опухоли

humanized animalsxenograftingimmunodefi cient micehuman disease modellingmalignant tumours

References1

Гематология: национальное руководство / Под ред. О.А. Рукавицына. М.: ГЭОТАР-Медиа, 2015. 776 с.

Gematologiya: nacional’noe rukovodstvo [Hematology: national guidelines]. Ed. by O.A. Rukavitsyn. Moscow: GEOTAR-Media, 2015. 776 p. (In Russian).

Дейкин А.В. Современные подходы и перспективы использования технологии модификации генома при моделировании патологических состояний человека на животных моделях. Russian scientist. 2017;2:16–17.

Deykin A.V. Sovremennye podhody i perspektivy ispol’zovaniya tekhnologii modifi kacii genoma pri modelirovanii patologicheskih sostoyanij cheloveka na zhivotnyh modelyah [Modern approaches and prospects of using the technology of genome editing in modeling the pathological conditions of human in animal models]. Russian scientist. 2017;2:16– 17. (In Russian).

Каркищенко Н.Н., Рябых В.П., Каркищенко В.Н., Колоскова Е.М. Создание гуманизированных мышей для фармакотоксикологических исследований (успехи, неудачи и перспективы). Биомедицина. 2014;3:4–22.

Karkischenko N.N., Ryabyh V.P., Karkischenko V.N., Koloskova Е.M. Sozdanie gumanizirovannyh myshej dlya farmakotoksikologicheskih issledovanij (uspekhi, neudachi i perspektivy) [Creation of humanized mice for pharmacological and toxicological research (progress, failures and prospects)]. Biomedicine. 2014;3:4–22. (In Russian).

Каркищенко Н.Н., Капанадзе Г.Д., Петрова Н.В. Новая модель оценки избирательной токсичности антибластомных средств на трансгенных мышах с генами Nat1 hom человека. Биомедицина. 2015;3:4–19.

Karkischenko N.N., Kapanadze G.D., Petrova N.V. Novaya model’ ocenki izbiratel’noj toksichnosti antiblastomnyh sredstv na transgennyh myshah s genami Nat1 hom cheloveka [A new model for the evaluation of selective toxicity of antineoplastic funds in transgenic mice with human genes Nat1hom]. Biomedicine. 2015;3:4–19. (In Russian).

Кит О.И., Колесников Е.Н., Максимов А.Ю., Протасова Т.П., Гончарова А.С., Лукбанова Е.А. Методы создания ортотопических моделей рака пищевода и их применение в доклинических исследованиях. Современные проблемы науки и образования. 2019;2.

Kit O.I., Kolesnikov Е.N., Maksimov A.Yu., Protasova T.P., Goncharova A.S., Lukbanova Е.A. Metody sozdaniya ortotopicheskih modelej raka pishchevoda i ih primenenie v doklinicheskih issledovaniyah [Methods of creation and application of orthotopic models of esophageal cancer in preclinical studies (literature review)]. Sovremennye problemy nauki i obrazovaniya [Modern problems of science and education]. 2019;2. (In Russian).

Banuelos S.J., Shultz L.D., Greiner D.L., Burzenski L.M., Gott B., Lyons B.L., et al. Rejection of human islets and human HLA-A2.1 transgenic mouse islets by alloreactive human lymphocytes in immunodefi cient NOD-scid and NOD-Rag1(null) Prf1(null) mice. Clin. Immunol. 2004;112:273–283. PubMed: 15308121.

Brady J.L., Harrison L.C., Goodman D.J., Cowan P.J., Hawthorne W.J., et al. Preclinical screening for acute toxicity of therapeutic monoclonal antibodies in a huSCID model. Clin. Transl. Immunology. 2014;3:e29. PubMed: 25587392.

Brehm M.A., Bortell R., Verma M., Shultz L.D., Greiner D.L. Humanized Mice in Translational Immunology. In: Translational Immunology: Mechanisms and Pharmacological Approaches. Ed. by S.L. Tan. Elsevier, 2016:285–326.

Cany J., van der Waart A.B., Tordoir M., Franssen G.M., Hangalapura B.N., et al. Natural killer cells generated from cord blood hematopoietic progenitor cells effi ciently target bone marrow-residing human leukemia cells in NOD/SCID/IL2Rg(null) mice. PLoS ONE. 2013;8:e64384. PubMed: 23755121.

Cassidy J.W., Caldas C., Bruna A. Maintaining Tumor Heterogeneity in Patient-Derived Tumor Xenografts. Cancer Res. 2015;75:2963–2968. PubMed: 26180079.

Fisher T.S., Kamperschroer C., Oliphant T., Love V.A., Lira P.D., et al. Targeting of 4-1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity. Cancer Immunol. Immunother. 2012;61:1721–1733. PubMed: 22406983.

Fujii H., Trudeau J.D., Teachey D., Fish J.D., Grupp S.A., Schultz K.R., et al. In vivo control of acute lymphoblastic leukemia by immunostimulatory CpG oligonucleotides. Blood. 2007;109:2008–2013. PubMed: 17068155.

Hanazawa А., Ito R., Katano I., Kawai K., Goto M., Suemizu H., et al. Generation of human immunosuppressive Myeloid cell Populations in human interleukin-6 Transgenic NOG Mice. Front. Immunol. 2018;9:152. DOI: 10.3389/fimmu.2018.00152.

Kloss C.C., Condomines M., Cartellieri M., Bachmann M., Sadelain M. Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T-cells. Nat. Biotechnol. 2013;31:71–75. PubMed: 23242161.

Lang J., Weiss N., Freed B.M., Torres R.M., Raul M.Т., Pelanda R. Generation of hematopoietic humanized mice in the newborn BALB/c-Rag2nullIl2rγnull mouse model: a multivariable optimization approach. Clin. Immunol. 2011 July;140(1):102–116. DOI: 10.1016/j.clim.2011.04.002.

Lim W.H., Kireta S., Russ G.R., Coates P.T. Human plasmacytoid dendritic cells regulate immune responses to Epstein — Barr virus (EBV) infection and delay EBV-related mortality in humanized NODSCID mice. Blood. 2007;109:1043–1050. PubMed: 17018863.

Liu D., Song L., Wei J., Courtney A.N., Gao X., et al. IL-15 protects NKT cells from inhibition by tumorassociated macrophages and enhances antimetastatic activity. J. Clin. Invest. 2012;122:2221–2233. PubMed: 22565311.

Maykel J., Liu J.H., Li H., Shultz L.D., Greiner D.L., Houghton J. NOD-scidIl2rg (tm1Wjl) and NOD-Rag1 (null) Il2rg (tm1Wjl): a model for stromal cell-tumor cell interaction for human colon cancer. Dig. Dis. Sci. 2014;59:1169–1179. PubMed: 24798995.

Morton J.J., Bird G., Keysar S.B., Astling D.P., Lyons T.R., et al. XactMice: humanizing mouse bone marrow enables microenvironment reconstitution in a patient-derived xeno-graft model of head and neck cancer. Oncogene. 2016;35:290–300. PubMed: 25893296.

Mullard A. New checkpoint inhibitors ride the immunotherapy tsunami. Nat. Rev. Drug Discov. 2013;12:489–492. PubMed: 23812256.

Murphy A.J., Macdonald L.E., Stevens S., Karow M., Dore A.T., Pobursky K, et al. Mice with megabase humanization of their immunoglobulin genes generate antibodies as effi ciently as normal mice. PNAS. 2014;111(14):5153–5158. DOI: 10.1073/pnas.1324022111.

Najima Y., Tomizawa-Murasawa M., Saito Y., Watanabe T., Ono R., et al. Induction of WT1-specifi c human CD8+ T-cells from human HSCs in HLA class I Tg NOD/SCID/IL2rgKO mice. Blood. 2016;127:722– 734. PubMed: 26702062.

Ono A., Hattori S., Kariya R., Iwanaga S., Taura M., Harada H., et al. Comparative Study of Human Hematopoietic Cell Engraftment into Balb/c and C57BL/6 Strain of Rag-2/Jak3 Double-Defi cient Mice. Journal of Biomedicine and Biotechnology. 2011;539748:6. DOI: 10.1155/2011/539748.

Pearson Т., Greiner D.L., Shultz L.D. Creation of “Humanized” Mice to Study Human Immunity. Curr. Protoc. Immunol. 2008; CHAPTER: Unit-15.21. DOI: 10.1002/0471142735.im1521s81.

Provasi E., Genovese P., Lombardo A., Magnani Z., Liu P.Q., et al. Editing T-cell specifi city towards leukemia by zinc fi nger nucleases and lentiviral gene transfer. Nat. Med. 2012;18:807–815. PubMed: 22466705.

Raimon D.-S., Robert C.D. Principles of Bone Marrow Transplantation (BMT): Providing Optimal Veterinary and Husbandry Care to Irradiated Mice in BMT Studies. J. of the Am. Association for Laboratory Animal Science. 2009;48(1):11–22.

Rongvaux A., Willinger T., Martinek J., Strowig T., Gearty S.V., et al. Development and function of human innate immune cells in a humanized mouse model. Nat. Biotechnol. 2014;32:364–372. PubMed: 24633240.

Rosenberg S.A., Restifo N.P., Yang J.C., Morgan R.A., Dudley M.E. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat. Rev. Cancer. 2008;8:299–308. PubMed: 18354418.

Rosfjord E., Lucas J., Li G., Gerber H.P. Advances in patient-derived tumor xeno-grafts: from target identifi cation to predicting clinical response rates in oncology. Biochem. Pharmacol. 2014;91:135–143. PubMed: 24950467.

Roth M.D., Harui A. Human tumor infi ltrating lymphocytes cooperatively regulate prostate tumor growth in a humanized mouse model. J. Immunother. Cancer. 2015;3:12. PubMed: 25901284.

Sanmamed M.F., Rodriguez I., Schalper K.A., Onate C., Azpilikueta A., et al. Nivolumab and Urelumab Enhance Antitumor Activity of Human T-Lymphocytes Engrafted in Rag2-/-IL2Rgammanull Immunodefi cient Mice. Cancer. Res. 2015;75:3466– 3478. PubMed: 26113085.

Shankavaram U.T., Bredel M., Burgan W.E., Carter D., Tofi lon P., Camphausen K. Molecular profi ling indicates orthotopicxenograft of glioma cell lines simulate a subclass of human glioblastoma. J. Cell. Mol. Med. 2012;16:545–554. PubMed: 21595825.

Schilbach K., Alkhaled M., Welker C., Eckert F., Blank G., et al. Cancer-targeted IL-12 controls human rhabdomyosarcoma by senescence induction and myogenic differentiation. Oncoimmunology. 2015;4:e1014760. PubMed: 26140238.

Shultz L.D., Brehm M.A., Garcia-Martinez J.V., Greiner D.L. Humanized mice for immune system investigation: progress, promise and challenges. Nat. Rev. Immunol. 2012;12:786–798. PubMed: 23059428.

Shultz L.D., Goodwin N., Ishikawa F., Hosur V., Lyons B.L., Greiner D.L. Human cancer growth and therapy in immunodefi cient mouse models. Cold Spring Harb. Protoc. 2014:694–708. PubMed: 24987146.

Shultz L.D., Ishikawa F., Greiner D.L. Humanized mice in translational biomedical research. Nat. Rev. Immunol. 2007;7:118–130. PubMed: 17259968.

Song D.G., Powell D.J. Pro-survival signaling via CD27 costimulation drives effective CAR T-cell therapy. Oncoimmunology. 2012;1:547–549. PubMed: 22754782.

Strowig T., Gurer C., Ploss A., Liu Y.F., Arrey F., et al. Priming of protective T-cell responses against virusinduced tumors in mice with human immune system components. J. Exp. Med. 2009;206:1423–1434. PubMed: 19487422.

Tanaka S., Saito Y., Kunisawa J., Kurashima Y., Wake T., Suzuki N., et al. Development of Mature and Functional Human Myeloid Subsets in Hematopoietic Stem Cell-Engrafted NOD/SCID/IL2rγKO Mice. Immunol. 2012;188(12):6145–6155. DOI: 10.4049/jimmunol.1103660.

Traggiai E, Chicha L., Mazzucchelli L., Bronz L., Piffaretti J.C., Lanzavecchia A., et al. Development of a human adaptive immune system in cord blood cell-transplanted mice. Science. 2004;304:104–107. PubMed: 15064419.

Turgeon N.A., Banuelos S.J., Shultz L.D., Lyons B.L., Iwakoshi N., Greiner D.L., et al. Alloimmune injury and rejection of human skin grafts on human peripheral blood lymphocyte-reconstituted nonobese diabetic severe combined immunodefi cient beta2-microglobulin-null mice. Exp. Biol. Med. 2003;228:1096–1104.

Urbanska K., Lanitis E., Poussin M., Lynn R.C., Gavin B.P., et al. A universal strategy for adoptive immunotherapy of cancer through use of a novel T-cell antigen receptor. Cancer Res. 2012;72:1844–1852. PubMed: 22315351.

van Lent A.U., Centlivre M., Nagasawa M., Karrich J.J., Pouw S.M., Weijer K., et al. In Vivo Modulation of Gene Expression by Lentiviral Transduction in “Human Immune System” Rag2-/-c-/- Mice. Methods Mol. Biol. 2010;595:87–115. DOI: 10.1007/978-1-60761-421-0_6.

Walsh N., Kenney L., Jangalwe S., Aryee K.-E., Greiner D.L., Brehm M.A., et al. Humanized mouse models of clinical disease. Annu. Rev. Pathol. 2017;12:187– 215. DOI: 10.1146/annurev-pathol-052016-100332.

Wang H., Ge W., Zhuang Y., Fu J., Li D., Ju X. Fast recovery of platelet production in NOD/SCID mice after transplantation with ex vivo expansion of megakaryocyte from cord blood CD34+ cells. Journal of Cancer Research and Therapeutics. 2018;14(1):233– 239. DOI: 10.4103/0973-1482.193893.

Wang L.X., Kang G., Kumar P., Lu W., Li Y., et al. Humanized-BLT mouse model of Kaposi’s sarcomaassociated herpesvirus infection. Proc. Natl. Acad. Sci. USA. 2014;111:3146–3141. PubMed: 24516154.

Wege A.K., Ernst W., Eckl J., Frankenberger B., Vollmann-Zwerenz A., et al. Humanized tumor miceA new model to study and manipulate the immune response in advanced cancer therapy. Int. J. Cancer. 2011;129:2194–2206. PubMed: 21544806.

Weissmuller S., Kronhart S., Kreuz D., Schnierle B., Kalinke U., et al. TGN1412 Induces Lymphopenia and Human Cytokine Release in a Humanized Mouse Model. PLoS ONE. 2016;11:e0149093. PubMed: 26959227.

Zhao Y., Moon E., Carpenito C., Paulos C.M., Liu X., et al. Multiple injections of electroporated autologous T-cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor. Cancer Res. 2010;70:9053–9061. PubMed: 20926399.

Zschaler J., Schlorke D., Arnhold J. Differences in innate immune response between man and mouse. Crit. Rev. Immunol. 2014;34:433–454. PubMed: 25404048.

The authors declare that there are no conflicts of interest present.