Humanized mouse

{{Short description|Mouse carrying functioning human genes, etc.}}

A humanized mouse is a genetically modified mouse that has functioning human genes, cells, tissues and/or organs.{{cite journal | vauthors = Chuprin J, Buettner H, Seedhom MO, Greiner DL, Keck JG, Ishikawa F, Shultz LD, Brehm MA | display-authors = 6 | title = Humanized mouse models for immuno-oncology research | journal = Nature Reviews. Clinical Oncology | volume = 20 | issue = 3 | pages = 192–206 | date = March 2023 | pmid = 36635480 | pmc = 10593256 | doi = 10.1038/s41571-022-00721-2 }} Humanized mice are commonly used as small animal models in biological and medical research for human therapeutics.{{cite journal | vauthors = Brehm MA, Wiles MV, Greiner DL, Shultz LD | title = Generation of improved humanized mouse models for human infectious diseases | journal = Journal of Immunological Methods | volume = 410 | pages = 3–17 | date = August 2014 | pmid = 24607601 | pmc = 4155027 | doi = 10.1016/j.jim.2014.02.011 }}

A humanized mouse or a humanized mouse model is one that has been xenotransplanted with human cells and/or engineered to express human gene products, so as to be utilized for gaining relevant insights in the in vivo context for understanding of human-specific physiology and pathologies.{{cite journal | vauthors = Stripecke R, Münz C, Schuringa JJ, Bissig KD, Soper B, Meeham T, Yao LC, Di Santo JP, Brehm M, Rodriguez E, Wege AK, Bonnet D, Guionaud S, Howard KE, Kitchen S, Klein F, Saeb-Parsy K, Sam J, Sharma AD, Trumpp A, Trusolino L, Bult C, Shultz L | display-authors = 6 | title = Innovations, challenges, and minimal information for standardization of humanized mice | journal = EMBO Molecular Medicine | volume = 12 | issue = 7 | pages = e8662 | date = July 2020 | pmid = 32578942 | pmc = 7338801 | doi = 10.15252/emmm.201708662 }} Several human biological processes have been explored using animal models like rodents and non-human primates. In particular, small animals such as mice are advantageous in such studies owing to their small size, brief reproductive cycle, easy handling and due to the genomic and physiological similarities with humans; moreover, these animals can also be genetically modified easily. Nevertheless, there are several incongruencies of these animal systems with those of humans, especially with regard to the components of the immune system. To overcome these limitations and to realize the full potential of animal models to enable researchers to get a clear picture of the nature and pathogenesis of immune responses mounted against human-specific pathogens, humanized mouse models have been developed. Such mouse models have also become an integral aspect of preclinical biomedical research.{{cite journal | vauthors = Walsh NC, Kenney LL, Jangalwe S, Aryee KE, Greiner DL, Brehm MA, Shultz LD | title = Humanized Mouse Models of Clinical Disease | journal = Annual Review of Pathology | volume = 12 | issue = 1 | pages = 187–215 | date = January 2017 | pmid = 27959627 | doi = 10.1146/annurev-pathol-052016-100332 | pmc = 5280554 }}

History

The discovery of the athymic mouse, commonly known as the nude mouse, and that of the SCID mouse were major events that paved the way for humanized mice models. The first such mouse model was derived by backcrossing C57BL/Ka and BALB/c mice, featuring a loss of function mutation in the PRKDC gene. The PRKDC gene product is necessary for resolving breaks in DNA strands during the development of T cells and B cells. A mutation in the Foxn1 gene on chromosome 11 resulted in impaired thymus development, leading to a deficiency in mature T lymphocytes. Dysfunctional PRKDC gene leads to impaired development of T and B lymphocytes which gives rise to severe combined immunodeficiency (SCID). In spite of the efforts in developing this mouse model, poor engraftment of human hematopoietic stem cells (HSCs) was a major limitation that called for further advancement in the development humanized mouse models.{{cite journal | vauthors = Ito R, Takahashi T, Katano I, Ito M | title = Current advances in humanized mouse models | journal = Cellular & Molecular Immunology | volume = 9 | issue = 3 | pages = 208–14 | date = May 2012 | pmid = 22327211 | pmc = 4012844 | doi = 10.1038/cmi.2012.2 }} Nude mice were the earliest immunodeficient mouse model. These mice primarily produced IgM and had minimal or no IgA. As a result, they did not exhibit a rejection response to allogeneic tissue. Commonly utilized strains included BALB/c-nu, Swiss-nu, NC-nu, and NIH-nu, which were extensively employed in the research of immune diseases and tumors. However, due to the retention of B cells and NK cells, they were unable to fully support engraftment of human immune cells, thus making them unsuitable as an ideal humanized mouse model.

The next big step in the development of humanized mice models came with transfer of the scid mutation to a non-obese diabetic mouse. This resulted in the creation of the NOD-scid mice which lacked T cells, B cells, and NK cells. This mouse model permitted for a slightly higher level of human cell reconstitution. Nevertheless, a major breakthrough in this field came with the introduction of the mutant IL-2 receptor (IL2rg) gene in the NOD-scid model. This accounted for the creation of the NOD-scid-γcnull mice (NCG, NSG or NOG) models which were found to have defective signaling of interleukins IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. Researchers evolved this NSG model by knocking out the RAG1 and RAG2 genes (recombination activation genes), resulting into the RAG^null version of the NSG model that was devoid of major cells of the immune system including the natural killer cells, B lymphocytes and T lymphocytes, macrophages and dendritic cells, causing the greatest immunodeficiency in mice models so far. The limitation with this model was that it lacked the human leukocyte antigen. In accordance to this limitation, the human T cells when engrafted in the mice, failed to recognize human antigen-presenting cells, which consequated in defective immunoglobulin class switching and improper organization of the secondary lymphoid tissue.{{cite journal | vauthors = Bosma GC, Custer RP, Bosma MJ | title = A severe combined immunodeficiency mutation in the mouse | journal = Nature | volume = 301 | issue = 5900 | pages = 527–30 | date = February 1983 | pmid = 6823332 | doi = 10.1038/301527a0 | bibcode = 1983Natur.301..527B | s2cid = 4267981 }}

To circumvent this limitation, the next development came with the introduction of transgenes encoding for HLA I and HLA II in the NSG RAG^null model that enabled buildout of human T-lymphocyte repertoires as well as the respective immune responses.{{cite journal | vauthors = Yong KS, Her Z, Chen Q | title = Humanized Mice as Unique Tools for Human-Specific Studies | journal = Archivum Immunologiae et Therapiae Experimentalis | volume = 66 | issue = 4 | pages = 245–266 | date = August 2018 | pmid = 29411049 | pmc = 6061174 | doi = 10.1007/s00005-018-0506-x }} Mice with such human genes are technically human-animal hybrids.

Types

Engrafting an immunodeficient mouse with functional human cells can be achieved by intravenous injections of human cells and tissue into the mouse, and/or creating a genetically modified mouse from human genes. These models have been instrumental in studying human diseases, immune responses, and therapeutic interventions. This section highlights the various humanized mice models developed using the different methods.

= Hu-PBL-''scid'' model =

The human peripheral blood lymphocyte-severe combined immunodeficiency mouse model has been employed in a diverse array of research, encompassing investigations into Epstein-Barr virus (EBV)-associated lymphoproliferative disease, toxoplasmosis, human immunodeficiency virus (HIV) infection, and autoimmune diseases.{{cite journal | vauthors = Ahmed EH, Baiocchi RA | title = Murine Models of Epstein-Barr Virus-Associated Lymphomagenesis | journal = ILAR Journal | volume = 57 | issue = 1 | pages = 55–62 | date = 2016-03-31 | pmid = 27034395 | pmc = 6302257 | doi = 10.1093/ilar/ilv074 }} These studies have highlighted the effectiveness of the hu-PBL-SCID mouse model in examining various facets of human diseases, including pathogenesis, immune responses, and therapeutic interventions. Furthermore, the model has been utilized to explore genetic and molecular factors linked to neuropsychiatric disorders such as schizophrenia, offering valuable insights into the pathophysiology and potential therapeutic targets for these conditions.{{cite journal | vauthors = Nomura J, Takumi T | title = Animal models of psychiatric disorders that reflect human copy number variation | journal = Neural Plasticity | volume = 2012 | pages = 589524 | date = 2012 | pmid = 22900207 | pmc = 3414062 | doi = 10.1155/2012/589524 | doi-access = free }} This model is developed by intravenously injecting human PBMCs into immunodeficient mice. The peripheral blood mononuclear cells to be engrafted into the model are obtained from consented adult donors. The advantages associated with this method are that it is comparatively an easy technique, the model takes relatively less time to get established and that the model exhibits functional memory T cells.{{cite journal | vauthors = Tary-Lehmann M, Saxon A, Lehmann PV | title = The human immune system in hu-PBL-SCID mice | journal = Immunology Today | volume = 16 | issue = 11 | pages = 529–533 | date = November 1995 | pmid = 7495490 | doi = 10.1016/0167-5699(95)80046-8 }} It is particularly very effective for modelling graft vs. host disease. The model lacks engraftment of B lymphocytes and myeloid cells. Other limitations with this model are that it is suitable for use only in short-term experiments (<3 months) and the possibility that the model itself might develop graft vs. host disease.

= Hu-SRC-''scid'' model =

The humanized severe combined immunodeficiency (SCID) mouse model, also known as the hu-SRC-scid model, has been extensively utilized in various research areas, including immunology, infectious diseases, cancer, and drug development. This model has been instrumental in studying the human immune response to xenogeneic and allogeneic decellularized biomaterials, providing valuable insights into the biocompatibility and gene expression regulation of these materials.{{cite journal | vauthors = Wang RM, Johnson TD, He J, Rong Z, Wong M, Nigam V, Behfar A, Xu Y, Christman KL | display-authors = 6 | title = Humanized mouse model for assessing the human immune response to xenogeneic and allogeneic decellularized biomaterials | journal = Biomaterials | volume = 129 | pages = 98–110 | date = June 2017 | pmid = 28334641 | pmc = 5434867 | doi = 10.1016/j.biomaterials.2017.03.016 }} Hu-SRC-scid mice are developed by engrafting CD34+ human hematopoietic stem cells into immunodeficient mice. The cells are obtained from human fetal liver, bone marrow or from blood derived from the umbilical cord,{{cite journal | vauthors = Pearson T, Greiner DL, Shultz LD | title = Creation of "humanized" mice to study human immunity | journal = Current Protocols in Immunology | volume = Chapter 15 | issue = 1 | pages = 15.21.1–15.21.21 | date = May 2008 | pmid = 18491294 | pmc = 3023233 | doi = 10.1002/0471142735.im1521s81 }} and engrafted via intravenous injection. The advantages of this model are that it offers multilineage development of hematopoietic cells, generation of a naïve immune system, and if engraftment is carried out by intrahepatic injection of newborn mice within 72 hours of birth, it can lead to enhanced human cell reconstitution. Nevertheless, limitations associated with the model are that it takes a minimum of 10 weeks for cell differentiation to occur, it harbors low levels of human RBCs, polymorphonuclear leukocytes, and megakaryocytes.

= BLT (bone marrow/liver/thymus) model =

The BLT model is constituted with human HSCs, bone marrow, liver, and thymus. The engraftment is carried out by implantation of liver and thymus under the kidney capsule and by transplantation of HSCs obtained from fetal liver. The BLT model has a complete and totally functional human immune system with HLA-restricted T lymphocytes. The model also comprises a mucosal system that is similar to that of humans. Moreover, among all models the BLT model has the highest level of human cell reconstitution.{{cite journal | vauthors = Karpel ME, Boutwell CL, Allen TM | title = BLT humanized mice as a small animal model of HIV infection | journal = Current Opinion in Virology | volume = 13 | pages = 75–80 | date = August 2015 | pmid = 26083316 | pmc = 4550544 | doi = 10.1016/j.coviro.2015.05.002 | series = Animal models for viral diseases / Oncolytic viruses }}

However, since it requires surgical implantation, this model is the most difficult and time-consuming to develop. Other drawbacks associated with the model are that it portrays weak immune responses to xenobiotics, sub-optimal class switching and may develop GvHD.

= Transplanted human organoids =

Bio- and electrical engineers have shown that human cerebral organoids transplanted into mice functionally integrate with their visual cortex.{{cite news | vauthors = Firtina N |title=In a first, human brain organoids placed in the mouse cortex react to visual stimuli |url=https://interestingengineering.com/science/human-brain-organoids-mouse-cortex |access-date=17 January 2023 |work=Interesting Engineering |date=3 January 2023}}{{cite journal | vauthors = Wilson MN, Thunemann M, Liu X, Lu Y, Puppo F, Adams JW, Kim JH, Ramezani M, Pizzo DP, Djurovic S, Andreassen OA, Mansour AA, Gage FH, Muotri AR, Devor A, Kuzum D | display-authors = 6 | title = Multimodal monitoring of human cortical organoids implanted in mice reveal functional connection with visual cortex | journal = Nature Communications | volume = 13 | issue = 1 | pages = 7945 | date = December 2022 | pmid = 36572698 | pmc = 9792589 | doi = 10.1038/s41467-022-35536-3 | doi-access = free | bibcode = 2022NatCo..13.7945W }} Such models may raise similar ethical issues as organoid-based humanization of other animals.

= Mouse-human hybrid =

A mouse-human hybrid is a genetically modified mouse whose genome has both mouse and human genes, thus being a murine form of a human-animal hybrid. For example, genetically modified mice may be born with human leukocyte antigen genes in order to provide a more realistic environment when introducing human white blood cells into them in order to study immune system responses.{{cite journal | vauthors = Yong KS, Her Z, Chen Q | title = Humanized Mice as Unique Tools for Human-Specific Studies | journal = Archivum Immunologiae et Therapiae Experimentalis | volume = 66 | issue = 4 | pages = 245–266 | date = August 2018 | pmid = 29411049 | pmc = 6061174 | doi = 10.1007/s00005-018-0506-x }} One such application is the identification of hepatitis C virus (HCV) peptides that bind to HLA, and that can be recognized by the human immune system, thereby potentially being targets for future vaccines against HCV.{{cite web|url=https://www.jax.org/strain/003475|website=The Jackson Laboratory|title=Mouse strain C57BL/6-Mcph1^{Tg(HLA-A2.1)1Enge}|accessdate=2023-01-06}}

Established models for human diseases

Several mechanisms underlying human maladies are not fully understood. Utilization of humanized mice models in this context allows researchers to determine and unravel important factors that bring about the development of several human diseases and disorders falling under the categories of infectious disease, cancer, autoimmunity, and GvHD.

= Infectious diseases =

Among the human-specific infectious pathogens studied on humanized mice models, the human immunodeficiency virus has been successfully studied. Besides this, humanized models for studying Ebola virus,{{cite journal | vauthors = Lüdtke A, Oestereich L, Ruibal P, Wurr S, Pallasch E, Bockholt S, Ip WH, Rieger T, Gómez-Medina S, Stocking C, Rodríguez E, Günther S, Muñoz-Fontela C | display-authors = 6 | title = Ebola virus disease in mice with transplanted human hematopoietic stem cells | journal = Journal of Virology | volume = 89 | issue = 8 | pages = 4700–4 | date = April 2015 | pmid = 25673711 | pmc = 4442348 | doi = 10.1128/JVI.03546-14 }} Hepatitis B,{{cite journal | vauthors = Bility MT, Cheng L, Zhang Z, Luan Y, Li F, Chi L, Zhang L, Tu Z, Gao Y, Fu Y, Niu J, Wang F, Su L | display-authors = 6 | title = Hepatitis B virus infection and immunopathogenesis in a humanized mouse model: induction of human-specific liver fibrosis and M2-like macrophages | journal = PLOS Pathogens | volume = 10 | issue = 3 | pages = e1004032 | date = March 2014 | pmid = 24651854 | pmc = 3961374 | doi = 10.1371/journal.ppat.1004032 | doi-access = free }} Hepatitis C,{{cite journal | vauthors = Bility MT, Zhang L, Washburn ML, Curtis TA, Kovalev GI, Su L | title = Generation of a humanized mouse model with both human immune system and liver cells to model hepatitis C virus infection and liver immunopathogenesis | journal = Nature Protocols | volume = 7 | issue = 9 | pages = 1608–17 | date = September 2012 | pmid = 22899330 | pmc = 3979325 | doi = 10.1038/nprot.2012.083 }} Kaposi's sarcoma-associated herpesvirus,{{cite journal | vauthors = Wang LX, Kang G, Kumar P, Lu W, Li Y, Zhou Y, Li Q, Wood C | display-authors = 6 | title = Humanized-BLT mouse model of Kaposi's sarcoma-associated herpesvirus infection | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 8 | pages = 3146–51 | date = February 2014 | pmid = 24516154 | pmc = 3939909 | doi = 10.1073/pnas.1318175111 | bibcode = 2014PNAS..111.3146W | doi-access = free }} Leishmania major,{{cite journal | vauthors = Wege AK, Florian C, Ernst W, Zimara N, Schleicher U, Hanses F, Schmid M, Ritter U | display-authors = 6 | title = Leishmania major infection in humanized mice induces systemic infection and provokes a nonprotective human immune response | journal = PLOS Neglected Tropical Diseases | volume = 6 | issue = 7 | pages = e1741 | date = 2012-07-24 | pmid = 22848771 | doi = 10.1371/journal.pntd.0001741 | pmc = 3404120 | s2cid = 7657105 | doi-access = free }} malaria,{{cite journal | vauthors = Amaladoss A, Chen Q, Liu M, Dummler SK, Dao M, Suresh S, Chen J, Preiser PR | display-authors = 6 | title = De Novo Generated Human Red Blood Cells in Humanized Mice Support Plasmodium falciparum Infection | journal = PLOS ONE | volume = 10 | issue = 6 | pages = e0129825 | date = 2015-06-22 | pmid = 26098918 | doi = 10.1371/journal.pone.0129825 | pmc = 4476714 | bibcode = 2015PLoSO..1029825A | s2cid = 543860 | doi-access = free }} and tuberculosis{{cite journal | vauthors = Calderon VE, Valbuena G, Goez Y, Judy BM, Huante MB, Sutjita P, Johnston RK, Estes DM, Hunter RL, Actor JK, Cirillo JD, Endsley JJ | display-authors = 6 | title = A humanized mouse model of tuberculosis | journal = PLOS ONE | volume = 8 | issue = 5 | pages = e63331 | date = 2013-05-17 | pmid = 23691024 | doi = 10.1371/journal.pone.0063331 | pmc = 3656943 | bibcode = 2013PLoSO...863331C | s2cid = 17215038 | doi-access = free }} have been reported by various studies.

NOD/scid mice models for dengue virus{{cite journal | vauthors = Frias-Staheli N, Dorner M, Marukian S, Billerbeck E, Labitt RN, Rice CM, Ploss A | title = Utility of humanized BLT mice for analysis of dengue virus infection and antiviral drug testing | journal = Journal of Virology | volume = 88 | issue = 4 | pages = 2205–18 | date = February 2014 | pmid = 24335303 | pmc = 3911540 | doi = 10.1128/JVI.03085-13 }} and varicella-zoster virus,{{cite journal | vauthors = Moffat JF, Stein MD, Kaneshima H, Arvin AM | title = Tropism of varicella-zoster virus for human CD4+ and CD8+ T lymphocytes and epidermal cells in SCID-hu mice | journal = Journal of Virology | volume = 69 | issue = 9 | pages = 5236–42 | date = September 1995 | pmid = 7636965 | doi = 10.1128/jvi.69.9.5236-5242.1995 | pmc = 189355 }} and a Rag2^null𝛾c^null model for studying influenza virus{{cite journal | vauthors = Zheng J, Wu WL, Liu Y, Xiang Z, Liu M, Chan KH, Lau SY, Lam KT, To KK, Chan JF, Li L, Chen H, Lau YL, Yuen KY, Tu W | display-authors = 6 | title = The Therapeutic Effect of Pamidronate on Lethal Avian Influenza A H7N9 Virus Infected Humanized Mice | journal = PLOS ONE | volume = 10 | issue = 8 | pages = e0135999 | date = 2015-08-18 | pmid = 26285203 | doi = 10.1371/journal.pone.0135999 | pmc = 4540487 | bibcode = 2015PLoSO..1035999Z | s2cid = 10461525 | doi-access = free }} have also been developed.

= Cancers =

On the basis of the type of human cells/tissues that have been used for engraftment, humanized mouse models for cancer can be classified as patient-derived xenografts or cell line-derived xenografts.{{Cite journal| vauthors = Tian H, Lyu Y, Yang YG, Hu Z |date=2020|title=Humanized Rodent Models for Cancer Research |journal=Frontiers in Oncology |volume=10|page=1696|doi=10.3389/fonc.2020.01696|pmid=33042811|pmc=7518015|s2cid=221589508|issn=2234-943X|doi-access=free}} PDX models are considered to retain the parental malignancy characteristics at a greater extent and hence these are regarded as the more powerful tool for evaluating the effect of anticancer drugs in pre-clinical studies.{{cite journal | vauthors = Hausser HJ, Brenner RE | title = Phenotypic instability of Saos-2 cells in long-term culture | journal = Biochemical and Biophysical Research Communications | volume = 333 | issue = 1 | pages = 216–22 | date = July 2005 | pmid = 15939397 | doi = 10.1016/j.bbrc.2005.05.097 }} Humanized mouse models for studying cancers of various organs have been designed. A mouse model for the study of breast cancer has been generated by the intrahepatic engraftment of SK-BR-3 cells in NSG mice.{{cite journal | vauthors = Wege AK, Schmidt M, Ueberham E, Ponnath M, Ortmann O, Brockhoff G, Lehmann J | title = Co-transplantation of human hematopoietic stem cells and human breast cancer cells in NSG mice: a novel approach to generate tumor cell specific human antibodies | journal = mAbs | volume = 6 | issue = 4 | pages = 968–77 | date = 2014-05-08 | pmid = 24870377 | doi = 10.4161/mabs.29111 | pmc = 4171030 | s2cid = 34234807 }} Similarly, NSG mice intravenously engrafted with patient-derived AML cells,{{cite journal | vauthors = Her Z, Yong KS, Paramasivam K, Tan WW, Chan XY, Tan SY, Liu M, Fan Y, Linn YC, Hui KM, Surana U, Chen Q | display-authors = 6 | title = An improved pre-clinical patient-derived liquid xenograft mouse model for acute myeloid leukemia | journal = Journal of Hematology & Oncology | volume = 10 | issue = 1 | pages = 162 | date = October 2017 | pmid = 28985760 | pmc = 5639594 | doi = 10.1186/s13045-017-0532-x | doi-access = free }} and those engrafted (via subcutaneous, intravenous or intra-pancreatic injections) with patient-derived pancreatic cancer tumors{{cite journal | vauthors = Her Z, Yong KS, Paramasivam K, Tan WW, Chan XY, Tan SY, Liu M, Fan Y, Linn YC, Hui KM, Surana U, Chen Q | display-authors = 6 | title = An improved pre-clinical patient-derived liquid xenograft mouse model for acute myeloid leukemia | journal = Journal of Hematology & Oncology | volume = 10 | issue = 1 | pages = 162 | date = October 2017 | pmid = 28985760 | doi = 10.1186/s13045-017-0532-x | pmc = 5639594 | s2cid = 25506701 | doi-access = free }} have also been developed for the study of leukemia and pancreatic cancer respectively. Several other humanized rodent models for the study of cancer and cancer immunotherapy have also been reported.{{cite journal | vauthors = Chen Q, Wang J, Liu WN, Zhao Y | title = Cancer Immunotherapies and Humanized Mouse Drug Testing Platforms | journal = Translational Oncology | volume = 12 | issue = 7 | pages = 987–995 | date = July 2019 | pmid = 31121491 | pmc = 6529825 | doi = 10.1016/j.tranon.2019.04.020 }}

= Autoimmune diseases =

Problems posed by the differences in the human and rodent immune systems have been overcome using a few strategies, so as to enable researchers to study autoimmune disorders using humanized models. As a result, the use of humanized mouse models has extended to various areas of immunology and disease research. For instance, humanized mice have been utilized to study human-tropic pathogens, liver cancer models, and the comparison of mouse models to human diseases NSG mice engrafted with PBMCs and administered with myelin antigens in Freund's adjuvant, and antigen-pulsed autologous dendritic cells have been used to study multiple sclerosis.{{cite journal | vauthors = Zayoud M, El Malki K, Frauenknecht K, Trinschek B, Kloos L, Karram K, Wanke F, Georgescu J, Hartwig UF, Sommer C, Jonuleit H, Waisman A, Kurschus FC | display-authors = 6 | title = Subclinical CNS inflammation as response to a myelin antigen in humanized mice | journal = Journal of Neuroimmune Pharmacology | volume = 8 | issue = 4 | pages = 1037–47 | date = September 2013 | pmid = 23640521 | doi = 10.1007/s11481-013-9466-4 | s2cid = 503830 }} Similarly, NSG mice engrafted with hematopoietic stem cells and administered with pristane have been used for studying lupus erythematosus.{{cite journal | vauthors = Gunawan M, Her Z, Liu M, Tan SY, Chan XY, Tan WW, Dharmaraaja S, Fan Y, Ong CB, Loh E, Chang KT, Tan TC, Chan JK, Chen Q | display-authors = 6 | title = A Novel Human Systemic Lupus Erythematosus Model in Humanised Mice | journal = Scientific Reports | volume = 7 | issue = 1 | pages = 16642 | date = November 2017 | pmid = 29192160 | doi = 10.1038/s41598-017-16999-7 | pmc = 5709358 | bibcode = 2017NatSR...716642G | s2cid = 5604139 }} Furthermore, NOG mice engrafted with PBMCs has been used to study mechanisms of allografts rejection in vivo.{{cite journal | vauthors = King M, Pearson T, Shultz LD, Leif J, Bottino R, Trucco M, Atkinson MA, Wasserfall C, Herold KC, Woodland RT, Schmidt MR, Woda BA, Thompson MJ, Rossini AA, Greiner DL | display-authors = 6 | title = A new Hu-PBL model for the study of human islet alloreactivity based on NOD-scid mice bearing a targeted mutation in the IL-2 receptor gamma chain gene | journal = Clinical Immunology | volume = 126 | issue = 3 | pages = 303–314 | date = March 2008 | pmid = 18096436 | doi = 10.1016/j.clim.2007.11.001 }} The development of humanized mouse models has significantly advanced the study of autoimmune disorders and various areas of immunology and disease research. These models have provided a platform for investigating human diseases, immune responses, and therapeutic interventions, bridging the gap between human and rodent immune systems and offering valuable insights into disease pathogenesis and potential therapeutic strategies.