NSGS mice humanized with cord blood mononuclear cells show sustained and functional myeloid-lymphoid representation with limited graft-versus-host disease.
Por:
Panisello, C, Aschero MR, Martinez-Moreno, A, Ho, HR, Falgas, A, González-Navarro, EA, Carabelli, J, Pradenas, E, Lázaro-Díez, M, Prado, JG, Blanco, J, Carrillo, J, Juan, ME, Carcaboso AM, Bueno, C and Menendez, P
Publicada:
7 oct 2024
Ahead of Print:
7 oct 2024
Resumen:
Humanized immunodeficient mice serve as critical models for investigating the functional interplay between transplanted human cells and a pre-reconstituted human immune system. These models facilitate the study of molecular and cellular pathogenic mechanisms and enable the evaluation of the efficacy and toxicity of immunotherapies, thereby accelerating their preclinical and clinical development. Current strategies rely on inefficient, long-term/delayed hematopoietic reconstitution by CD34+ hematopoietic progenitors or short-term reconstitution with peripheral blood mononuclear cells (PB-MNCs) associated with high rates of graft-versus-host disease (GvHD) and an inefficient representation of immune cell populations. Here, we hypothesized that immunologically naïve cord blood mononuclear cells (CB-MNCs) could serve as a superior alternative, providing long-lasting and functionally effective immune reconstitution. We conducted a comprehensive comparison between the non-obese diabetic (NOD).Cg-Prkdc?ˆscid-IL2rg?ˆtm1Wjl/SzJ (NSG) and NSG-Tg(CMV-IL3,CSF2,KITLG)?ˆ1Eav/MloySzJ (NSGS) immunodeficient mouse models following humanization with either PB-MNCs or CB-MNCs. We assessed the engraftment dynamics of various human immune cells over time and monitored the development of GvHD in both models. For the most promising model, we extensively evaluated immune cell functionality in vitro and in vivo using sarcoma and leukemia xenografts. Humanizing NSGS mice with CB-MNCs results in a rapid, robust, and sustained representation of a diverse range of functional human lymphoid and myeloid cell populations while minimizing GvHD incidence. In this model, human immune cell populations significantly impair the growth and engraftment of sarcoma and B-cell acute lymphoblastic leukemia cells, with a significant inverse correlation between immune cell levels and tumor growth. This study establishes a fast, efficient, and reliable in vivo platform for various applications in cancer immunotherapy, particularly for exploring the complex interactions between cancer cells, immune cells, and the tumor microenvironment in vivo, prior to clinical development.
Filiaciones:
Panisello, C:
Josep Carreras Leukaemia Res Inst IJC, Barcelona, Spain
Inst Salud Carlos III ISCIII, Red Espanola Terapias Avanzadas TERAV, Madrid, Spain
Germans Trias i Pujol Res Inst IGTP, Badalona, Spain
Aschero MR:
St Joan de Deu Res Inst, Paediat Canc Treatment, Barcelona, Spain
Martinez-Moreno, A:
Josep Carreras Leukaemia Res Inst IJC, Barcelona, Spain
Inst Salud Carlos III ISCIII, Red Espanola Terapias Avanzadas TERAV, Madrid, Spain
Ho, HR:
Josep Carreras Leukaemia Res Inst IJC, Barcelona, Spain
Inst Salud Carlos III ISCIII, Red Espanola Terapias Avanzadas TERAV, Madrid, Spain
Falgas, A:
Josep Carreras Leukaemia Res Inst IJC, Barcelona, Spain
Inst Salud Carlos III ISCIII, Red Espanola Terapias Avanzadas TERAV, Madrid, Spain
González-Navarro, EA:
Hosp Clin Barcelona, Dept Immunol & Immunotherapy, Barcelona, Spain
August Pi i Sunyer Inst Biomed Res IDIBAPS, Barcelona, Spain
Carabelli, J:
IrsiCaixa AIDS Res Inst, Badalona, Spain
Pradenas, E:
IrsiCaixa AIDS Res Inst, Badalona, Spain
Lázaro-Díez, M:
IrsiCaixa AIDS Res Inst, Badalona, Spain
Prado, JG:
Germans Trias i Pujol Res Inst IGTP, Badalona, Spain
IrsiCaixa AIDS Res Inst, Badalona, Spain
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Enfermedades Infecciosas CIB, Madrid, Spain
Blanco, J:
Germans Trias i Pujol Res Inst IGTP, Badalona, Spain
IrsiCaixa AIDS Res Inst, Badalona, Spain
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Enfermedades Infecciosas CIB, Madrid, Spain
Univ Autonoma Barcelona, Dept Microbiol, Bellaterra, Spain
Carrillo, J:
Germans Trias i Pujol Res Inst IGTP, Badalona, Spain
IrsiCaixa AIDS Res Inst, Badalona, Spain
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Enfermedades Infecciosas CIB, Madrid, Spain
Juan, ME:
Inst Salud Carlos III ISCIII, Red Espanola Terapias Avanzadas TERAV, Madrid, Spain
Hosp Clin Barcelona, Dept Immunol & Immunotherapy, Barcelona, Spain
August Pi i Sunyer Inst Biomed Res IDIBAPS, Barcelona, Spain
Carcaboso AM:
St Joan de Deu Res Inst, Paediat Canc Treatment, Barcelona, Spain
Bueno, C:
Josep Carreras Leukaemia Res Inst IJC, Barcelona, Spain
Inst Salud Carlos III ISCIII, Red Espanola Terapias Avanzadas TERAV, Madrid, Spain
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Oncol CIBERONC, Madrid, Spain
Menendez, P:
Josep Carreras Leukaemia Res Inst IJC, Barcelona, Spain
Inst Salud Carlos III ISCIII, Red Espanola Terapias Avanzadas TERAV, Madrid, Spain
Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Oncol CIBERONC, Madrid, Spain
Inst Catalana Recerca & Estudis Avancats ICREA, Barcelona, Spain
Univ Barcelona, Sch Med, Dept Biomed, Barcelona, Spain
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