This disclosure relates to genetically modified rodent animals and rodent models of human diseases. More specifically, this disclosure relates to genetically modified rodents whose genome comprises a humanized Il1rl2 gene (coding for the IL1rl2 subunit of the IL-36R protein) and human IL-36α, β and γ ligand genes. The genetically modified rodents disclosed herein display enhanced skin and intestinal inflammation as a preclinical model of psoriasis and IBD, respectively, and serve as a rodent model of human DITRA disease.

Disclosed herein are rodents (such as, but not limited to, mice and rats) genetically modified to comprise a humanized Cxcl13 gene. The rodents disclosed herein have been shown to support better engraftment and proliferation of human cells such as chronic lymphocytic leukemic cells. Compositions and methods for making such genetically modified rodents, as well as methods of using such genetically modified rodents for testing candidate therapeutic agents (e.g., candidate anti-cancer drugs), are provided.

The present disclosure relates to genetically modified non-human animals that express a human or chimeric (e.g., humanized) CD94 and/or NKG2A, and methods of use thereof.

The disclosure provides immunogenic cells expressing LMP1, and use thereof in activating T cells and treating cancer. Also provided are methods of producing the immunogenic cells.

A new DNA knock-in approach is provided based on the usage of three single guide RNA (sgRNA) to increase the integration efficiency of donor DNA based on the CRISRP-Cas system. The approach uses a pair of universal sgRNAs complementary to the donor DNA and a single sgRNA that targets the locus of interest. In various embodiments, targeting is achieved by pre-forming a DNA:RNA:protein (DNA:RNP) complex in vitro and introducing the complex into the embryo or cells of interest either by microinjection or transfection.

Non-human animal genomes, non-human animal cells, and non-human animals comprising a humanized TRKB locus and methods of making and using such non-human animal genomes, non-human animal cells, and non-human animals are provided. Non-human animal cells or non-human animals comprising a humanized TRKB locus express a human TRKB protein or a chimeric transthyretin protein, fragments of which are from human TRKB. Methods are provided for using such non-human animals comprising a humanized TRKB locus to assess in vivo efficacy of human-TRKB-targeting reagents such as nuclease agents designed to target human TRKB.

Methods and compositions are provided for making non-human animals with reduced tolerance of a foreign antigen of interest and making antigen-binding proteins against that foreign antigen of interest using such animals. The methods and compositions employ CRISPR/Cas9 systems using multiple guide RNAs to reduce or eliminate expression of a self-antigen homologous to or sharing an epitope of interest with the foreign antigen of interest or to reduce or eliminate expression of an epitope on the self-antigen that is shared with the foreign antigen of interest.

The invention relates generally to genetically modified non-human animals expressing human polypeptides and their methods of use.

Mice having a restricted immunoglobulin heavy chain locus are provided, wherein the locus is characterized by a single polymorphic human V.sub.H gene segment, a plurality of human D.sub.H gene segments and a plurality of J.sub.H gene segments. Methods for making antibody sequences that bind an antigen (e.g., a viral antigen) are provided, comprising immunizing a mouse with an antigen of interest, wherein the mouse comprises a single human V.sub.H gene segment, a plurality of human D.sub.H gene segments and a plurality of J.sub.H gene segments, at the endogenous immunoglobulin heavy chain locus.

The present disclosure relates to genetically modified non-human animals that express a human or chimeric (e.g., humanized) CD276, and methods of use thereof.