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

Provided herein are mice that are heterozygous knock outs for Ctla4 and homozygous knockouts for Pdcd1 (Ctla4.sup.+/− Pdcd1.sup.−/− mice), which may suffer from autoimmunity, including myocarditis and insulin-dependent diabetes mellitus. Also provided are methods of using such mice to screen for therapeutic agents that mitigate immune-related adverse events.

The present disclosure relates generally to the field of immunotherapy. In particular, the present disclosure describes to 20 single nucleotide variants (SNVs) within the A20 coding sequence that can differentially impact the immune system. Differential expression of the identified A20 SNVs can be used to “tune” the immune system of a subject e.g., tune up or tune down the sensitivity and/or strength of the immune system of a subject in response to a treatment or a pathogen. On the basis, the present disclosure provides methods for modulating the immune system of a subject by modulating the A20 SNV expression profile in the subject, thereby “tuning” the immune system. The present disclosure also describes reagents for use in such methods. The methods and reagents may have application in the treatment and/or management of diseases/conditions such as, for example, cancer, autoimmune disease, pathogenic infection, complement deficiency, and transplant rejection, where the strength of a subject's immune system plays an important role. The present disclosure also describes methods in which the A20 SNVs are used as biomarkers to stratify subjects according to the strength of their immune system e.g., strong or poor immune response relative to a reference A20 genotype, and the use of such methods in personalised medicine.

The present disclosure relates to the genetically modified non-human animals that express a human or chimeric (e.g., humanized) T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and methods of use thereof.

The genetic basis for severe combined immunodeficiency disease (SCID) in pigs is described. In addition, tests for detecting pigs that are carriers for SCID or pigs with SCID are also described. Further, methods for producing pigs or herds of pigs with SCID are also described. Further, methods and compositions for treating, ameilioraing, inhibiting or correcting SCID are provided.

Disclosed herein are conditioning regimens and methods for inducing MHC- or HLA-mismatched mixed chimerism by conditioning a recipient with radiation-free, low-doses of cyclophosphamide (CY), pentostatin (PT), and anti-thymocyte globulin (ATG) prior to transplantation of donor bone marrow cells. In certain embodiments, the donor bone marrow cells may be CD4+ T-depleted bone marrow cells. The conditioning regimens and methods may also include administering one or more populations of conditioning donor cells selected from donor CD4.sup.+ T-depleted spleen cells, donor CD8.sup.+ T cells, and donor G-CSF-mobilized peripheral blood mononuclear cells. The conditioning regimen is clinically acceptable and can be used for treating hereditary hematological diseases and autoimmune diseases, as well as for promoting organ transplantation immune tolerance.

Disclosed herein are nucleic acids encoding for and proteins expressing chimeric C1q polypeptides, non-human animals comprising said nucleic acids, and methods of making or using said non-human animals.

Non-human animals, cells, methods and compositions for making and using the same are provided, wherein the non-human animals and cells comprise a humanized a proliferation-inducing ligand gene. Non-human animals and cells that express a human or humanized a proliferation-inducing ligand protein from an endogenous a proliferation-inducing ligand locus are described.

The receptor for Interleukin 35 (IL-35) is provided. The Interleukin 35 Receptor (IL-35R) comprises a heterodimeric complex of the Interluekin12Rβ2 receptor and the gp130 receptor. Various compositions comprising the IL-35R complex, along with polynucleotides encoding the same and kits and methods for the detection of the same the same are provided. Methods of modulating the activity of IL-35R or modulating effector T cell functions are also provided. Such methods employ various IL-35R antagonists and agonists that modulate the activity of the IL-35R complex and, in some embodiments, modulate effector T cell function. Further provided are methods for screening for IL-35R binding agents and for IL-35R modulating agents. Various methods of treatment are further provided.

The invention described herein provides non-HLA matched humanized mouse model (e.g., NSG mouse model) with patient-derived xenograft (PDX), as well as methods of making and using the same.