A biologically relevant animal model for psoriasis is provided. Epidermal-immune interactions governing epidermal tissue homeostasis are altered in psoriasis, an inflammatory disease affecting one in thirty adults. Here, we characterize Rac1 as a key mediator of this process. Rac1 activation was consistently elevated in psoriatic epidermis and primary psoriatic human keratinocytes (PHKC).

The receptor for Interleukin 35 (IL-35) is provided. The Interleukin 35 Receptor (IL-35R) comprises a heterodimeric complex of the Interluekin12R2 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 present invention describes combination treatment comprising a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and/or activity and methods for use thereof, including methods of treating conditions where enhanced immunogenicity is desired such as increasing tumor immunogenicity for the treatment of cancer or chronic infection.

This invention relates to the engineering of animal cells, preferably mammalian, more preferably rat, that are deficient due to the disruption of tumor suppressor gene(s) or gene product(s). In another aspect, the invention relates to genetically modified rats, as well as the descendants and ancestors of such animals, which are animal models of human cancer and methods of their use.

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.

A construction method for an immunodeficient rat model includes the following steps. The gRNAs targeted for knocking out a Prkdc gene and an IL2R gene are mixed with CAS9 mRNA respectively, and frozen in RNase-free ultrapure water to obtain injections A and B correspondingly. A human SIRP genomic DNA is amplified, purified, and frozen in RNase-free ultrapure water to obtain an injection C. The injections A and B are injected into cytoplasm of fertilized eggs of different rats, and the injection C is injected into a pronucleus of a fertilized egg of another rat. The three fertilized eggs are then transplanted into different pseudo-pregnant female rats to breed second-generation rats A, B and C, respectively. The second-generation rats A, B and C are intercrossed to breed an F1 generation; and the F1 generation is further intercrossed to obtain IL2R and Prkdc gene knockout immunodeficient rat models with human SIRP gene.

We demonstrate herein that neuritin controls the homeostasis of regulatory T cells in an antigen dependent manner. Based on this discovery, we describe herein the application of neuritin as a therapeutic agent to manipulate antigen specific regulatory T cells in various disease settings is described. Thus manipulation of Treg cells and DCs through neuritin can be used to enhance immunotherapy of autoimmune diseases, cancer and infectious diseases, as well as enhance lymphocyte engraftment in settings of donor lymphocyte infusion, bone marrow transplant, as well as other types of transplants, and adoptive transfer.

The present invention includes compositions and methods for treating diseases or disorders associated with pathological calcification or pathological ossification. In certain embodiments, the diseases or disorders are selected from the group consisting of Generalized Arterial Calcification of Infancy (GACI), Idiopathic Infantile Arterial Calcification (IIAC), Ossification of the Posterior Longitudinal Ligament (OPLL), hypophosphatemic rickets, osteoarthritis, calcification of atherosclerotic plaques, PXE, hereditary and non-hereditary forms of osteoarthritis, ankylosing spondylitis, hardening of the arteries occurring with aging, calciphylaxis resulting from end stage renal disease and progeria.

Methods and compositions are provided for modifying one or more target loci in a cell. Such methods comprise providing a cell comprising a first polynucleotide encoding a first selection marker operably linked to a first promoter active in the cell, wherein the first polynucleotide further comprises a first recognition site for a first nuclease agent. A first nuclease agent is introduced into a cell, wherein the first nuclease agent induces a nick or double-strand break at the first recognition site. Further introduced into the cell is a first targeting vector comprising a first insert polynucleotide flanked by a first and a second homology arm that correspond to a first and a second target site located in sufficient proximity to the first recognition site. At least one cell is then identified comprising in its genome the first insert polynucleotide integrated at the target locus.

The compositions and methods described herein are based, in part, on the discovery that regulatory B cells (Bregs) differentially express a specific set of coinhibitory molecules, including TIGIT, LAG-3, PD-1, CTLA4, and TIM-3. The data described herein indicate that TIGIT is required for both Breg-mediated tolerance maintenance at the steady state, and inflammation restraint during autoimmune and inflammatory diseases. Accordingly, provided herein are compositions and methods targeting coinhibitory molecules, such as TIGIT, LAG-3, PD-1, CTLA4, and TIM-3, in B cells, as novel therapeutic strategies for modulating immune suppression and treating diseases mediated or impacted by immune suppression mechanisms, such as autoimmune diseases and cancers.